KR20190031865A - 밀베마이신 d를 생산하는 재조합 미생물 및 밀베마이신 d 생산 방법 - Google Patents

밀베마이신 d를 생산하는 재조합 미생물 및 밀베마이신 d 생산 방법 Download PDF

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KR20190031865A
KR20190031865A KR1020170119833A KR20170119833A KR20190031865A KR 20190031865 A KR20190031865 A KR 20190031865A KR 1020170119833 A KR1020170119833 A KR 1020170119833A KR 20170119833 A KR20170119833 A KR 20170119833A KR 20190031865 A KR20190031865 A KR 20190031865A
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Abstract

밀베마이신 D를 효과적으로 생산하는 재조합 스트렙토마이세스 아베르미틸리스(Streptomyces avermitilis) 균주 및 이를 이용한 밀베마이신 D 생산 방법이 제공된다.

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밀베마이신 D를 생산하는 재조합 미생물 및 밀베마이신 D 생산 방법{Recombinant Microorganisms Producing Milbemycin D and Method of Preparing Milbemycin D Using the Same}
밀베마이신 합성효소 시작모듈 구조에 기반하여 합리적으로 설계한 돌연변이 도입을 통해 생산하는 밀베마이신의 조성이 변화한 생산하는 재조합 스트렙토마이세스 아베르미틸리스(Streptomyces avermitilis) 균주 및 이를 이용한 밀베마이신 생산 방법이 제공된다.
밀베마이신(Milbemycin)은 스트렙토마이세스 밀베마이시니쿠스 (Streptomyces milbemycinicus) (이전 명칭은 스트렙토마이세스 하이그로스코피쿠스 아속 아우레오라크리모수스(Streptomyces hygroscopicus subsp . aureolacrimosus), 스트렙토마이세스 난찬젠시스(Streptomyces nanchangensis) 또는 스트렙토마이세스 빙쳉젠시스(Streptomyces bingchenggensis), 등으로부터 생산되는 폴리케타이드 계열의 16-원환 매크로라이드 화합물로서 다양한 형태의 생물학적, 화학적 유도체로서 농업 및 동물의약품 용도로 상품화되어 있다.
밀베마이신의 대표적 화학적 구조는 다음과 같으며, 작물보호제로서 사용되고 있는 밀베멕틴의 경우 밀베마이신 A3와 A4의 비율이 3:7 인 혼합물이다.
Figure pat00001
또한, 대사물인 밀베마이신 D (Milbemycin D)의 경우 심장사상충 등의 동물기생충에 높은 효과를 보여 일본 Sankyo 사에 의해 일본내에서 동물의약품으로 상업화되었다. 이외에도, 밀베마이신을 화학적으로 개량하여 작물보호제 및 동물의약품으로 사용되고 있는데, 밀베멕틴의 화학적 유도체인 레피멕틴(Lepimectin)이 살충제로서 이용되고 있으며, 동물의약품으로서 밀베마이신 옥심(Milbemycin Oxime)과 네마덱틴(Nemadectin)의 화학적 유도체인 목시덱틴(Moxidectin)이 상업화되어 있다.
한편, 아베멕틴(Avermectin)은 밀베마이신과 같이 멕틴계 살충제로 분류되며, 스트렙토마이세스 아베르미틸리스 등으로부터 생산되는 폴리케타이드 계열의 16-원환 매크로라이드 화합물이다. 이들 중 아베멕틴 B1a와 아베멕틴 B1b의 혼합물은 아바멕틴(Abamectin)으로서 응애 등에 대한 살충제로, 아베멕틴의 화학적 유도체인 에마멕틴 벤조에이트(Emamectin benzoate)는 나방 등에 대한 살충제 성분으로 사용되고 있으며, 동물의약품으로서 아베멕틴의 화학적, 생물학적 유도체인 이버멕틴(Ivermectin), 도라멕틴(Doramectin), 셀라멕틴(Selamectin), 에프리노멕틴(Eprinomectin) 등이 상업화되어 있다.
스트렙토마이세스 아베르미틸리스의 아베멕틴 생산성을 향상시키기 위하여 무작위적인 돌연변이법, 트랜스포존(transposon) 돌연변이법 등이 적용되었으며, 이를 효율적으로 스크리닝하기 위한 고속스크리닝법이 개발되었다[Ikeda et al. 1993; Weaden and Dyson 1998; Gao1 et al. 2010; Gao2 et al. 2010; Wang et al. 2010]. 또한, 생산균주의 주요 유전자를 제거하거나 과발현하여 생산성을 증가시키는 연구가 성공적으로 진행되었다[Duong et al. 2009; Li et al. 2010; Zhuo et al. 2010; Qiu et al. 2011; He et al. 2014; Liu et al. 2015]. 이케다 등은 스트렙토마이세스 아베르미틸리스가 외래의 물질합성 유전자를 효과적으로 발현하여 물질을 생산할 수 있음을 밝히고 지놈엔지니어링을 통해 보다 효과적인 발현 균주로 개발하고 있다 [Ikeda et al. 2014]. 또한, 아베멕틴의 경우 현재 대규모의 상업적 생산이 이뤄지고 있어 아베멕틴 생산균주인 스트렙토마이세스 아베르미틸리스가 산업균주로서 보다 유리할 것으로 여겨지고 있다.
밀베마이신의 생산은 스트렙토마이세스 속에 속하는 세균을 배양하고, 균체를 배양액으로부터 분리하여 생산된 밀베마이신을 균체로부터 유기 용매로 추출한 후, 얻어진 목적 화합물을 포함하는 물질을 정제하는 등의 방법에 의해 행해지고 있다. 종래 밀베마이신의 생산에 관한 기술들을 살펴보면, 일본의 Sankyo 사에서 1980년대 스트렙토마이세스 밀베마이시니쿠스가 밀베마이신을 생산하는 것을 발견한 후, 무작위적인 돌연변이 개발 기술을 통해 상업적 수준의 밀베마이신의 생산을 시작하였다. 그러나, 이와 같이 개발된 균주를 이용하여 밀베마이신을 대량생산 할 때 발효조 내의 용존 산소량에 의한 생산성 변화가 상당히 크다는 것이 보고되었고, 개발된 균주의 생산성을 유지시키는 것이 상당히 어렵다는 것이 보고된 바 있다[Okada and Iwamatu. 1997; Ide et al.1993]. 또한 상기 균주외 밀베마이신을 생산하는 스트렙토마이세스 빙쳉젠시스에서 조절 유전자인 nsdA의 삭제를 통하여 밀베마이신 A4의 생산성을 향상시켰다는 보고가 있고[Wang et al. 2009], 스트렙토마이세스 빙쳉젠시스에서 milD를 삭제하여 밀베마이신 A3/A4의 생산성을 향상시켰다는 보고가 있다[Zhang et al. 2013].
또한, 산업적으로 활용하는 스트렙토마이세스 아베르미틸리스의 아바멕틴 합성효소군 중 일부를 치환하여 신규 물질을 생산하는 재조합 미생물을 제작한 보고가 있다. Huang 등은 밀베마이신을 생산하는 스트렙토마이시스 하이그로스코피쿠스 HS023(S. hygroscopicus HS023)의 밀베마이신 합성효소군의 첫번째 유전자를 스트렙토마이세스 아베르미틸리스의 아바멕틴 합성효소군의 첫번째 유전자인 aveA1과 치환하여 25-methyl-23,25-dihydroavermectin과 25-ethyl-23,25-dihydroavermectin을 합성할 수 있음을 보고하였으며 [Huang et al. 2015], Zhang 등 역시 aveA1의 일부 도메인을 스트렙토마이세스 빙쳉젠시스의 밀베마이신 합성효소군의 첫번째 유전자의 일부 도메인으로 치환하였을 때, Ivermectin 및 25-methyl-23,25-dihydroavermectin과 25-ethyl-23,25-dihydroavermectin을 합성할 수 있음을 보고하였다 [Zhang et al. 2015]. 본 연구진 역시 추가의 연구개발을 통해 스트렙토마이세스 아베르미틸리스의 아베멕틴 합성효소군의 두개의 유전자인 aveA1과 aveA3의 유전자 전부 혹은 일부를 치환함으로써 밀베마이신을 생산하는 스트렙토마이세스 아베르미티리스 재조합균주 및 생산방법을 보고한 바 있다 [대한민국 특허공개 제10-2017-0035346호].
한편, Takiguchi 등은 밀베마이신을 생산하는 균주에 돌연변이를 통해 밀베마이신 D를 주로 생산하는 균주인 Au-3를 확보하였으나, 발효 결과 밀베마이신 D외에 밀베마이신 α2, 밀베마이신 β1 등 다른 밀베마이신을 상당량 생산함을 확인한 바 있다 [Takiguchi et al. 1983].
밀베마이신 D는 개의 심장사상충 등 동물기생충에 대해 높은 활성을 보여 동물의약품으로서 일본내에서 상업화되었으나, 낮은 발효 생산성으로 인해 경제성이 낮아 현재는 상업적으로 사용되고 있지 않다 [Ibe et al. 1993]. 최근 Nishio 등은 Hippo 신호경로 이상에 의해 발생하는 종양 치료제로서 밀베마이신 D의 가능성을 보고한 바 있다 [Nishio et al. 2016].
밀베마이신 D의 상업적 가능성에도 불구하고 종래 기술은 원 균주인 스트렙토마이세스 밀베마이시니쿠스 Au-3을 이용하여 밀베마이신 D를 생산하는 경우에도 경제성있는 대량생산이 어렵다. 특히 종래 기술의 특성상 밀베마이신 D를 다른 밀베마이신에 비해 고비율로 생산하기 어렵기 때문에 정제 비용이 많이 소요된다는 단점이 있다.
이에, 본 발명은 밀베마이신 중 밀베마이신 D를 높은 비율로 생산하는 재조합 미생물 및 이를 이용한 밀베마이신 D 생산 방법을 제공하고자 한다.
일예로, 본 발명은 밀베마이신 합성효소의 시작 모듈 (starting module)에 돌연변이를 도입하여 밀베마이신 D를 주요하게 생산하도록 합리적으로 디자인한 밀베마이신 합성효소 및 이를 포함하는 재조합미생물을 제공한다.
다른 예로, 본 발명은 상기 재조합 미생물을 이용한 밀베마이신 생산 방법을 제공하고자 한다.
상기 문제를 해결하기 위한 하나의 방안으로서, 본 명세서에서는, 밀베마이신 폴리케타이드 합성효소의 시작 모듈 (starting module 혹은 loading module)의 아실트랜스퍼라제 (acyltransferase) 활성을 갖는 도메인 (이하 AT0)의 기질 결합부위에 돌연변이를 도입되어 고비율로 밀베마이신 D를 생산하는 재조합 미생물, 상기 재조합 미생물의 제작 방법, 및 상기 재조합 미생물을 이용하여 밀베마이신 D 또는 밀베마이신 D의 함량이 높은 밀베마이신의 제조 방법이 제공된다.
하나의 양태로서, 본 발명은 밀베마이신 폴리케타이드 합성효소의 AT0에 기질특이성을 변화시키는 돌연변이가 도입된 재조합 미생물에 관한 것이다. 상기 재조합 미생물은 밀베마이신 D를 고효율로 생산하는 특징으로 갖는 것일 수 있다.
도 1a는 아베멕틴과 밀베마이신의 분자구조를 보여주고, 도 1b 및 1c는 아베멕틴과 밀베마이신의 분자구조 차이를 유발하는 유전자의 구성을 보여주고, 도 1d는 밀베마이신 폴리케타이드 합성효소 유전자군 (gene cluster)과 아베멕틴 폴리케타이드 합성효소 유전자군을 비교하여 보여주는 그림이다. 도 1a-1d에서, 각 원은 각각 도메인을 나타내며, 각 도메인으로부터 코딩되는 단백질은 각각 다음의 활성을 갖는다:
AT: 아실트랜스퍼라제,
KS: 케토-아실기 합성효소 (ketosynthase),
KR: 케토-아실기 환원효소 (ketoreductase),
DH: 탈수효소 (dehydratase),
ER: 에놀 환원효소 (enoyl reductase),
ACP: 아실기 운반단백질 (Acyl Carrier Protein),
TE: 티오에스터라제 (Thioesterase)).
각각의 합성효소는 모듈로 구성되고 각 모듈은 도메인들로 구성되며, 합성효소 유전자군은 모듈 코딩 유전자들로 구성되며, 각 모듈 코딩 유전자는 각 도메인 코딩 유전자들로 구성된다.
각 모듈 내의 각 도메인은 KS 도메인부터 시작하여 ACP 도메인으로 끝나는 순서로 배열될 수 있다 [예컨대, N-말단에서 C-말단 방향으로, (KS)-(AT)-(DH 및/또는 KR; in any order)-(ACP) 순서로 배열, milA3의 모듈 7의 경우 (KS)-(AT)-(DH)-(ER)-(KR)-(ACP) 순서로 배열]. 밀베마이신- 및 아베멕틴-폴리케타이드 합성효소의 모듈 10의 KR 도메인은 폴리케타이드 합성에 관여하지 않으며, 밀베마이신 폴리케타이드 합성효소 모듈 11의 KR 도메인과 아베멕틴 폴리케타이드 합성효소 모듈 7의 DH 도메인은 활성이 없다.
도 1a-1d에서 알 수 있듯이, 아베멕틴과 밀베마이신의 분자 구조가 매우 유사하고, 아베멕틴 합성효소 유전자군과 밀베마이신 합성효소 유전자군은 그 구성이 매우 유사하다.
두 화합물(아베멕틴과 밀베마이신)의 합성에 있어 차이는 다음에 기인한다:
1) 폴리케타이드 합성효소의 AT0의 기질특이성 차이로, 밀베마이신 합성효소의 시작 모듈의 AT 도메인 (이하, 'mil-AT0' 또는 'mei-AT0')은 Acetyl-CoA와 propionyl-CoA를 주요 기질로 사용하고, 아베멕틴 합성효소의 시작모듈의 AT 도메인 (이하 'ave-AT0')은 isobutyryl-CoA와 2-methylbutanoyl-CoA를 주요 기질로 사용하고 있다. 이와 같은 주요 기질 차이로 인하여, 이들 합성효소에 의하여 생산되는 두 화합물 (밀베마이신과 아베멕틴)의 각 탄소위치 25번에 연결되어 있는 탄소 사슬의 길이가 달라진다. 야생형의 밀베마이신 합성효소의 경우 밀베마이신 D를 소량 생산하기 때문에 isopropyl-CoA를 기질로 이용할 수는 있으나 선호하지 않음을 알 수 있다. 그러나, 야생형의 아베멕틴 합성효소의 경우, 25-methylavermectin 혹은 25-ethylavermectin을 생산하는 경우가 보고된 바 없다.
밀베마이신과 아버멕틴의 종류에 따른 시작모듈 AT 도메인의 기질 및 25번 위치의 탄소 사슬을 다음의 표 1에 정리하였다:
Polyketide 시작모듈 AT (AT0) 기질 탄소사슬
Milbemycin A3 Acetyl-CoA Methyl
A4 Propionyl-CoA Ethyl
D Isobutyryl-CoA Isopropyl
Avermectin B1a Isobutyryl-CoA Isopropyl
B1b 2-methylbutanoyl-CoA sec-butyl
2) 두 화합물의 탄소위치 22-23의 탄소결합은 각 합성효소의 모듈 2의 도메인 구성에 의해 결정되어, DH-KR 도메인을 갖는 아베멕틴 폴리케타이드 합성효소 모듈 2의 경우 이중 결합 또는 -OH 결합을 생성하는 반면, DH-ER-KR 도메인을 갖는 밀베마이신 폴리케타이드 합성효소 모듈 2는 단일결합을 생성한다.
3) 두 화합물의 탄소위치 13의 -OH기의 생성은 각 합성효소의 모듈 7의 도메인 구성에 의한다. 아베멕틴 폴리케타이드 합성효소의 경우 KR 도메인만 작용하여 -OH가 생성되지만, 밀베마이신 폴리케타이드 합성효소의 경우 DH-ER-KR 도메인이 있어 탄소 단일결합의 형태가 생성된다.
상기 내용에 기초하여 밀베마이신 생산균주에 의해 생산된 밀베마이신 A3, A4 및 D의 조성이 mil-AT0 또는 mei-AT0가 물질 합성시 받아들이는 기질의 종류에 의해 영향 받음을 알 수 있다. 또한, 아베멕틴 합성효소의 ave-AT0의 경우 mil-AT0 또는 mei-AT0 보다 크기가 큰 기질을 선호함을 알 수 있다. 따라서, 밀베마이신 내 밀베마이신 D의 비율을 증가시키기 위해서 mil-AT0 또는 mei-AT0의 기질 결합부위를 변형하여 밀베마이신 생산균주 내의 isobutyryl-CoA를 잘 활용할 수 있도록 하고 이로 인해 밀베마이신 D의 비율 증가를 시도하였다.
보다 구체적으로, 밀베마이신 합성효소가 밀베마이신 D 합성의 시작 기질인 isobutyryl-CoA를 보다 선호하도록 하기 위하여 AT0의 기질 결합부위를 분석하였다. 이를 위해, 스트렙토마이세스 밀베마이시니쿠스의 mil-AT0(서열번호 4 (milA1)의 아미노산 1-419 부위; 서열번호 17), 스트렙토마이세스 난찬젠시스의 mei-AT0 (서열번호 8 (meiA1)의 아미노산 1-410 부위; 서열번호 18), 및 스트렙토마이세스 아베르미틸리스의 ave-AT0(서열번호 2의 아미노산 1-354 부위)의 아미노산 서열을 비교하여 그 결과를 도 2에 나타내었다. 도 2에서 알 수 있듯이, 각 균주의 mil-AT0와 mei-AT0는 기질 결합부위를 구성하는 아미노산 종류가 동일하였으나 (mei-AT0 아미노산 서열은 mil-AT0 아미노산 서열과 97%의 상동성 (positive: 98%)을 가짐), ave-AT0와 다소 차이를 보였다. 따라서, 기질 결합부위의 차이가 각 AT 도메인의 기질특이성을 결정할 것으로 예상하였다.
도 2에서 보여지는 바와 같은 milA1, meiA1, 및 aveA1 간의 알 수 있듯이, mil-AT0의 기질 결합부위 아미노산 중, ave-AT0에서 기질과 상호작용하는 아미노산과 상응하는 위치에 있으면서 종류가 다른 잔기는 Cys192-Ile193 (mil-A0) 및 Cys183-Ile184 (mei-A0) (ave-AT0의 Ser120-Leu121와 상응), Ser217 (mil-A0) 및 Ser208 (mei-A0) (ave-AT0의 Trp145와 상응), Val288 (milA1) 및 Val279 (meiA1) (ave-AT0의 Ile220와 상응), Ile290 (mil-A0) 및 Ile281 (mei-A0) (ave-AT0의 Val222와 상응), Ile292 (mil-A0) 및 Ile283 (mei-A0) (ave-AT0의 Val224와 상응)로 분석되었으며, 이들 아미노산 잔기의 차이에 의해 아베멕틴과 밀베마이신 합성효소 시작모듈의 AT 도메인의 기질특이성 차이가 발생하는 것으로 예상하였다 (아미노산 표기에 있어서, 아미노산 잔기 뒤에 기재된 숫자는 아미노산 서열 중의 해당 아미노산 잔기의 위치를 의미함, 이하 동일함).
도 3에서와 같이 스트렙토마이세스 밀베마이시니쿠스의 mil-AT0의 구조를 ave-AT0의 구조를 기반으로 모델링 한 후 두 구조를 상호 비교한 결과, 아미노산의 상호 비교에서 예측된 바와 같이, mil-AT0 (서열번호 17)의 Ile290과 Ile292의 크기가 이에 해당 위치의 ave-AT0의 아미노산 잔기인 Val222와 Val224의 크기에 비해 크기 때문에, 기질 결합부위의 공간이 작고 이로 인해 보다 작은 기질인 acetyl-CoA와 propionyl-CoA를 선호할 것으로 예측하였다. 이러한 예측은 mil-AT0와 98% 이상의 서열 상동성을 갖는 스트렙토마이세스 난찬젠시스의 mei-AT0 (서열번호 18)에도 동일하게 적용될 수 있다. 따라서, 밀베마이신 합성효소 mil-AT0 도메인의 Ile290과 Ile292 또는 이에 대응하는 mei-AT0 도메인의 Ile281 및 Ile283이 기질의 선택에 가장 큰 영향을 미칠 것으로 예상하여, 상기 두 부위의 아미노산을 변화시켜 밀베마이신 D를 주로 생산하도록 할 수 있다.
일 예에서, 스트렙토마이세스 아베르미틸리스 균주에서,
(1) 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 1번 유전자(aveA1)가, 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소의 mil-AT0 도메인 (서열번호 17)의 아미노산 잔기 Ile290 (또는 이에 대응하는 mei-AT0 도메인(서열번호 18)의 아미노산 잔기 Ile281) 및 Ile292 (또는 이에 대응하는 mei-AT0 도메인(서열번호 18)의 아미노산 잔기 Ile283) 중 하나 이상이 각각 독립적으로 발린(Val) 또는 류신(Leu)으로 치환된 변형 mil-AT0 도메인를 포함하는 변형 밀베마이신 폴리케타이드 합성효소를 암호화하는 변형 폴리케타이드 합성효소 유전자군의 1번 유전자 (이하, 'm_milA1'로 표시)로 치환되거나 (변이 (1)),
(2) 상기 변이 (1)과 함께, 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자 (aveA3)의 전부 또는 일부가 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자 (milA3 또는 meiA3)의 전부 또는 일부로 치환된 (변이 (2)),
재조합 스트렙토마이세스 아베르미틸리스 균주가 제공된다.
상기 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 1번 유전자(aveA1)는, 예컨대, Streptomyces avermitilis MA-4680의 aveA1 유전자 (GeneBank Accession number AB032367.1의 101번째부터 12019번째까지의 폴리뉴클레오타이드 부위(핵산 서열: 서열번호 1; 아미노산 서열: 서열번호 2 (BAA84474.1)))일 수 있다.
상기 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 1번 유전자(milA1)는, 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소 유전자군 1번 유전자, 예컨대, Streptomyces milbemycinicus의 milA1 유전자 (핵산 서열: 서열번호 3, 아미노산 서열: 서열번호 4), 스트렙토마이세스 빙첸젠시스 (Streptomyces bingchenggensis)의 milA1 유전자 (GeneBank Accession number CP002047의 1146684번째부터 1159715번째까지의 폴리뉴클레오타이드 부위 (핵산 서열: 서열번호 5, 아미노산 서열(ADI03910.1): 서열번호 6), 스트렙토마이세스 난찬젠시스 (Streptomyces nanchangensis) (예컨대, GeneBank Accession no. FJ952082)의 meiA1 유전자 (핵산 서열: 서열번호 7, 아미노산 서열: 서열번호 8) 등으로 이루어진 군에서 선택될 수 있다.
상기 m_milA1에서 변형되는 Ile290 및 Ile292 아미노산 잔기 (mil-AT0 도메인 (서열번호 17)의 경우) 또는 Ile281 및 Ile283 아미노산 잔기 (mil-AT0 도메인 (서열번호 18)의 경우)는 스트렙토마이세스 아베르미틸리스 균주의 aveA1의 ave-AT0 도메인 중의 Val222와 Val224의 위치에 상응하는 아미노산 잔기이다. 일 예에서, 상기 m_milA1은 서열번호 17의 Ile290 또는 서열번호 18의 Ile281이 발린으로 치환되고, 서열번호 17의 Ile292 또는 서열번호 18의 Ile283이 발린 또는 류신으로 치환된(이하, milA1 I290VI292V (또는 meiA1 I281VI283V) 또는 milA1 I290VI292L (또는 meiA1 I281VI283L)) 변형 mil-AT0 또는 mei-AT0를 포함하는 것일 수 있다.
상기 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자 aveA3는 스트렙토마이세스 아베르미틸리스 균주의 유전체, 예컨대, GeneBank Accession number AB032367.1 중, 33436번째부터 50034번째까지의 폴리뉴클레오타이드 부위(핵산 서열: 서열번호 9; 아미노산 서열 (BAA84478.1): 서열번호 10)일 수 있다.
폴리케타이드 합성효소 상에서 도메인, 모듈, 및/또는 단백질의 변이(예컨대, 치환) 시에, 각 영역을 암호화하는 유전자를 연결하는 docking 부분간의 상호작용이 해당 폴리케타이드 합성효소의 정상적 발현에 매우 중요하다. 특히 KS 도메인, AT 도메인, DH 도메인, ER 도메인, KR 도메인, ACP 도메인 등을 포함하는 복합효소를 포함하는 폴리케타이드 합성효소 (상기한 도메인들은 N-말단에서 C-말단 방향으로 상기 기재 순서대로 위치하는 것일 수 있다)에서, 각 모듈의 KS와 AT는 upstream의 ACP와 상호작용한다. 이를 고려할 때, 아베멕틴 폴리케타이드 합성효소의 정상적 발현을 위해서, aveA3 유전자의 일부가 milA3 유전자의 일부 또는 meiA3 유전자의 일부로 치환 시 치환이 일어나는 염기서열의 위치가 중요하게 고려되어야 한다.
상기 aveA3 유전자의 일부의 치환은 aveA3 (예컨대, Streptomyces avermitilis MA-4680의 aveA3 유전자; 핵산 서열: 서열번호 9; 아미노산 서열: 서열번호 10)의 적어도 모듈 7 코딩 유전자의 전부 또는 일부 (적어도 모듈 7의 DH (dehydratase) 도메인 코딩 유전자를 포함)가 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자 (milA3 또는 meiA3)의 적어도 모듈 7 코딩 유전자의 전부 또는 일부 (적어도 모듈 7의 DH 도메인 코딩 유전자 및/또는 ER (enoyl reductase) 도메인 코딩 유전자를 포함)로 치환된 것을 의미할 수 있다.
예컨대, 상기 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자 aveA3는 스트렙토마이세스 아베르미틸리스 균주의 유전체, 예컨대, GeneBank Accession number AB032367.1 중, 33436번째부터 50034번째까지의 폴리뉴클레오타이드 부위(핵산 서열: 서열번호 9; 아미노산 서열 (BAA84478.1): 서열번호 10)일 수 있으며, 상기 aveA3의 일부는 모듈 7 (BAA84478.1 (서열번호 10)의 35번째부터 1841번째까지의 부위)의 코딩 유전자의 전부 또는 일부 (적어도 DH 도메인 (BAA84478.1 (서열번호 10)의 976번째부터 1148번째까지의 부위)의 코딩 유전자를 포함)를 포함하는 것일 수 있다. 예컨대, 상기 스트렙토마이세스 아베르미틸리스 균주에서 치환되는 aveA3 유전자의 전부 또는 일부는, 적어도 서열번호 10의 35번째부터 1841번째까지의 부위 (모듈 7), 또는 서열번호 10의 976번째부터 1148번째까지의 부위 (모듈 7의 DH 도메인)을 포함하는 연속하는 173 내지 1807개의 아미노산의 코딩 유전자 부위를 포함하는 것일 수 있다.
aveA3 유전자의 각 모듈, 도메인 및 이의 코딩 유전자는 웹사이트 (http://www.ncbi.nlm.nih.gov/protein/5902891)를 통하여 명확하게 특정할 수 있다.
또한, aveA3 유전자의 일부를 밀베마이신 생산 균주의 milA3 유전자의 일부 또는 meiA3유전자의 일부로 치환 시, aveA3 유전자의 N-말단 코딩 부위 및 C-말단 코딩 부위의 docking 영역에 더하여, 모듈 7의 KS (KS7), 모듈 7의 AT 도메인 (AT7), 및/또는 모듈 9의 ACP 도메인 (ACP9)의 코딩 유전자 부위들이 아베멕틴 폴리케타이드 합성효소(aveA3 유전자)의 상기 도메인의 코딩 유전자 부위들로 보존되도록 (즉, 밀베마이신 생산 균주의 milA3 유전자의 일부 또는 meiA3유전자의 일부로 치환되지 않도록) 유전자 치환이 일어날 수 있다.
예컨대, aveA3 유전자의 일부 치환은,
(a) aveA3 유전자 중 모듈 7 코딩 유전자 또는 모듈 7 내의 적어도 DH 도메인 코딩 유전자를 포함하는 유전자 부위가 밀베마이신 생산 균주의 milA3 유전자의 모듈 7 코딩 유전자 또는 모듈 7 내의 적어도 DH 도메인 및/또는 ER 도메인 코딩 유전자를 포함하는 유전자 부위로 치환되거나; 또는
(b) 상기 (a) 치환에 더하여, 다음의 치환을 추가로 포함하는 것일 수 있다:
(i) aveA3 유전자의 모듈 7 코딩 유전자 중의 DH 도메인 코딩 유전자를 제외한 나머지 도메인 중 하나 이상의 코딩 유전자 (예컨대, KS 도메인 코딩 유전자, AT 도메인 코딩 유전자, KR 도메인 코딩 유전자 및 ACP 도메인 코딩 유전자로 이루어진 군에서 선택된 하나 이상의 유전자)의 밀베마이신 생산 균주의 milA3 유전자의 모듈 7 코딩 유전자 중의 DH 도메인 및 ER 도메인을 제외한 나머지 도메인 중 하나 이상의 코딩 유전자 (예컨대, KS 도메인 코딩 유전자, AT 도메인 코딩 유전자, KR 도메인 코딩 유전자 및 ACP 도메인 코딩 유전자로 이루어진 군에서 선택된 하나 이상)로의 치환;
(ii) aveA3 유전자의 모듈 8 및 모듈 9의 도메인들 중 하나 이상의 코딩 유전자의 밀베마이신 생산 균주의 milA3 유전자 또는 meiA3유전자의 모듈 8 및 모듈 9의 도메인들 중 하나 이상의 코딩 유전자로의 치환; 또는
(iii) 치환 (i) 및 (ii)의 조합.
앞서 설명한 aveA1 유전자의 전부가 m_milA1 유전자의 전부로 치환 및 aveA3 유전자의 전부 또는 일부가 milA3 유전자의 전부 또는 일부, 또는 meiA3유전자의 전부 또는 일부로 치환된 균주는, aveA1 및 aveA3 유전자의 유전자 치환 부위의 N-말단 및/또는 C-말단의 docking 영역 코딩 부위가 보존되어 있는 것일 수 있다. 즉, aveA1 유전자의 전부가 m_milA1 유전자의 전부로 치환 및 aveA3 유전자의 전부 또는 일부가 milA3 유전자의 전부 또는 일부 또는 meiA3유전자의 전부 또는 일부로 치환된 균주는, aveA1 및 aveA3 유전자의 유전자 치환 부위의 upstream 및/또는 downstream 영역과 상동성을 가지는 부위를 상기 치환(도입)된 milA1 유전자 및 milA3 유전자의 전부 또는 일부 또는 또는 meiA3유전자의 전부 또는 일부의 어느 한 말단 또는 양쪽 말단에 연결된 형태로 포함할 수 있다. 이러한 상동성을 가지는 부위의 도입은 상동 재조합시에 유리할 수 있다. 상기 상동성은 원래의 유전자 서열과 90% 이상, 95% 이상, 또는 98% 이상 동일성을 가짐을 의미한다.
상기 사용된 용어 "Docking 영역"은 폴리케타이드 합성효소를 코딩하고 있는 유전자 양 끝 부위에 의하여 코딩되는 부위로, 폴리케타이드 합성시 다음 단계의 합성효소와의 단백질-단백질 상호작용을 원활하게 하는 역할을 하는 부위이다. 통상적인 상동성 염기서열 분석을 범위의 특정이 가능하다.
상기 밀베마이신 생산 균주는,
스트렙토마이세스 밀베마이시니쿠스 (Streptomyces milbemycinicus) (milA1 유전자: 서열번호 3; milA1 단백질: 서열번호 4; mil-AT0: 서열번호 17; milA3 유전자: 서열번호 11; milA3 단백질: 서열번호 12 (BAA84478.1) (Module 7: 34번째부터 2139 번째까지 폴리펩타이드; Module 8: 2163번째부터 3927번째까지 폴리펩타이드; Module 9: 3951번째부터 5731 번째까지 폴리펩타이드: DH-ER domain in module 7: 953번째부터 1775 번째까지 폴리펩타이드 (DH domain in module 7: 953번째부터 1129 번째까지 폴리펩타이드; ER domain in module 7: 1497 번째부터 1775 번째까지 폴리펩타이드))),
스트렙토마이세스 난찬젠시스(Streptomyces nanchangensis; 예컨대, Accession no. FJ952082; meiA1 유전자: 서열번호 7; meiA1 단백질: 서열번호 8 (Streptomyces nanchangensis가 생산하는 meilingmycin는 Streptomyces milbemycinicus가 생산하는 milbemycin은 서로 구조가 유사하고 기능이 동일하여, 본 명세서에서는 meiA1 단백질 및 meiA1 유전자와, milA1 단백질 및 milA1 유전자를 서로 동일한 의미로 사용하고, m_milA1는 앞서 설명한 변이를 포함하는 변형 milA1 (유전자 또는 단백질)와 변형 meiA1 (유전자 또는 단백질) 중 하나 이상을 의미하기 위하여 사용함): 서열번호 7; meiA3 유전자: 서열번호 13 (GenBank: FJ952082 Sequence 영역 78606번째부터 96074번째까지 폴리뉴클레오타이드); meiA3 단백질: 서열번호 14 (milA3 단백질(서열번호 12)과 96%의 서열상동성을 가짐) (Module 7: 39번째부터2143 번째까지 폴리펩타이드; Module 8: 2166번째부터 3931 번째까지 폴리펩타이드; Module 9: 3952번째부터 5734 번째까지 폴리펩타이드; Module 7의 DH-ER didomain 957번째부터 2143 번째까지 폴리펩타이드 (Module 7의 DH domain: 957번째부터 1133 번째까지 폴리펩타이드; 모듈 7의 ER domain: 1501번째부터 1779 번째까지 폴리펩타이드))), 또는
스트렙토마이세스 빙첸젠시스(Streptomyces bingchenggensis; 예컨대, Accession no. CP002047.1; milA1 유전자: 서열번호 5; milA1 단백질: 서열번호 6; mil-AT0: 서열번호 17; milA3 유전자: 서열번호 15 (Accession no. CP002047.1 중 1063754::1081234 (유전자가 3'->5' 이어서 reverse complement seq를 기재함)); 단백질: 서열번호 16 (Genbank Accession No. ADI03854; Module 7: 35번째부터 2150번째까지의 폴리펩타이드, Module 8: 2173번째부터 3938번째까지의 폴리펩타이드, Module 9: 3990번째부터 5738번째까지의 폴리펩타이드, DH-ER didomain in module 7: 950번째부터 1772번째까지의 폴리펩타이드 (DH domain: 950번째부터 1126번째까지의 폴리펩타이드; ER domain: 1494번째부터 1772번째까지의 폴리펩타이드)))
일 수 있다.
상기 재조합 스트렙토마이세스 아베르미틸리스 균주는 밀베마이신을 고효율로 생산할 수 있으며, 야생형 스트렙토마이세스 아베르미틸리스 균주 또는 상기 설명한 변이 (1) 및/또는 (2)가 도입되지 않은 스트렙토마이세스 아베르미틸리스 균주와 비교하여, 밀베마이신 중 밀베마이신 D를 고비율로 생산하는 것을 특징으로 한다. 예컨대, 상기 재조합 스트렙토마이세스 아베르미틸리스 균주는 생산된 전체 밀베마이신 중의 밀베마이신 D의 함량이, 중량 기준으로, 약 50중량% 이상, 약 60중량% 이상, 약 65중량% 이상, 약 70중량% 이상, 약 75중량% 이상, 또는 약 80중량% 이상 (예컨대, 50~100중량%, 50~95중량%, 50~90중량%, 50~85중량%, 60~100중량%, 60~95중량%, 60~90중량%, 60~85중량%, 65~100중량%, 65~95중량%, 65~90중량%, 65~85중량%, 70~100중량%, 70~95중량%, 70~90중량%, 70~85중량%, 75~100중량%, 75~95중량%, 75~90중량%, 75~85중량%, 80~100중량%, 80~95중량%, 80~90중량%, 또는 80~85중량%) 일 수 있다.
다른 구체예로, 상기 재조합 균주는 밀베마이신 중 밀베마이신 D를 주요하게 생산하며 기타 밀베마이신 A3, 밀베마이신 A4로 이루어진 군에서 선택되는 1종 이상의 밀베마이신을 생산할 수 있다.
앞서 설명한 바와 같이, 상기 aveA3 유전자는 전체가 milA3 유전자 또는 meiA3 유전자로 치환될 수도 있으나, milA3 유전자 또는 meiA3 유전자 중에서 숙주 균주에 밀베마이신을 생산능을 부여할 수 있는 최소한의 부위만 aveA3 유전자의 상응하는 부위에 치환(삽입, 도입)되는 것이 가능하다. 예를 들어, 상기 milA3 유전자 또는 meiA3 유전자 중에서 숙주 균주에 밀베마이신을 생산능을 부여할 수 있는 최소한의 부위는 milA3 유전자 또는 meiA3 유전자 중 모듈 7 전부 또는 모듈 7의 DH-ER 도메인의 코딩 유전자를 포함할 수 있으며, aveA3 유전자 중 모듈 7 전부 또는 적어도 모듈 7의 DH 도메인을 포함하는 모듈 7의 일부의 코딩 유전자가, 밀베마이신 생산 균주의 milA3 유전자 중 모듈 7 전부 또는 모듈 7의 DH-ER 도메인의 코딩 유전자로 치환될 수 있다.
일 구현의 예로, 스트렙토마이세스 아베르미틸리스 균주에서 aveA1 유전자가 m_milA1 유전자로 치환되고, aveA3 유전자의 모듈 7의 코딩 유전자 부위가 밀베마이신 생산 균주의 milA3 유전자 또는 meiA3 유전자의 모듈 7의 코딩 유전자 부위로 치환된 균주는,
aveA1이 milA1 I290VI292L로 치환된 스트렙토마이세스 아베르미틸리스 LB-50006 균주 (수탁번호: KCTC13325BP), 또는 aveA1이 milA1 I290VI292V로 치환된 스트렙토마이세스 아베르미틸리스 LB-50006 균주 (수탁번호 KCTC13326BP)일 수 있다.
다른 예는 앞서 설명한 m_milA1 유전자를 제공한다. m_milA1 유전자는 아베멕틴 생성 균주 (예컨대, 스트렙토마이세스 아베르미틸리스 균주)의 aveA1 유전자를 치환함으로써, 상기 유전자가 치환(삽입, 도입)되지 않은 균주와 비교하여, 스트렙토마이세스 아베르미틸리스 균주의 밀베마이신, 특히 밀베마이신 D의 생산 효율을 증진시킬 수 있다.
다른 양태로서, 앞서 설명한 m_milA1 및 milA3 (또는 meiA3)의 전부 또는 일부 (적어도 모듈 7 코딩 유전자 또는 모듈 7의 DH-ER 도메인 코딩 유전자를 포함)를 포함하는 재조합 벡터, 상기 재조합 벡터를 적절한 숙주세포 (예컨대, 스트렙토마이세스 아베르미틸리스와 같은 아베멕틴 생성 균주)에 도입시킨 재조합 미생물, 및 상기 재조합 벡터를 적절한 숙주세포 (예컨대, 스트렙토마이세스 아베르미틸리스와 같은 아베멕틴 생성 균주)에 도입하는 단계를 포함하는, 재조합 미생물 (예컨대, 재조합 스트렙토마이세스 아베르미틸리스 균주)의 제조 방법을 제공한다.
상기와 같이 제조된 재조합 미생물은, 상기 재조합 벡터가 도입되지 않은 미생물과 비교하여, 밀베마이신 D의 생산 효율 및/또는 생산된 전체 밀베마이신 중의 밀베마이신 D의 비율이 현저히 증가한 것을 특징으로 한다.
상기 도입시에, 숙주세포 (예컨대, 스트렙토마이세스 아베르미틸리스와 같은 아베멕틴 생성 균주)의 폴리케타이드 합성효소 유전자 aveA1 및 aveA3의 전부 또는 일부 (적어도 모듈 7 코딩 유전자 또는 모듈 7의 DH 도메인 코딩 유전자를 포함)가 각각 m_milA1 및 milA3(또는 meiA3)의 전부 또는 일부 (적어도 모듈 7 코딩 유전자 또는 모듈 7의 DH-ER 도메인 코딩 유전자를 포함)로 치환이 일어날 수 있다. 또한, aveA1 및 aveA3의 활성이 제거된 상태에서 m_milA1 및 milA3(또는 meiA3)의 전부 또는 일부 (적어도 모듈 7 코딩 유전자 또는 모듈 7의 DH-ER 도메인 코딩 유전자를 포함)를 포함하는 재조합 벡터가 도입되는 경우 보다 상승된 밀베마이신 (예컨대, 밀베마이신 D)의 생산 효과를 얻을 수 있다.
또 하나의 양태로서, 상기 재조합 미생물 (즉, 상기 재조합 스트렙토마이세스 아베르미틸리스 균주) 및/또는 상기 재조합 벡터를 포함하는 밀베마이신 (예컨대, 밀베마이신 D) 제조용 조성물이 제공된다. 또 하나의 양태로서, 상기 재조합 미생물 (즉, 상기 재조합 스트렙토마이세스 아베르미틸리스 균주) 및/또는 상기 재조합 벡터의 밀베마이신 (예컨대, 밀베마이신 D) 제조에 사용하기 위한 용도가 제공된다.
또 하나의 양태로서, 상기 재조합 미생물을 이용한 밀베마이신 (예컨대, 밀베마이신 D) 생산 방법이 제공된다. 구체예로, 상기 재조합 미생물 (예컨대, 재조합 스트렙토마이세스 아베르미틸리스 균주)를 배양하는 단계, 및 임의로 상기 배양된 균주 또는 균주의 배양물로부터 밀베마이신을 수득(분리) 및/또는 정제하는 단계를 포함하는, 밀베마이신 생산 방법을 제공한다.
스트렙토마이세스 아베르미틸리스는 아베멕틴을 생산하는 균주로서, 그 예로는, S. avermitilis SA-01 균주, S. avermitilis MA-4680 균주(NCBI 등록번호: NC_003155.4), S. avermitilis 76-02-e 균주(He et al. 2014), S. avermitilis 14-12A 균주(Gao et al. 2009), S. avermitilis 3-115 균주(Gao et al. 2010) 등을 들 수 있으나, 이에 제한되는 것은 아니다.
스트렙토마이세스 아베르미틸리스는 아베멕틴을 생산하기 위한 PKS 클러스터(Polyketide synthase gene cluster; 폴리케타이드 합성효소 유전자 클러스터)라는 거대 유전자군을 포함하고 있다. 상기 아베멕틴 PKS 유전자군은 aveA1, aveA2, aveA3 및 aveA4 유전자를 포함하고 있으며, aveA1 유전자는 로딩 모듈과 모듈 1번과 모듈 2번, aveA2 유전자는 모듈 3번 내지 모듈 6번, aveA3 유전자는 모듈 7 내지 모듈 9, aveA4 유전자는 모듈 10번 내지 모듈 12번을 포함하고 있고, 각 모듈은 하위 도메인들로 구성되어 있다.
밀베마이신 생산 균주는 스트렙토마이세스 밀베마이시니쿠스 (스트렙토마이세스 하이그로스코피쿠스 아속 아우레오라크리모수스), 스트렙토마이세스 난찬젠시스, 스트렙토마이세스 빙첸젠시스, 또는 밀베마이신을 생산하기 위해 아버멕틴 생산유전자인 aveA1 및/또는 aveA3의 전부 또는 일부가 각각 밀베마이신 생산유전자인 m_milA1 및/또는 milA3의 전부 또는 일부로 치환된 재조합 스트렙토마이세스 아베르미틸리스를 포함하나, 이에 제한되는 것은 아니다. 스트렙토마이세스 하이그로스코피쿠스 아속 아우레오라크리모수스로는, 스트렙토마이세스 밀베마이시니쿠스 NRRL 5739 균주를 사용할 수 있으나, 이에 제한되는 것은 아니다.
밀베마이신 생산 균주는 밀베마이신을 생산하기 위한 PKS 클러스터 유전자군을 포함하고 있다. 상기 밀베마이신 PKS 유전자군의 구성은 아베멕틴 PKS 유전자군의 구성과 유사하며, milA1 또는 meiA1 (재조합 스트렙토마이세스 아베르미틸리스의 경우는 m_milA1), milA2 또는 meiA2 (재조합 스트렙토마이세스 아베르미틸리스의 경우는 aveA2), milA3 또는 meiA3 (재조합 스트렙토마이세스 아베르미틸리스의 경우는 aveA3 일부를 포함할 수 있음) 및 milA4 또는 meiA4 (재조합 스트렙토마이세스 아베르미틸리스의 경우는 aveA4)유전자를 포함하고 있으며, 각 유전자는 모듈 및 하위 도메인들로 구성되어 있다.
앞서 설명한 바와 같이, 아베멕틴 생산 균주인 스트렙토마이세스 아베르미틸리스의 aveA1 유전자 및/또는 aveA3 유전자의 전체 또는 일부 (적어도 aveA3의 모듈 7 또는 모듈 7의 DH 도메인 코딩 유전자를 포함)를 각각, 밀베마이신 생산 균주의 mil-AT0 또는 mei-AT0의 기질특이성을 변화시키기 위한 돌연변이가 도입된 밀베마이신 합성 효소의 1번 유전자인 m_milA1 및/또는 milA3 유전자(또는 meiA3 유전자)의 전체 또는 일부 (적어도 milA3 또는 meiA3의 모듈 7 또는 모듈 7의 DH-ER 도메인 코딩 유전자를 포함)로 치환시킴으로써, 스트렙토마이세스 아베르미틸리스 내에 하이브리드 PKS 유전자가 포함되도록 하였고, 상기 하이브리드 PKS 유전자를 포함하는 재조합 균주가 밀베마이신을 생산하고 이중 밀베마이신 D를 주요하게 생산할 수 있음이 확인되었다.
따라서, 다른 예는, 앞서 설명한 바와 같이, mil-AT0의 기질특이성을 변화시키기 위한 돌연변이가 도입된 밀베마이신 합성 효소의 1번 유전자인 m_milA1 유전자, 상기 유전자를 포함하는 재조합 벡터, 또는 이들의 조합을 포함하는, 밀베마이신 D 생산 또는 생산 증진용 조성물을 제공한다. 상기 m_milA1 유전자, 상기 유전자를 포함하는 재조합 벡터, 또는 이들의 조합은 스트렙토마이세스 아베르미틸리스에 도입되어 aveA1 유전자를 치환함으로써, 이들이 도입되지 않은 경우와 비교하여, 스트렙토마이세스 아베르미틸리스의 밀베마이신, 특히 밀베마이신 D의 생산을 증가시킬 수 있다. 상기 밀베마이신 D 생산용 조성물은 milA3(또는 meiA3) 유전자의 전부 또는 일부 (적어도 모듈 7의 DH 도메인 코딩 유전자 및/또는 ER (enoyl reductase) 도메인 코딩 유전자를 포함), 상기 milA3 유전자의 전부 또는 일부를 포함하는 재조합 벡터, 또는 이들의 조합을 추가로 포함할 수 있다. 다른 예는 m_milA1 유전자, 상기 유전자를 포함하는 재조합 벡터, 또는 이들의 조합의 밀베마이신 D 생산에 사용하기 위한 용도를 제공한다. 다른 예는 상기 밀베마이신 D 생산용 조성물을 아베멕틴 생산 균주 (예컨대, 스트렙토마이세스 아베르미틸리스)에 도입 (형질전환)시키는 단계를 포함하는, 밀베마이신 D 생산 증진 방법을 제공한다.
그러나, 상기 기탁 균주들은 본 발명의 대표적인 구현예에 불과하며, 본 발명의 범위가 이에 제한되는 것은 아니다.
스트렙토마이세스 아베르미틸리스의 aveA1 및/또는 aveA3 유전자의 치환은, 당업계에 알려진 공지의 기술들, 예를 들어 상동 재조합((homologous recombination)에 의하여 수행될 수 있다.
일 구현예로, 밀베마이신 생산 균주에서 분리한 milA1 및 또는 milA3 (또는 meiA3) 유전자의 전부 또는 일부가 상동 재조합을 통하여 숙주 균주 게놈에 통합될 수 있도록 하기 위한 유전자 치환용 벡터를 제조할 수 있다. m_milA1의 경우 milA1의 mil-AT0의 Ile290 및/또는 Ile292 의 아미노산을 치환하기 위하여 PCR 방법을 통해 염기서열을 치환한 후 유전자 치환용 벡터를 제조하였다. 상기 벡터는 숙주 게놈의 특정 유전자 위치로 목적하는 유전자를 제거 또는 삽입할 수 있는 벡터로, 상동 재조합이 일어나도록 타겟팅하고자 하는 특정 유전자 부위에 상동인 염기 서열을 포함할 수 있다.
상기 재조합 벡터를 보다 상세히 설명하면 다음과 같다:
상기 재조합 벡터는,
(1) 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소의 mil-AT0 도메인 (서열번호 17)의 아미노산 잔기 Ile290이 발린(Val)으로 치환되고, Ile292가 발린(Val) 또는 류신(Leu)으로 치환되거나, mei-AT0 도메인 (서열번호 18)의 아미노산 잔기 Ile281이 발린(Val)으로 치환되고, Ile283이 발린(Val) 또는 류신(Leu)으로 치환된, 변형 mil-AT0 도메인를 포함하는 변형 밀베마이신 폴리케타이드 합성효소를 암호화하는 변형 폴리케타이드 합성효소 유전자군의 1번 유전자 (이하, 'm_milA1'로 표시); 및/또는
(2) 밀베마이신 생산 균주의 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소의 3번 유전자(milA3 또는 meiA3)의 전부 또는 일부 (milA3 또는 meiA3 유전자 중 적어도 모듈 7 코딩 유전자 또는 모듈 7의 DH 도메인 코딩 유전자 및 ER 도메인 코딩 유전자를 포함)
을 포함하는 것일 수 있다. 이 경우 m_milA1 유전자와 milA3 (또는 meiA3)의 전부 또는 일부는 하나의 벡터에 함께 포함되거나 각각 별개의 벡터에 포함될 수 있다.
일 구체예에서, 상기 재조합 벡터는 밀베마이신 생산 균주의 m_milA1 유전자; 및 밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자 또는 밀베마이신 생산 균주의 milA3 (또는 meiA3)의 전부 또는 모듈 7의 전부 또는 일부의 코딩 유전자에 더하여, 다음으로 이루어진 군에서 선택된 하나 이상을 추가로 포함할 수 있다:
밀베마이신 생산 균주의 milA3 (또는 meiA3)의 모듈 7의 DH-ER 도메인을 제외한 도메인들 (예컨대, KS, AT, KR, 및 ACP 도메인) 중에서 선택된 하나 이상의 코딩 유전자;
밀베마이신 생산 균주의 milA3(또는 meiA3)의 모듈 8의 코딩 유전자 또는 모듈 8의 도메인들 중 하나 이상의 코딩 유전자; 및
밀베마이신 생산 균주의 milA3(또는 meiA3)의 모듈 9의 코딩 유전자 또는 모듈 9의 도메인들 중 하나 이상의 코딩 유전자.
일 구체예에서, 상기 재조합 벡터는
밀베마이신 생산 균주의 m_milA1 유전자 및 다음에서 선택된 milA3 (또는 meiA3) 유전자 일부 또는 이의 변이체를 포함할 수 있다:
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 7 중의KS 도메인의 코딩 유전자 부위가 결실된, 예컨대, milA3 (또는 meiA3) 유전자의 모듈 7의AT 도메인, DH 도메인, ER 도메인, KR 도메인 및 ACP 도메인의 코딩 유전자를 포함하거나 이들로 구성된 milA3 (또는 meiA3) 유전자의 일부;
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 7 중의 KS 도메인의 코딩 유전자가 aveA3 유전자의 모듈 7의 KS 도메인의 코딩 유전자로 치환된 milA3(또는 meiA3)의 모듈 7코딩 유전자 변이체;
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 7 중의 AT 도메인의 코딩 유전자 부위가 결실된, 예컨대, milA3 (또는 meiA3) 유전자의 모듈 7의KS 도메인, DH 도메인, ER 도메인, KR 도메인 및 ACP 도메인의 코딩 유전자를 포함하는 milA3(또는 meiA3)의 모듈 7코딩 유전자 변이체;
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 7 중의 AT 도메인의 코딩 유전자가 aveA3 유전자의 모듈 7의 AT 도메인의 코딩 유전자로 치환된 milA3(또는 meiA3)의 모듈 7의 코딩 유전자 변이체;
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 7 중의 KS 도메인 및 AT 도메인의 코딩 유전자가 결실된, 예컨대, milA3 (또는 meiA3) 유전자의 모듈 7의 DH 도메인, ER 도메인, KR 도메인 및 ACP 도메인의 코딩 유전자를 포함하는 milA3(또는 meiA3)의 모듈 7의 코딩 유전자 변이체; 및
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 7 중의 KS 도메인 및 AT 도메인의 코딩 유전자가 각각 aveA3 유전자의 모듈 7의 KS 도메인 및 AT 도메인의 코딩 유전자로 치환된 milA3(또는 meiA3)의 모듈 7의 코딩 유전자 부위 변이체.
상기 재조합 벡터는 다음으로 이루어진 군에서 선택된 하나 이상을 추가로 포함할 수 있다:
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 9 중의 ACP 도메인의 코딩 유전자가 결실된, 예컨대, milA3 (또는 meiA3) 유전자의 모듈 9의 KS 도메인, AT 도메인, DH 도메인, 및 KR 도메인의 코딩 유전자를 포함하는 milA3(또는 meiA3)의 모듈 9의 코딩 유전자 변이체; 및
밀베마이신 생산 균주의 milA3 (또는 meiA3) 유전자의 모듈 9 중의 ACP 도메인의 코딩 유전자가 aveA3 유전자의 모듈 9의 ACP 도메인의 코딩 유전자로 치환된 milA3(또는 meiA3)의 모듈 9의 코딩 유전자 변이체.
일 예에서, 상기 재조합 벡터에 포함되는 milA3 (또는 meiA3) 유전자 변이체는
밀베마이신 생산 균주의 milA3 유전자 중의 모듈 7의 DH 도메인부터 모듈 9의 KR 도메인까지의 영역(예컨대, milA3(또는 meiA3)의 모듈 7의 DH 도메인, ER 도메인, KR 도메인, 및 ACP 도메인, 모듈 8, 모듈 9의 KS 도메인, AT 도메인, DH 도메인, ER 도메인, 및 KR 도메인을 N-말단에서 C-말단 방향으로 포함하는 영역)의 코딩 유전자를 포함하는 milA3 (또는 meiA3) 유전자 변이체 (일부)일 수 있으나 이에 제한되는 것은 아니다.
본원의 일 실시예에서, m_milA1을 치환하기 위한 재조합 벡터는 아바멕틴 합성효소의 ave-AT0의 Val222와 Val224에 상응하는 밀베마이신 합성효소의 mil-AT0 (서열번호 17)의 아미노산인 Ile290이 발린으로 치환되고 Ile292를 발린 혹은 류신으로 치환되도록(이하 milA1 I290VI292V 혹은 milA1 I290VI292L) 염기서열이 변형된 변형 milA1 유전자 전체 또는 mei-AT0 (서열번호 18)의 Ile281이 발린으로 치환되고 Ile283를 발린 혹은 류신으로 치환되도록 염기서열이 변형된 변형 meiA1 유전자 전체 (이상, 'm_milA1'로 총칭함)을 포함하는 상동 재조합을 위하여, aveA1 유전자의 upstream 및 downstream 지역과 상동성을 가지는 부위를 m_milA1의 어느 한쪽 말단 또는 양쪽 말단에 연결된 형태로 구성될 수 있다. 또한, 다른 실시예에서는, milA3(또는 meiA3)을 치환하기 위한 재조합 벡터는, milA3(또는 meiA3) 유전자의 7번 모듈의 코딩 유전자의 전체 또는 일부를 포함하고, 상동 재조합을 위하여 aveA3 및/또는 aveA4 유전자 지역과 상동성을 가지는 부위를 milA3(또는 meiA3) 유전자의 7번 모듈의 코딩 유전자의 전체 또는 일부의 어느 한쪽 말단 또는 양쪽 말단에 연결된 형태로 구성될 수 있다. 상기 벡터는 본원의 대표적인 실시예일뿐이며, 본원의 범위가 이에 제한되는 것은 아니다.
상기 벡터는, 상동 재조합을 위하여 숙주 유전자 부위와 상동성을 가지는 부위를 포함하는데, 여기에서 상동이란 숙주 유전자 부위의 염기 서열과의 동일성 정도를 나타내는 것으로, 예를 들어, 숙주 유전자의 염기서열과 90% 이상, 95% 이상 또는 98% 이상 동일한 것일 수 있다.
스트렙토마이세스에서 사용하기 위한 다양한 여러 벡터들, 예를 들어 파지, 고 카피수(high copy number) 플라스미드, 저 카피수 플라스미드, 및 대장균(E. Coli)-스트렙토마이세스 셔틀 벡터들이 개발되어 왔으며, 이들 벡터들을 본 발명을 구현하기 위하여 사용할 수 있다. 예를 들어, pCR-Blunt, pCR2.1(Invitrogen), pGEM3Zf(Promega) 및 셔틀 벡터 pWHM3, pKC1139 등을 예시할 수 있으나, 이에 제한되는 것은 아니다.
상기 벡터는, 형질전환된 세포를 선별하기 위한 목적으로 선별마커(selection marker)를 더욱 포함할 수 있으며, 예를 들어, 약물 내성, 영양 요구성, 세포 독성제에 대한 내성 또는 표면 단백질의 발현과 같은 선택가능 표현형을 부여하는 마커들이 사용될 수 있고, 포지티브 선별마커와 네가티브 선별마커를 예시할 수 있다. 포지티브 선별마커란 선택제(selective agent)가 처리된 환경에서 선택 마커를 발현하는 세포만 생존하도록 하여 포지티브 선택을 가능하게 하는 마커로, 아프라마이신, 네오마이신, 하이그로마이신, 히스티디놀 디하이드로게나제(histidinol dehydrogenase gene: hisD) 또는 구아닌 포스포리보실트랜스퍼라제(guanine phosphosribosyltransferase: Gpt) 등이 있으나, 이에 제한되지 않는다. 네가티브 선별마커란 무작위적 삽입(random insertion)이 일어난 세포를 선별하여 제거하는 네가티브 선택을 가능하게 하는 마커로, 허피스 심플렉스 바이러스-싸이미딘 키나제(Herpes simplex virus-thymidine kinase: HSV-tk), 하이포잔틴 포스포리보실 트랜스퍼자제(hypoxanthine phosphoribosyl transferase: Hprt), 싸이토신 디아미네즈(cytosine deaminase), 디프테리아 톡신(Diphtheria toxin) 등이 있으나, 이에 제한되지 않는다.
상기 벡터 제작은 당해 기술분야에서 잘 알려진 유전자 재조합 기술을 이용하여 제조할 수 있으며, 부위-특이적 DNA 절단 및 연결은 당해 기술 분야에서 일반적으로 알려진 제한효소 등을 사용할 수 있다.
본 발명의 벡터는 스트렙토마이세스 세포에서 작용하지만, 예를 들어 클로닝 또는 발현 목적을 위해 다른 박테리아 또는 진핵 세포로 또한 형질전환될 수 있다. 예를 들어, 아메리칸 타입 컬쳐 컬렉션(American Type Culture Collection; ATCC)로부터 구입할 수 있거나, 시판 중인 DH5α 균주와 같은 에스케리키아 콜라이 균주가 전형적으로 사용될 수 있다. 바람직한 진핵 숙주 세포로는 포유동물 세포, 곤충 세포 또는 효모 세포가 또한 효과적으로 사용될 수 있다.
숙주 균주 내로 본 발명의 벡터를 도입 방법은 핵산을 세포 내로 도입하는 어떠한 방법도 포함되며, 당 분야에서 공지된 바와 같이 적합한 표준 기술을 선택하여 수행할 수 있다. 예들 들어, 원형질체(protoplast) 형질전환, 전기천공법(electroporation), 전기주입법(electroinjection), 미세주입법 (microinjection), 인산칼슘공동-침전법(calcium phosphate co-precipitation), 염화캄슘/염화루비듐법, 레트로바이러스 감염(retroviral infection), DEAE-덱스트란(DEAE-dextran), 양이온 리포좀(cationic liposome)법, 폴리에틸렌글리콜 침전법(polyethylene glycol-mediated uptake), 유전자총(gene gun) 등을 이용할 수 있으나, 이에 제한되는 것은 아니다. 이 때 원형의 벡터를 적절한 제한효소로 절단하여 선형의 벡터 형태 또는 플라스미드를 제거한 선형의 벡터 형태로 도입할 수 있다. 형질전환체는 선별마커, 예를 들어 전술한 바와 같이 재조합 벡터와 연관된 항생물질 저항성을 발현시키는 세포를 선택하는 방법과 같은 표준 절차에 따라 선택할 수 있다.
이와 같이 제조된 재조합 균주를 배양하여 밀베마이신을 생산할 수 있으며, 예를 들어, 밀베마이신 D를 주요하게 생산하고, 밀베마이신 A3, 밀베마이신 A4, 밀베마이신 D로 이루어진 군에서 선택되는 1종 이상의 밀베마이신을 생산할 수 있다.
재조합 균주의 배양은 균주의 생육과 밀베마이신의 대량 생산에 적합하도록 온도, 배지의 pH 및 배양시간 등의 조건들을 적절하게 조절할 수 있다. 상기 배양 방법의 예에는, 회분식, 연속식 및 유가식 배양이 포함되나, 이에 제한되는 것은 아니다.
배양에 사용되는 배지는 특정한 균주의 요구조건을 적절하게 만족시켜야 한다. 상기 배지는 다양한 탄소원, 질소원, 인원 및 미량원소 성분을 포함할 수 있다. 발현 벡터가 유도성 촉진자를 포함하는 경우에는, 온도 변화, 영양원의 고갈, 무상 유도 물질(예를 들어, 이소프로필-β-D-티오갈락토피라노시드(IPTG)와 같은 탄수화물의 유사 물질)의 첨가, 과잉 대사 부산물의 축적 등과 같은 적절한 유도 조건은 발현을 유도하는데 필요에 따라 적용될 수 있다.
배지 내 탄소원으로는 글루코즈, 사카로즈, 락토즈, 프락토즈, 말토즈, 전분, 셀룰로즈와 같은 당 및 탄수화물, 대두유, 해바라기유, 피마자유, 코코넛유 등과 같은 오일 및 지방, 팔미트산, 스테아린산, 리놀레산과 같은 지방산, 글리세롤, 에탄올과 같은 알코올, 아세트산과 같은 유기산을 예시할 수 있으나, 이에 제한되는 것은 아니다. 이들 물질은 개별적으로 또는 혼합물로서 사용될 수 있다. 배지 내 질소원으로는 펩톤, 효모 추출물, 육즙, 맥아 추출물, 옥수수 침지액, 대두밀 및 요소 또는 무기 화합물, 예를 들면 황산암모늄, 염화암모늄, 인산암모늄, 탄산암모늄 및 질산암모늄을 예시할 수 있으나, 이에 제한되는 것은 아니다. 질소원 또한 개별적으로 또는 혼합물로서 사용할 수 있다. 배지 내 인원으로는 인산이수소칼륨 또는 인산수소이칼륨 또는 상응하는 나트륨-함유 염을 예시할 수 있으나, 이에 제한되는 것은 아니다. 또한, 배양 배지는 성장에 필요한 황산마그네슘 또는 황산철과 같은 금속염을 포함하거나, 아미노산 및 비타민과 같은 필수 성장 물질을 포함할 수 있으나, 이에 제한되는 것은 아니다. 상기된 원료들은 배양 과정에서 배양물에 적절한 방식에 의해 회분식으로 또는 연속식으로 첨가될 수 있다.
또한, 필요에 따라, 수산화나트륨, 수산화칼륨, 암모니아와 같은 기초 화합물 또는 인산 또는 황산과 같은 산 화합물을 적절한 방식으로 사용하여 배양물의 pH를 조절할 수 있다. 또한, 지방산 폴리글리콜 에스테르와 같은 소포제를 사용하여 기포 생성을 억제할 수 있다. 호기 상태를 유지하기 위해 배양물 내로 산소 또는 산소-함유 기체(예, 공기)를 주입할 수 있으며, 배양물의 온도는 보통 20 내지 45, 바람직하게는 25 내지 40 일 수 있다. 배양은 원하는 밀베마이신의 생산량이 최대로 얻어질 때까지 계속될 수 있다.
재조합 미생물로부터 생산된 밀베마이신은, 당업계에 널리 알려져 있는 방법으로 세포, 세포 용해물 또는 배양 배지로부터 단리되거나 실질적으로 정제될 수 있다. 밀베마이신의 회수 방법의 예로서, 유기용매 추출법, 원심분리, 초음파파쇄, 여과, 결정법(crystallization), 이온교환 크로마토그래피, 친화성 크로마토그래피, 고성능 액체 크로마토그래피(high performance liquid chromatography: HPLC) 등의 방법이 있으나, 이들 예에 한정되는 것은 아니다. 구체예로, 균주 배양물로부터 유기용매를 이용하여 생성 물질들을 추출한 후, 실리카겔, 알루미나, 덱스트란겔, 이온교환 수지, 합성흡착제, 분자체, C8H17, C18H37, C6H5 등의 화학 결합형 실리카겔 등의 담체를 사용한 크로마토그래피에 부여하여, 얻어진 목적 화합물을 함유하는 분획을 농축 건조시키는 방법으로 회수할 수 있다.
본 명세서에 기재된 유전자 서열 및 아미노산 서열은 기능성 동등성을 유지하는 한, 80% 이상, 85% 이상, 90% 이상, 92% 이상, 94% 이상, 96% 이상, 98% 이상, 또는 99% 이상의 서열 상동성을 갖는 경우를 포함하는 것으로 해석될 수 있다.
본 발명에서 제공된 재조합 균주를 이용하여 밀베마이신 D를 경제적으로 생산할 수 있으며, 이에 의해 생산된 밀베마이신 D는 농업, 동물의약품 및 의약품으로서 폭넓게 활용될 수 있다.
도 1a-c는 아베멕틴과 밀베마이신의 분자구조 차이 및 이를 유발하는 유전자의 구성을 보여주는 그림이고, 도 1d는 밀베마이신 폴리케타이드 합성효소 유전자군 (gene cluster)과 아베멕틴 폴리케타이드 합성효소 유전자군을 비교하여 보여주는 그림이다.
도 2는 스트렙토마이세스 아베르미틸리스 MA-4680의 아버멕틴 합성효소 시작 모듈의 AT 도메인의 아미노산 염기서열 (aveA1)과 스트렙토마이세스 난찬젠시스 및 스트렙토마이세스 밀베마이시니쿠스의 밀베마이신 합성효소의 시작 모듈의 AT 도메인의 아미노산 염기서열 (각각 meiA1 과 milA1)을 비교한 것이다. "+"는 ave-AT0에서 기질 결합부위를 구성하는 아미노산이며, "*"는 AT0의 효소 반응에 관여하는 아미노산이다. 기질과 근접할 것으로 예상된 13개의 아미노산은 회색 박스로 나타내었다.
도 3은 스트렙토마이세스 아베르미틸리스 MA-4680의 아버멕틴 합성효소의 ave-AT0의 단백질 구조 (PDB No. 4RL1)와 이를 기반으로 하여 SWISS-MODEL로 추정한 스트렙토마이세스 밀베마이시니쿠스의 밀베마이신 합성효소의 mil-AT0의 단백질 구조 모델을 비교한 것이다. ave-AT0의 구조는 밀색 (wheat)로 mil-AT0의 구조는 lightblue로 나타내었으며, 기질과 소수성 상호작용을 하는 것으로 예측된 ave-AT0의 아미노산 잔기는 라임색으로, 이와 상응하는 위치에 있는 mil-AT0의 아미노산 잔기는 lightblue로 나타내었다. mil-AT0의 Ile290, Ile292 잔기는 붉은색으로 나타내었다.
도 4는 일 실시예에 따른 pCR2.1-V290L292, pCR2.1-V290V292, pCR2.1-V290I292, 및 pCR2.1-V290M292 벡터를 제조하는 과정을 나타낸 것이다.
도 5는 일 실시예에 따른 스트렙토마이세스 아베르미틸리스 000의 배양액으로부터 생성된 물질을 HPLC를 통해 분석한 결과를 보여준다. 형성된 각 peak 중 retention time이 표기된 peak는 Milbemycin 표준품과 동일한 UV-흡광패턴 보여주는 것이다. 도 5a는 밀베마이신 표준품의 HPLC 분석결과, 도 5b는 스트렙토마이세스 아베르미틸리스 LB-50002, 도 5c는 스트렙토마이세스 아베르미틸리스 LB-50005 (milA1 I290VI292L), 도 5d는 스트렙토마이세스 아베르미틸리스 LB-50006 (milA1 I290VI292V), 도 5e는 스트렙토마이세스 아베르미틸리스 LB-50007 (milA1 I290VI292I), 도 5f는 스트렙토마이세스 아베르미틸리스 LB-50008 (milA1 I290VI292M)이 생성한 물질의 분석결과를 보여준다.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예에 의해 한정되는 것은 아니다.
실시예 1. mil- AT0 돌연변이 도입을 위한 벡터의 제작
밀베마이신 생산 균주인 스트렙토마이세스 아베르미틸리스 DBM-03-A (수탁번호: KCTC12890BP; 스트렙토마이세스 밀베마이시니쿠스의 milA3 유전자의 모듈 7을 포함하는 재조합 스트렙토마이세스 아베르미틸리스 균주, 대한민국 특허공개 제2017-0035346호 (본 명세서에 참조로 포함됨) 참조)에서 밀베마이신의 5-hydroxyl group에 메틸기를 전달하는 메틸트랜스퍼라제의 활성을 제거하여 5-hydroxy 형태의 밀베마이신 만을 생산하는 스트렙토마이세스 아베르미틸리스 LB-50002를 제작하였다. 구체적으로, DBM-03-A가 milbemycin A3, A4, D를 주로 생산하도록 하기 위해, 5-methyl form의 congener를 생산하는 메틸트렌스퍼라제를 코딩하는 aveD 유전자에 종료코돈 (stop codon)을 도입하여 메틸트랜스퍼라제 활성을 제거하여, LB-50002 균주를 제작하고, 대한민국 대전광역시에 소재하는 한국생명공학연구원에 2017년 9월 1일자로 기탁하여, 수탁번호 KCTC13324B를 수여받았다.
LB-50002 균주의 mil-AT0의 Ile290 및 Ile292 위치에 돌연변이를 도입하기 위해 PCR을 통해 돌연변이가 도입되도록 표 2의 프라이머를 디자인하여 PCR을 통해 증폭하였다 (도 4).
Primer name 서열 비고
AF-XNF 5'-gccctctagatgcatAGTGACGGCAACGGGAATA-3' (서열번호 19) Cloning 용 N-terminal primer
Mm1-HR 5'-gattacgccaagcttACGTAATCCGACGGCTTG-3' (서열번호 20) Cloning 용 C-terminal primer
290V292L-F 5'-CGGTCGACCTCCCCGCGCACTCG-3' (서열번호 21) LB-50005 제작용
290V292L-R 5'-CGGGGAGGTCGACCGCCACCTCG-3' (서열번호 22)
290V292V-F 5'-CGGTCGACGTCCCCGCGCACTCG-3' (서열번호 23) LB-50006 제작용
290V292V-R 5'-CGGGGACGTCGACCGCCACCTCG-3' (서열번호 24)
290V-F 5'-CGGTCGACATCCCCGCGCACTCG-3' (서열번호 25) LB-50007 제작용
290V-R 5'-CGGGGATGTCGACCGCCACCTCG-3' (서열번호 26)
290V292M-F 5'-CGGTCGACATGCCCGCGCACTCG-3' (서열번호 27) LB-50008 제작용
290V292M-R 5'-CGGTCGACCTCCCCGCGCACTC-3' (서열번호 28)
M1O408F 5'-CGAACCGTATGTCTCCTGG-3' (서열번호 29) 염기서열 분석용
증폭된 DNA fragment를 Infusion ligation kit (Takara)를 활용하여 ligation 하고 pCR2.1-V290L292, pCR2.1-V290V292, pCR2.1-V290I292, 및 pCR2.1-V290M292 벡터를 제작하였다 (도 4). 이를 LB-50002로 도입하기 위해 XbaI과 HindIII를 이용하여 자른 후, insert만을 스트렙토마이시스-대장균 셔틀벡터인 pKC1139 벡터(M. Bierman et al., Gene, 116:43-49)로 서브클로닝하여 각각 pKC-V290L292, pKC-V290V292, pKC-V290I292 및 pKC-V290M292를 제작하였다.
실시예 2. milA1 치환 균주 제작 및 생성물질 확인
Mil-AT0 돌연변이 도입을 위해 각각 pKC-V290L292, pKC-V290V292, pKC-V290I292 및 pKC-V290M292를 스트렙토마이세스 아베르미틸리스 LB-50002 균주 내로 도입시키고, 상동재조합이 일어나도록 유도하여 스트렙토마이세스 아베르미틸리스 LB-50002 균주의 mil-AT0의 Ile290 및 Ile292 위치의 염기가 치환된 형태의 균주를 확보하고, 배양을 통해 생성되는 밀베마이신을 확인하였다.
2-1. 접합법을 통한 형질전환
pKC-V290L292, pKC-V290V292, pKC-V290I292 및 pKC-V290M292 벡터를 각각 포함하고 있는 E. coli 균주(ET12567/pUZ8002 strain)를 클로람페니콜, 카나마이신, 아프라마이신(apramycin)을 넣은 LB 액체배지 (Difco LB broth; BD, 미국) 3 mL에 접종한 후 진탕배양기(Shaking incubator)에서 37℃, 200 rpm 조건으로 18~24시간 배양하였다. 멸균된 250 mL flask에 25 mL LB broth를 위의 항생제와 함께 넣고, 배양액 250ul을 접종한 뒤 동일 조건으로 3시간 배양하였다. OD가 0.4~0.5에 이르렀을 때, 배양을 종료하고 5000 rpm에서 5분간 원심분리하였고 펠렛만 취하여 냉각된 LB broth 1 mL에 풀어주고 세척하여 균체 현탁액을 확보하였다.
또한, 실시예 1에서 준비된 스트렙토마이세스 아베르미틸리스 LB-50002 균주를 germination 하기 위하여, ISP4 agar plate(Difco ISP4 agar 배지; BD, 미국)에 호스트(host)로 사용할 방선균을 7일 이상 배양하고, 포자(Spore)를 루프로 긁어서 2X TY 배지 (Bacto-Trypton 16g/L (Duchefa사, 네덜란드), Yeast Extract 10g/L (BD사), Sodium chloride 5g/L (Duchefa 사))에 풀어주고, 50℃ heating block에 넣고 10분간 activation을 실시하였다. 이와 같이 준비된 E. coli 균주 500 ㎕와 germination된 host 균주 LB-50002 500 ㎕를 마이크로튜브에 넣고 inverting으로 섞고, 8000 rpm 에서 2분간 원심분리하여 상층액을 제거하는 방법으로 접합(conjugation)을 유도하여, 각 벡터를 스트렙토마이세스 아베르미틸리스 LB-50002 균주 내로 도입시켰다.
2-2. 교차에 의한 유전자 치환
상기와 같이 치환 벡터가 도입된 균주에서 1차 교차를 유도하여 벡터 전체가 균주의 염색체에 삽입되도록 하였다. 이를 위하여, 아프라마이신이 25 ㎍/mL 농도로 첨가된 ISP-4 고체배지를 제조한 후, 치환벡터 도입에 의해 생성된 콜로니를 취한 후, 준비된 고체 배지에 스트리킹(streaking)하였다. 이후 고온에 민감한 pKC1139 벡터의 성질을 이용하여 벡터가 복제되는 것을 막기 위하여 37℃에서 7일간 배양하였다.
2-3. 2차 교차
상기 1차 교차가 일어난 균주에서 mil-AT0 유전자의 Ile290 및 Ile292 위치의 염기를 치환하기 위해 2차 교차를 유도하였다. 이를 위하여, 아프라마이신이 25 ㎍/mL 농도로 첨가된 ISP-4 고체배지와 항생제가 첨가 되지 않은 배지를 각각 제조하고, 1차 교차를 유도한 균주를 ISP-4 고체 배지에 도말하여 2차 교차를 유도한 후, 아프라마이신 저항성 유무로 후보 균주를 선발하였다.
의도한 변이가 일어났음을 확인하기 위해 표 1의 Mm1-HR 프라이머와 M1O408F 프라이머를 이용하여 PCR을 수행하고 단편에 대한 염기서열 분석을 통해 변이가 일어난 콜로니를 확인하고 각각 LB-50005 (290V292L 변이 포함), LB-50006 (290V292V 변이 포함), LB-50007 (290V 변이 포함), LB-50008 (290V292M 변이 포함)으로 각각 명명하였다. 이 중에서 LB-50005와 LB-50006를 대한민국 대전광역시에 소재하는 한국생명공학연구원에 2017년 9월 1일자로 기탁하여 수탁번호 KCTC13325BP (LB-50005) 및 KCTC13325BP (LB-50006)를 각각 부여받았다.
2-4. LB-50005, LB-50006, LB-50007, 및 LB-50008의 생성물질 확인
S. avermitilis LB-50005, LB-50006, LB-50007, 및 LB-50008 균주를 배양하기 위한 종균 배양용 배지와 생산 배양용 배지를 각각 제조하였다. 종균 배지를 제조하기 위하여, soluble starch 30 g/L(Junsei, Japan), yeast extract 15 g/L(Duchefa, 네덜란드), KH2PO4 0.4 g/L(Junsei)의 농도가 되도록 적정량의 DW에 혼합한 후, pH를 7.2로 맞추고 121℃, 15분간 고압살균을 수행하였다. 충분히 식은 후, 별살한 Corn steep liquor(Sigma)를 5 g/L의 농도가 되도록 첨가하였다. 또한, 생산 배지를 제조하기 위하여, soluble starch 80 g/L, soybean meal 10 g/L(Sigma), skim milk 15 g/L(Difco), KH2PO4 0.5 g/L의 농도가 되도록 적정량의 DW에 혼합한 후, pH를 7.2로 맞추고, 121℃, 15 분간 고압살균을 실시하였다. 생산 배양에 접종할 균주의 양을 충분히 만들기 위해, 상기 제조한 종균 배지 25 mL을 멸균된 250 mL baffled flask에 넣고, 균주 mycelium을 agar plate로부터 1 루프씩 떠서 종균 배지에 접종하였다. 230 rpm 및 28℃ 조건하에서 48시간 동안 배양하였다. 또한, 생산배지 25 mL을 멸균된 250 mL non-baffled flask 넣고 종균 배양액 1.25 mL을 접종한 후, 230 rpm 및 28℃ 조건하에서 10일 동안 배양하였다. 생산 배양액으로부터 생성된 물질을 추출하기 위하여, 에탄올 9 mL과 배양액 3 mL 섞고 충분히 볼텍싱(vortexing)하였다. 15분간 sonication 한 후, 12,000rpm에서 5분간 원심분리한 후 상등액만 취하여 분석하였다.
추출한 시료를 아래의 조건에서 HPLC/UVD 분석을 통해 분석하였다.
- Mobile phase: Acetonitrile/Water(v/v)= 50/50 (1분) → v/v(20분)
→ Acetonitrile/Water (v/v)= 85/15 (5분)
- Flow rate: 0.9 mL/min
- wavelength: 245 nm
- Run time: 25 min
그 결과, LB-50002의 발효액을 분석한 결과에서 나온 milbemycin A3, A4 및 D의 peak (도 5b 참조)와 비교할 때 LB-50005과 LB-50006 발효액은 밀베마이신 D를 주요하게 생산함을 알 수 있다 (도 5c-5d 참조). 반면, LB-50007과 LB-50008의 경우 밀베마이신을 50% 미만으로 생산하거나 생산하지 못하는 것을 알 수 있다 (도 5e-5f 참조).
표 3에서 각 균주의 발효액을 분석하여 밀베마이신 종류 별 비율을 비교하였다.
균주명 Milbemycins (mg/L) 밀베마이신 내 D의 비율 ( 중량% )
A3 A4 D
LB-50002 90.6 24.9 14.6 11%
LB-50005 10.6 8.5 35.4 65%
LB-50006 8.0 11.1 77.7 80%
LB-50007 22.8 8.9 12.8 29%
LB-50008 Not detected
따라서, 밀베마이신 합성효소 시작 모듈의 AT 도메인의 기질 결합부위의 아미노산을 치환함으로서 제작한 LB-50005과 LB-50006이 모균주인 LB-50002에 비해 밀베마이신 D를 효율적으로 생산함을 알 수 있었다.
한국생명공학연구원 KCTC13324 20170901 한국생명공학연구원 KCTC13325 20170901 한국생명공학연구원 KCTC13326 20170901
<110> FarmHannong Co., Ltd. <120> Recombinant Microorganisms Producing Milbemycins and Method of Preparing Milbemycins Using the Same <130> DPP20173675KR <160> 29 <170> KopatentIn 2.0 <210> 1 <211> 11919 <212> DNA <213> Artificial Sequence <220> <223> aveA1 gene of Streptomyces avermitilis MA-4680 <400> 1 gtgcagagga tggacggcgg ggaagaaccc cgccctgcgg caggggaggt cctcggagtg 60 gccgacgagg cggacggcgg cgtcgtcttc gtttttcccg ggcagggccc gcaatggccg 120 ggcatgggaa gggaacttct cgacgcttcc gacgtcttcc gggagagcgt ccgcgcctgc 180 gaagccgcgt tcgcgcccta cgtcgactgg tcggtggagc aggtgttgcg ggactcgccg 240 gacgctcccg ggctggaccg ggtggacgtc gtccagccga ccctgttcgc cgtcatgatc 300 tccctggccg ccctctggcg ctcgcaaggg gtcgagccgt gcgcggtgct gggacacagc 360 ctgggcgaga tcgcggcagc ccacgtctcg ggaggcctgt ccctggccga cgccgcacgc 420 gtggtgacgc tttggagcca ggcacagacc acccttgccg ggaccggcgc gctcgtctcc 480 gtcgccgcca cgccggatga gctcctgccc cgaatcgctc cgtggaccga ggacaacccg 540 gcgcggctcg ccgtcgcagc cgtcaacgga ccccggagca cagtcgtttc cggtgcccgc 600 gaggccgtcg cggacctggt ggccgacctc accgccgcgc aggtgcgcac gcgcatgatc 660 ccggtggacg ttcccgccca ctcccccctg atgtacgcca tcgaggaacg ggtcgtcagc 720 ggcctgctgc ccatcacccc acgcccctcc cgcatcccct tccactcctc ggtgaccggc 780 ggccgcctcg acacccgcga gctagacgcg gcgtactggt accgcaacat gtcgagcacg 840 gtccggttcg agcccgccgc ccggctgctt ctgcagcagg ggcccaagac gttcgtcgag 900 atgagcccgc acccggtgct gaccatgggc ctccaggagc tcgccccgga cctgggcgac 960 accaccggca ccgccgacac cgtgatcatg ggcacgctgc gccgcggcca gggcaccctg 1020 gaccacttcc tgacgtctct cgcccaacta cgggggcatg gtgagacgtc ggcgaccacc 1080 gtcctctcgg cacgcctgac cgcgctgtcc cccacgcagc agcagtcgct gctcctggac 1140 ctggtgcgcg cccacaccat ggcggtgctg aacgacgacg gaaacgagcg caccgcgtcg 1200 gatgccggcc catcggcgag tttcgcccac ctcggcttcg actccgtcat gggtgtcgaa 1260 ctgcgcaacc gcctcagcaa ggccacgggc ctgcggttgc ccgtgacgct catcttcgac 1320 cacaccacgc cggccgcggt cgccgcgcgc cttcggaccg cggcgctcgg ccacctcgac 1380 gaggacaccg cgcccgtacc ggactcaccc agcggccacg gaggcacggc agcggcggac 1440 gacccgatcg ccatcatcgg catggcatgc cgtttcccgg gcggagtccg gtccccgaag 1500 gacctgtggg agctggccgc ctcgggcgga gacgccatcg ggccgttccc caccgaccgc 1560 ggatggccca cggaacagcg tcacgcccag gaccccacgc agcccggcac gttctatccg 1620 cagggaggcg ggttccttca cgacgcggcg cacttcgacg ccggcttctt cggaatcagt 1680 ccacgtgagg cactggcgat ggatccgcag cagcggctgc tgctggagac gtcctgggag 1740 gcgttcgagc gggcgggaat cgatccgctg tcggtacgcg ggtcccgtac gggcgtcttc 1800 gcgggcgccc tctccttcga ctacggcccg cgtatggaca ccgcgtcgtc ggagggcgcc 1860 gcggacgtgg agggccacat cctcaccggt accacgggca gcgtcctgtc gggccgtatc 1920 gcctacagct tcgggctgga agggccggcg atcaccgtgg acacggggtg ctcggcatcg 1980 ctcgtgacgc tgcatctggc gtgccagtcg ctgcggtcgg gtgagtgcac gctcgcgctg 2040 gccggcggcg tctcggtcat gtccaccctc ggcatgttca tcgagttctc ccggcagcgc 2100 gggctgtcgg tggacggcag gtgcaaggcg tactcggctg cagccgacgg caccggctgg 2160 ggcgagggcg tcgggatgct gttggtggag cggttgtcgg atgcggtgcg gctggggcat 2220 cgggtgctgg cggtggtacg cggcagtgcg gtcaaccagg acggtgcgtc gaatgggctg 2280 acggcgccga acggtccggc tcaggagcgg gtgatccggc aggcgttggc gaacgcgggg 2340 ttgtccgtgg cggatgtgga tgtggtggag gggcacggga cgggcacgac gctgggtgat 2400 ccgatcgagg cacaggcgtt gctcgccacg tacgggcagc gggccggtga caggccgctg 2460 tggctggggt ctctgaagtc caacatcggg cacaccatgg ctgccgcggg tgtgggtggg 2520 gtcatcaaga tggtgatggc gttgcgggag ggggtgttgc cgcggacgtt gcatgtggat 2580 aagccgtcgc cgcaggtgga ctggtccgcg ggggcggtgc ggctgctgac ggaggcggtg 2640 ccgtggccgg gggacgcggc agggcggttg cggcgggcgg gagtgtcgtc gttcgggatc 2700 ggcggcacga atgcgcatgt gattttggag gaggcgccgg cggcgggggg ctgtgttgcc 2760 gggggtgggg tgttggaggg tgctccgggt cttgccattt cggtggctga gtcggtggcc 2820 gctccagtgg ctgtgtctgc gccggtggct gagtcggtgc cggtgccggt gccggtgccg 2880 gttcctgtgc cggtgtcggc taggtctgag gctgggttgc gggcgcaggc ggaggcgttg 2940 cgtcagtacg tggcagtccg gccggacgtt tcgcttgccg atgtgggtgc gggtctggcc 3000 tgtgggcggg ctgtgctgga gcatcgtgcg gtcgtcctgg ccgcggaccg tgaggagctg 3060 gtgcaagggt tgggggcgct ggcggcgggt gagccggatc ggcgggtgac cacgggtcat 3120 gcgccgggtg gtgaccgggg cggtgtcgtc ttcgtgtttc ccggacaggg tgggcagtgg 3180 gccgggatgg gtgtgcgtct gctcgcctcc tctccggtgt tcgcccggcg gatgcaggcg 3240 tgcgaggagg ctctggcgcc gtgggtggac tggtctgtgg tggacatcct gcgccgggac 3300 gcgggggatg cggtgtggga gcgggccgat gtggtccagc ctgtgctgtt cagcgtcatg 3360 gtgtctttgg ctgctctgtg gcgttcctac ggtatcgaac ccgacgcggt ccttggccat 3420 tcccagggcg agatcgcggc cgcgcatgtg tgtggggcgc tgagcctgaa ggacgcggcg 3480 aagactgttg cgctgcgcag ccgggcgctg gccgctgtgc ggggccgggg cggcatggcc 3540 tcagtgccgc tgcctgccca ggaggtggag cagctcattg gtgagcggtg ggcggggcgg 3600 ttgtgggtgg cggcggtcaa cggcccccgc tccaccgccg tctcggggga tgccgaggcg 3660 gtggacgagg tgctggcgta ctgtgccggc accggggtgc gggcccggcg gatcccggtc 3720 gactatgcct cgcactgccc ccatgtgcag cccctgcggg aggagttgct ggagctgctg 3780 ggggacatca gcccgcagcc gtccggcgtg ccgttcttct ccacggtgga gggcacctgg 3840 ctggacacca caaccctgga cgccgcctac tggtaccgca acctgcacca gccggtccgt 3900 ttcagcgatg ccgtccaggc cctggcggat gacggacacc gcgtcttcgt cgaagtcagc 3960 ccccacccca ccctcgtccc cgccatcgaa gacaccaccg aagacaccgc cgaagacgtc 4020 accgcgatcg gcagcctccg ccgcggcgac aacgacaccc gccgcttcct caccgccctc 4080 gcccacaccc ataccaccgg catcggcaca cccaccacct ggcaccacca ctacacccac 4140 caccacaccc acccccaccc ccacacgcac ctcgacctgc ccacctaccc cttccaacac 4200 cagcactact ggctcgagag ctcacagccg ggtgccggat ccggttcggg tgccggtgcc 4260 ggttcgggtg ccggttccgg gcgggcaggg actgcgggcg ggacggcaga ggtggagtcg 4320 cggttctggg acgcggtggc ccgccaggac ctggaaacgg tcgcgaccac actcgccgtg 4380 cccccctccg ccggcctgga cacggtggtg cccgcactct ccgcctggca ccgccaccaa 4440 cacgaccaag cccgcatcaa cacctggacc taccaggaaa cctggaaacc cctcaccctc 4500 cccaccaccc accaacccca ccaaacctgg ctcatcgcca tccccgaaac ccagacccac 4560 cacccccaca tcaccaacat cctcaccaac ctccaccacc acggcatcac ccccatcccc 4620 ctcaccctca accacaccca caccaacccc caacacctcc accacaccct ccaccacacc 4680 cgacaacaag cccaaaacca caccaccgga gccatcaccg gcctgctctc cctcctcgcc 4740 ctcgacgaaa caccccaccc ccaccacccc cacacaccca ccggcaccct cctcaacctc 4800 accctcaccc aaacccacac ccaaacccac ccaccaaccc ccctctggta cgccaccacc 4860 aacgccacca ccacccaccc caacgacccc ctcacacacc ccacccaagc ccaaacctgg 4920 ggactcgccc gcaccaccct cctcgaacac cccacccaca ccgccggaat catcgacctc 4980 cccaccaccc ccacccccca caccctccag cacctcaccc aaaccctcac ccaaccccac 5040 caccaaaccc aactcgccat ccgcaccacc ggcacccaca cccgccgcct cacccccacc 5100 accctcaccc ccacacacca accacccacc cccacccccc acggaaccac cctcatcacc 5160 ggcggaaccg gcgccctcgc cacccacctc acccaccacc tcaccaccca ccaacccacc 5220 caacacctcc tcctcaccag ccgaaccggc ccccacaccc cccacgcaca acacctcacc 5280 acccaactcc aacaaaaagg catccacctc accatcacca cctgcgacac cagcaaccca 5340 gaccaactcc aacaactcct caacaccatc cccccacaac accccctcac caccgtcatc 5400 cacaccgcag gcatcctcga cgacgccacc ctcaccaacc tcacccccac ccaactcaac 5460 aacgtcctcc gcgccaaagc ccacagcgcc cacctcctcc accaactcac ccaacacacc 5520 cccctcaccg ccttcgtcct ctactcctcc gccgccgcca ccttcggcgc acccggccaa 5580 gccaactacg ccgcagccaa cgcctacctc gacgccctcg cccaccaccg ccacacccac 5640 cacctccccg ccaccagcat cgcctggggc acctggcaag gaaacggact cgctgattcg 5700 gacaaggccc gcgcatatct cgaccgccgc gggtttcgac ccatgtcacc cgagttggcc 5760 acggcagcgg tcacgcaggc gatcgcggac accgaacggc cgtatgtcgt catcgccgac 5820 atcgactgga gcaagatcga acacacctct cagaccagcg acctggtgag cgcggcccgg 5880 gaaagggagc cagctgtcca gcgccccact ccaccggcgg agttgcacaa aacgctggcc 5940 catcagacgt cggccgacca acgggccgca ttgctcgagc tcgtacgaga ccatgtggcg 6000 gcagtgctcc ggcacgcgga cccgaaagcc atcgcgcccg accagtcgtt ccgtgcactc 6060 ggcttcgatt cactcacggc cgtcgagttc cgaaacctgc tgatcaaggc aacaggactc 6120 cgccttcctg tctcgctggt cttcgaccac ccgacccctg ccaaactcgc cgtacacctg 6180 cagaaccaac tgcggggcac agcagcggag tcggctcctt cagcggcagc cgttaccgcc 6240 gaggcttctg tcaccgagcc gatcgccatc gttggcatgg cctgtcgttt ccccggcgga 6300 gtgacctcgg cggacgactt ctgggatctg atctcctccg agcaggacgc gatcggcgga 6360 ttccccaccg accgcggctg ggacctggac acgctctacg accccgaccc cgaccacccc 6420 ggcacctgct acacccgaaa cggcggattc ctctacgacg caggccactt cgacgccgaa 6480 ttcttcggca tcagcccccg cgaagccctc gccatggacc cccagcaacg actcctcctc 6540 gaaaccgcct gggaaaccat cgaacacgcc ggcatcaacc cccacaccct ccacggcacc 6600 cccaccggag tcttcaccgg caccaacgga caggactacg cacttcgcgt gcacaacgcg 6660 ggccagtcaa ccgatggttt cgcactgacc ggaaccgccg gcagcgtcat ctccggtcgt 6720 atctcgtaca cgtttggttt tgagggtcct gcggtgtcgg tggacacggc ttgttcctcg 6780 tcgttggtgg ctttgcatct ggcctgtcag gcgttgcgtg cgggtgagtg ctcgatggcg 6840 cttgccgggg gtgtgacggt gatgtcgtct ccgggtgcct tcgtggagtt ttcgcggcag 6900 cggggtctgg ccgcggacgg gcattgcaag gcgttctcgg cggcggcgga cgggaccggc 6960 tggggtgagg gtgtggggat gctgctggtg gagcggctct ccgacgccca tcgcaacggt 7020 caccgtgtcc tggccgtggt gcgtggcagt gcggtcaacc aggacggtgc gagcaacggt 7080 ctgaccgcgc ccaacgggcc gtcccagcag cgtgtcatcc gccaggccct cgccaacgcc 7140 ggcttgtcgg ccggtgatgt cgacgcggtg gaggcccacg gcaccggcac cactttgggc 7200 gacccgatcg aggcccaggc cctcctcgcg acctacggac aggaccgtgc cggcgagggg 7260 ccgctgtggc tgggctcggt caagtccaat gtcggtcaca cacaggctgc cgcgggcgtc 7320 gccggggtga tcaagatggt gatggcgctg cggcatggtc tgctgccgcg gacgttgcat 7380 gtggatgagc cgtcgccgca tgtggactgg tccgcgggtg cggtgcagct gctgacggag 7440 acggtgccct ggcccggcgg ggaggggcgg ctacggcggg caggagtgtc atcattcggc 7500 gtcagcggca ccaacgccca cgtcatcctc gaagaagcac ccgccgacga cgttccgggg 7560 ggaccacccg ccggcgaggg tgacgcgggc agcgacgatg aggctgctgc cggcagtcct 7620 ggggtgtggc cgtggctggt gtcggccaag tcgcagccgg ccctgcgcgc ccaggcccag 7680 gccctgcacg cccacctcac cgaccacccc ggcctcgacc tcgcggatgt cggatacacc 7740 ctcgcccacg cccgcgccgt gttcgaccac cgcgccaccc tcatcgccgc ggaccgcgac 7800 acgttcctgc aagcactcca ggcactcgcc gcaggcgagc cccaccccgc cgtcatccac 7860 agcagcgccc cgggcgggac cgggaccggg gaggccgcag gaaagaccgc attcatctgc 7920 tccggacagg gcacccaacg ccccggcatg gcccacggcc tctaccacac ccaccccgtc 7980 ttcgccgccg cactcaacga catctgcacc cacctcgacc cccacctcga ccaccccctc 8040 ctccccctcc tcacccaaaa cgacaacgac aacgaggacg cggccgcact gctccagcag 8100 acccgctacg cccagcccgc cctcttcgcc ttccaggtcg ccctccaccg cctcctcacc 8160 gacggctacc acatcacccc ccactactac gccggacact ccctcggcga aatcaccgcc 8220 gcccacctcg ccggcatcct caccctcacc gacgccacca ccctcatcac ccaacgcgcc 8280 accctcatgc aaaccatgcc ccccggcacc atgaccaccc tccacaccac cccccaccac 8340 atcacccacc acctcaccgc ccacgaaaac gacctcgcca tcgccgccat caacaccccc 8400 acctccctcg tcatcagcgg caccccccac accgtccaac acatcaccac cctctgccaa 8460 caacaaggca tcaaaaccaa aaccctcccc accaaccacg ccttccactc cccccacacc 8520 aaccccatcc tcaaccaact ccaccagcac acccaaaccc tcacctacca cccaccccac 8580 acccccctca tcaccgccaa caccccaccc gaccaactcc tcacccccca ctactggacc 8640 caacaagccc gcaacaccgt cgactacgcc accaccaccc aaaccctcca ccaacacggc 8700 gtcaccacct acatcgaact cggacccgac aacaccctca ccaccctcac ccaccacaac 8760 ctccccaacc cccccaccac caccctcacc ctcacccacc cccaccacca cccccaaacc 8820 cacctcctca ccaacctcgc caaaaccacc accacctggc acccccacca ctacacccac 8880 cacgacaacc aaccccacac ccacacccac ctcgacctcc ccacctaccc cttccaacac 8940 caccactact ggctcgaaag cacacagccc ggtgccggca acgtgtcagc agccggactc 9000 gaccccaccg aacaccccct actcggcgcc acattggaac tggcgactga cggtggagcg 9060 cttcttgcag ggcgcttgtc tttgaggtcg catccgtggc tggctgacca tgccgtcggc 9120 ggcacggtgc tgctgtcggg cgccaccttc ctcgaactcg cccttcatgc gggcacatac 9180 gtgggctgcg accgagtgga tgagctgacg ctgcatgcgc cgctggtggt tcctgtggat 9240 gggggtgtga gtgtgcaggt tggggttgcg gctgcggatg gggaggggcg gcgtttggtg 9300 agtgtgtatg cgcggggtgg gagtgcttgt ggtgggggtg gtgcgtcggg tggggtgtgg 9360 acgtgtcatg cctcgggggt gctggttgag gctgctgctg gtggtgtggt ggtggatggt 9420 ctggcggggg tgtggccgcc gcggggtgcg gtggcggtgg atgtcgatgg tgtccgtgac 9480 cgtttggctg gggctggttg tgttttgggg ccggtgtttt cggggctgcg tgcggtgtgg 9540 cgtgatgggg gggatttgct ggctgaggtg tgtctgccgg aggaggcgtg gggtgatgcg 9600 gctggttttg ggctgcatcc ggcgttgctg gatggtgtgg tccagccgtt gtcggtgttg 9660 cttccgggtg ggacggggtt tggggagggg gcggggttcg gggagggtgt tcgggtgccg 9720 gctgtgtggg gtggtgtgtc gcttcaccgg gcgggtgtga ccggtgtgcg ggtgcgtgtg 9780 tcggctgtcg ggcggggcgg cgggcgtgag gcggtgtcgg tcgtggtcgg ggatgaggcg 9840 ggtgtgccgg tggcgtcggt cgatcgtctt gagttgcggc ctgtggatat gggtcagttg 9900 cgtgctgtct cggtttcggc ggggcggcgg ggttcgctgt atgcggtgca gtgggctgag 9960 gtgggtcctg tgccggtgtg tgggcaggcg tgggcgtggc acgaggacgt gggtgagagc 10020 ggtggtgggc ctgtgccggg ggtggtggtg ttgcggtgcc cggatgccgg tgccggtggc 10080 ggtggcggtg gcggtggtgg cggtggtgtg ggtgaggttg ttggtggggt gttgggtgtg 10140 gtgcaggggt ggctggggct ggagcggttt gcgggttcgc ggctggtggt ggtgacccgg 10200 ggtgcggtgg tggccggccc ggaggacggc ccggtggatg tggtgggtgc gtcggtgtgg 10260 gggctggtgc gttcggcgca ggctgagcat ccggaccggt ttgtcctcct cgacctcgac 10320 accgacaccg gcaccgacct cgacaccggt gctggtgctg gttggggcgt ggatggtggg 10380 cgtgtggcgg cggtggtggc gtgtggtgag ccgcagttgg cggtgcgtgg ggagcggttg 10440 ctggccgcac gcctgaaacg acttgagtca tccggtgatg ttccagccca gcggtccggt 10500 gacacacgag cccggcggtc cgacgtgcct gcccagcgct ccggtggcgt gcctgctcgg 10560 cggtcggttg atgtatcggg tcgggaggtg ttgccgtggt tgtcgggtgg gtcggtgttg 10620 gtgacgggtg ggacgggtgt gctgggtgcg gcggtggcgc ggcatctggc tggtgtgtgt 10680 ggggtgcggg atctgctgtt ggtgagccgg cgtggtccgg atgctccggg tgcggagggt 10740 ctgcgggcgg agctggccgc gttgggggcg gaggtgcgga ttgttgcgtg tgatgtgggg 10800 gagcggcggg aggtggtccg gctgctggag ggtgttcctg ccgggtgtcc gctgacgggt 10860 gtcgtgcatg cggctggtgt gctggacgat gcgacgatcg cctctctcac gcccgagcgg 10920 ctgggcacgg tgttcgcggc caaggtggat gccgctcttt tgctggatga gctgacgcgg 10980 ggtatggagc tgtcggcgtt cgtgctgttc tcctcggccg cggggatcct ggggtcggcc 11040 gggcagggca actacgccgc ggccaatgcc gctctggacg cgctggcgta ccggcggcgg 11100 gcggcgggtc tgccgggggt gtcgctggcg tgggggctgt gggaagaggc cagcgggatg 11160 accgggcacc tggccggcac cgaccaccgg cgcatcatcc gttccggtct gcatcccatg 11220 tcgaccccgg acgcactggc cctcttcgat gcggccctgg ctctggaccg gccggtcctg 11280 ctgcccgccg acctgcgtcc cgccccgccc ctgccgcccc tgctgcagga cctcctgccc 11340 gccacccgcc gccgcaccac ccgcaccacc actaccggtg gtgcggacaa cggcgcccag 11400 ctgcacgccc ggctggccgg ccagacacac gaacaacagc acaccaccct cctcgccctg 11460 gtccgctccc acatcgccac cgtcctgggc cacaccaccc ccgacaccat cccccccgac 11520 cgcgcgttcc gcgacctcgg cttcgactcc ctcaccgccg tcgaactacg caaccggctc 11580 tcccgcacca ccggactccg cctccccacc accctcgcct tcgaccaccc caaccccacc 11640 accctcaccc accacctcca cacacaactc cagccacaac cggacaacgc tgtcgccccc 11700 gtgttggcgg agctcgacaa actcgaatcc gccctctccg ccctcgacaa aaccgacagc 11760 gccagcgaaa gagtcaccct gcggctgaag tcactcatgt tgaggtggaa cgcaccccag 11820 catccgacag ccgaaagcgc tgatgacgac gagaagttca catcggcaac agaggctgag 11880 attttcaaat tcattgacaa cgacctcggc ctgtcctga 11919 <210> 2 <211> 3972 <212> PRT <213> Artificial Sequence <220> <223> type I polyketide synthase AVES 1 (BAA84474.1) <400> 2 Met Gln Arg Met Asp Gly Gly Glu Glu Pro Arg Pro Ala Ala Gly Glu 1 5 10 15 Val Leu Gly Val Ala Asp Glu Ala Asp Gly Gly Val Val Phe Val Phe 20 25 30 Pro Gly Gln Gly Pro Gln Trp Pro Gly Met Gly Arg Glu Leu Leu Asp 35 40 45 Ala Ser Asp Val Phe Arg Glu Ser Val Arg Ala Cys Glu Ala Ala Phe 50 55 60 Ala Pro Tyr Val Asp Trp Ser Val Glu Gln Val Leu Arg Asp Ser Pro 65 70 75 80 Asp Ala Pro Gly Leu Asp Arg Val Asp Val Val Gln Pro Thr Leu Phe 85 90 95 Ala Val Met Ile Ser Leu Ala Ala Leu Trp Arg Ser Gln Gly Val Glu 100 105 110 Pro Cys Ala Val Leu Gly His Ser Leu Gly Glu Ile Ala Ala Ala His 115 120 125 Val Ser Gly Gly Leu Ser Leu Ala Asp Ala Ala Arg Val Val Thr Leu 130 135 140 Trp Ser Gln Ala Gln Thr Thr Leu Ala Gly Thr Gly Ala Leu Val Ser 145 150 155 160 Val Ala Ala Thr Pro Asp Glu Leu Leu Pro Arg Ile Ala Pro Trp Thr 165 170 175 Glu Asp Asn Pro Ala Arg Leu Ala Val Ala Ala Val Asn Gly Pro Arg 180 185 190 Ser Thr Val Val Ser Gly Ala Arg Glu Ala Val Ala Asp Leu Val Ala 195 200 205 Asp Leu Thr Ala Ala Gln Val Arg Thr Arg Met Ile Pro Val Asp Val 210 215 220 Pro Ala His Ser Pro Leu Met Tyr Ala Ile Glu Glu Arg Val Val Ser 225 230 235 240 Gly Leu Leu Pro Ile Thr Pro Arg Pro Ser Arg Ile Pro Phe His Ser 245 250 255 Ser Val Thr Gly Gly Arg Leu Asp Thr Arg Glu Leu Asp Ala Ala Tyr 260 265 270 Trp Tyr Arg Asn Met Ser Ser Thr Val Arg Phe Glu Pro Ala Ala Arg 275 280 285 Leu Leu Leu Gln Gln Gly Pro Lys Thr Phe Val Glu Met Ser Pro His 290 295 300 Pro Val Leu Thr Met Gly Leu Gln Glu Leu Ala Pro Asp Leu Gly Asp 305 310 315 320 Thr Thr Gly Thr Ala Asp Thr Val Ile Met Gly Thr Leu Arg Arg Gly 325 330 335 Gln Gly Thr Leu Asp His Phe Leu Thr Ser Leu Ala Gln Leu Arg Gly 340 345 350 His Gly Glu Thr Ser Ala Thr Thr Val Leu Ser Ala Arg Leu Thr Ala 355 360 365 Leu Ser Pro Thr Gln Gln Gln Ser Leu Leu Leu Asp Leu Val Arg Ala 370 375 380 His Thr Met Ala Val Leu Asn Asp Asp Gly Asn Glu Arg Thr Ala Ser 385 390 395 400 Asp Ala Gly Pro Ser Ala Ser Phe Ala His Leu Gly Phe Asp Ser Val 405 410 415 Met Gly Val Glu Leu Arg Asn Arg Leu Ser Lys Ala Thr Gly Leu Arg 420 425 430 Leu Pro Val Thr Leu Ile Phe Asp His Thr Thr Pro Ala Ala Val Ala 435 440 445 Ala Arg Leu Arg Thr Ala Ala Leu Gly His Leu Asp Glu Asp Thr Ala 450 455 460 Pro Val Pro Asp Ser Pro Ser Gly His Gly Gly Thr Ala Ala Ala Asp 465 470 475 480 Asp Pro Ile Ala Ile Ile Gly Met Ala Cys Arg Phe Pro Gly Gly Val 485 490 495 Arg Ser Pro Lys Asp Leu Trp Glu Leu Ala Ala Ser Gly Gly Asp Ala 500 505 510 Ile Gly Pro Phe Pro Thr Asp Arg Gly Trp Pro Thr Glu Gln Arg His 515 520 525 Ala Gln Asp Pro Thr Gln Pro Gly Thr Phe Tyr Pro Gln Gly Gly Gly 530 535 540 Phe Leu His Asp Ala Ala His Phe Asp Ala Gly Phe Phe Gly Ile Ser 545 550 555 560 Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu 565 570 575 Thr Ser Trp Glu Ala Phe Glu Arg Ala Gly Ile Asp Pro Leu Ser Val 580 585 590 Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Ala Leu Ser Phe Asp Tyr 595 600 605 Gly Pro Arg Met Asp Thr Ala Ser Ser Glu Gly Ala Ala Asp Val Glu 610 615 620 Gly His Ile Leu Thr Gly Thr Thr Gly Ser Val Leu Ser Gly Arg Ile 625 630 635 640 Ala Tyr Ser Phe Gly Leu Glu Gly Pro Ala Ile Thr Val Asp Thr Gly 645 650 655 Cys Ser Ala Ser Leu Val Thr Leu His Leu Ala Cys Gln Ser Leu Arg 660 665 670 Ser Gly Glu Cys Thr Leu Ala Leu Ala Gly Gly Val Ser Val Met Ser 675 680 685 Thr Leu Gly Met Phe Ile Glu Phe Ser Arg Gln Arg Gly Leu Ser Val 690 695 700 Asp Gly Arg Cys Lys Ala Tyr Ser Ala Ala Ala Asp Gly Thr Gly Trp 705 710 715 720 Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala Val 725 730 735 Arg Leu Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn 740 745 750 Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ala Gln 755 760 765 Glu Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu Ser Val Ala 770 775 780 Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly Asp 785 790 795 800 Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Arg Ala Gly 805 810 815 Asp Arg Pro Leu Trp Leu Gly Ser Leu Lys Ser Asn Ile Gly His Thr 820 825 830 Met Ala Ala Ala Gly Val Gly Gly Val Ile Lys Met Val Met Ala Leu 835 840 845 Arg Glu Gly Val Leu Pro Arg Thr Leu His Val Asp Lys Pro Ser Pro 850 855 860 Gln Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr Glu Ala Val 865 870 875 880 Pro Trp Pro Gly Asp Ala Ala Gly Arg Leu Arg Arg Ala Gly Val Ser 885 890 895 Ser Phe Gly Ile Gly Gly Thr Asn Ala His Val Ile Leu Glu Glu Ala 900 905 910 Pro Ala Ala Gly Gly Cys Val Ala Gly Gly Gly Val Leu Glu Gly Ala 915 920 925 Pro Gly Leu Ala Ile Ser Val Ala Glu Ser Val Ala Ala Pro Val Ala 930 935 940 Val Ser Ala Pro Val Ala Glu Ser Val Pro Val Pro Val Pro Val Pro 945 950 955 960 Val Pro Val Pro Val Ser Ala Arg Ser Glu Ala Gly Leu Arg Ala Gln 965 970 975 Ala Glu Ala Leu Arg Gln Tyr Val Ala Val Arg Pro Asp Val Ser Leu 980 985 990 Ala Asp Val Gly Ala Gly Leu Ala Cys Gly Arg Ala Val Leu Glu His 995 1000 1005 Arg Ala Val Val Leu Ala Ala Asp Arg Glu Glu Leu Val Gln Gly Leu 1010 1015 1020 Gly Ala Leu Ala Ala Gly Glu Pro Asp Arg Arg Val Thr Thr Gly His 1025 1030 1035 1040 Ala Pro Gly Gly Asp Arg Gly Gly Val Val Phe Val Phe Pro Gly Gln 1045 1050 1055 Gly Gly Gln Trp Ala Gly Met Gly Val Arg Leu Leu Ala Ser Ser Pro 1060 1065 1070 Val Phe Ala Arg Arg Met Gln Ala Cys Glu Glu Ala Leu Ala Pro Trp 1075 1080 1085 Val Asp Trp Ser Val Val Asp Ile Leu Arg Arg Asp Ala Gly Asp Ala 1090 1095 1100 Val Trp Glu Arg Ala Asp Val Val Gln Pro Val Leu Phe Ser Val Met 1105 1110 1115 1120 Val Ser Leu Ala Ala Leu Trp Arg Ser Tyr Gly Ile Glu Pro Asp Ala 1125 1130 1135 Val Leu Gly His Ser Gln Gly Glu Ile Ala Ala Ala His Val Cys Gly 1140 1145 1150 Ala Leu Ser Leu Lys Asp Ala Ala Lys Thr Val Ala Leu Arg Ser Arg 1155 1160 1165 Ala Leu Ala Ala Val Arg Gly Arg Gly Gly Met Ala Ser Val Pro Leu 1170 1175 1180 Pro Ala Gln Glu Val Glu Gln Leu Ile Gly Glu Arg Trp Ala Gly Arg 1185 1190 1195 1200 Leu Trp Val Ala Ala Val Asn Gly Pro Arg Ser Thr Ala Val Ser Gly 1205 1210 1215 Asp Ala Glu Ala Val Asp Glu Val Leu Ala Tyr Cys Ala Gly Thr Gly 1220 1225 1230 Val Arg Ala Arg Arg Ile Pro Val Asp Tyr Ala Ser His Cys Pro His 1235 1240 1245 Val Gln Pro Leu Arg Glu Glu Leu Leu Glu Leu Leu Gly Asp Ile Ser 1250 1255 1260 Pro Gln Pro Ser Gly Val Pro Phe Phe Ser Thr Val Glu Gly Thr Trp 1265 1270 1275 1280 Leu Asp Thr Thr Thr Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu His 1285 1290 1295 Gln Pro Val Arg Phe Ser Asp Ala Val Gln Ala Leu Ala Asp Asp Gly 1300 1305 1310 His Arg Val Phe Val Glu Val Ser Pro His Pro Thr Leu Val Pro Ala 1315 1320 1325 Ile Glu Asp Thr Thr Glu Asp Thr Ala Glu Asp Val Thr Ala Ile Gly 1330 1335 1340 Ser Leu Arg Arg Gly Asp Asn Asp Thr Arg Arg Phe Leu Thr Ala Leu 1345 1350 1355 1360 Ala His Thr His Thr Thr Gly Ile Gly Thr Pro Thr Thr Trp His His 1365 1370 1375 His Tyr Thr His His His Thr His Pro His Pro His Thr His Leu Asp 1380 1385 1390 Leu Pro Thr Tyr Pro Phe Gln His Gln His Tyr Trp Leu Glu Ser Ser 1395 1400 1405 Gln Pro Gly Ala Gly Ser Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala 1410 1415 1420 Gly Ser Gly Arg Ala Gly Thr Ala Gly Gly Thr Ala Glu Val Glu Ser 1425 1430 1435 1440 Arg Phe Trp Asp Ala Val Ala Arg Gln Asp Leu Glu Thr Val Ala Thr 1445 1450 1455 Thr Leu Ala Val Pro Pro Ser Ala Gly Leu Asp Thr Val Val Pro Ala 1460 1465 1470 Leu Ser Ala Trp His Arg His Gln His Asp Gln Ala Arg Ile Asn Thr 1475 1480 1485 Trp Thr Tyr Gln Glu Thr Trp Lys Pro Leu Thr Leu Pro Thr Thr His 1490 1495 1500 Gln Pro His Gln Thr Trp Leu Ile Ala Ile Pro Glu Thr Gln Thr His 1505 1510 1515 1520 His Pro His Ile Thr Asn Ile Leu Thr Asn Leu His His His Gly Ile 1525 1530 1535 Thr Pro Ile Pro Leu Thr Leu Asn His Thr His Thr Asn Pro Gln His 1540 1545 1550 Leu His His Thr Leu His His Thr Arg Gln Gln Ala Gln Asn His Thr 1555 1560 1565 Thr Gly Ala Ile Thr Gly Leu Leu Ser Leu Leu Ala Leu Asp Glu Thr 1570 1575 1580 Pro His Pro His His Pro His Thr Pro Thr Gly Thr Leu Leu Asn Leu 1585 1590 1595 1600 Thr Leu Thr Gln Thr His Thr Gln Thr His Pro Pro Thr Pro Leu Trp 1605 1610 1615 Tyr Ala Thr Thr Asn Ala Thr Thr Thr His Pro Asn Asp Pro Leu Thr 1620 1625 1630 His Pro Thr Gln Ala Gln Thr Trp Gly Leu Ala Arg Thr Thr Leu Leu 1635 1640 1645 Glu His Pro Thr His Thr Ala Gly Ile Ile Asp Leu Pro Thr Thr Pro 1650 1655 1660 Thr Pro His Thr Leu Gln His Leu Thr Gln Thr Leu Thr Gln Pro His 1665 1670 1675 1680 His Gln Thr Gln Leu Ala Ile Arg Thr Thr Gly Thr His Thr Arg Arg 1685 1690 1695 Leu Thr Pro Thr Thr Leu Thr Pro Thr His Gln Pro Pro Thr Pro Thr 1700 1705 1710 Pro His Gly Thr Thr Leu Ile Thr Gly Gly Thr Gly Ala Leu Ala Thr 1715 1720 1725 His Leu Thr His His Leu Thr Thr His Gln Pro Thr Gln His Leu Leu 1730 1735 1740 Leu Thr Ser Arg Thr Gly Pro His Thr Pro His Ala Gln His Leu Thr 1745 1750 1755 1760 Thr Gln Leu Gln Gln Lys Gly Ile His Leu Thr Ile Thr Thr Cys Asp 1765 1770 1775 Thr Ser Asn Pro Asp Gln Leu Gln Gln Leu Leu Asn Thr Ile Pro Pro 1780 1785 1790 Gln His Pro Leu Thr Thr Val Ile His Thr Ala Gly Ile Leu Asp Asp 1795 1800 1805 Ala Thr Leu Thr Asn Leu Thr Pro Thr Gln Leu Asn Asn Val Leu Arg 1810 1815 1820 Ala Lys Ala His Ser Ala His Leu Leu His Gln Leu Thr Gln His Thr 1825 1830 1835 1840 Pro Leu Thr Ala Phe Val Leu Tyr Ser Ser Ala Ala Ala Thr Phe Gly 1845 1850 1855 Ala Pro Gly Gln Ala Asn Tyr Ala Ala Ala Asn Ala Tyr Leu Asp Ala 1860 1865 1870 Leu Ala His His Arg His Thr His His Leu Pro Ala Thr Ser Ile Ala 1875 1880 1885 Trp Gly Thr Trp Gln Gly Asn Gly Leu Ala Asp Ser Asp Lys Ala Arg 1890 1895 1900 Ala Tyr Leu Asp Arg Arg Gly Phe Arg Pro Met Ser Pro Glu Leu Ala 1905 1910 1915 1920 Thr Ala Ala Val Thr Gln Ala Ile Ala Asp Thr Glu Arg Pro Tyr Val 1925 1930 1935 Val Ile Ala Asp Ile Asp Trp Ser Lys Ile Glu His Thr Ser Gln Thr 1940 1945 1950 Ser Asp Leu Val Ser Ala Ala Arg Glu Arg Glu Pro Ala Val Gln Arg 1955 1960 1965 Pro Thr Pro Pro Ala Glu Leu His Lys Thr Leu Ala His Gln Thr Ser 1970 1975 1980 Ala Asp Gln Arg Ala Ala Leu Leu Glu Leu Val Arg Asp His Val Ala 1985 1990 1995 2000 Ala Val Leu Arg His Ala Asp Pro Lys Ala Ile Ala Pro Asp Gln Ser 2005 2010 2015 Phe Arg Ala Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Phe Arg Asn 2020 2025 2030 Leu Leu Ile Lys Ala Thr Gly Leu Arg Leu Pro Val Ser Leu Val Phe 2035 2040 2045 Asp His Pro Thr Pro Ala Lys Leu Ala Val His Leu Gln Asn Gln Leu 2050 2055 2060 Arg Gly Thr Ala Ala Glu Ser Ala Pro Ser Ala Ala Ala Val Thr Ala 2065 2070 2075 2080 Glu Ala Ser Val Thr Glu Pro Ile Ala Ile Val Gly Met Ala Cys Arg 2085 2090 2095 Phe Pro Gly Gly Val Thr Ser Ala Asp Asp Phe Trp Asp Leu Ile Ser 2100 2105 2110 Ser Glu Gln Asp Ala Ile Gly Gly Phe Pro Thr Asp Arg Gly Trp Asp 2115 2120 2125 Leu Asp Thr Leu Tyr Asp Pro Asp Pro Asp His Pro Gly Thr Cys Tyr 2130 2135 2140 Thr Arg Asn Gly Gly Phe Leu Tyr Asp Ala Gly His Phe Asp Ala Glu 2145 2150 2155 2160 Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln 2165 2170 2175 Arg Leu Leu Leu Glu Thr Ala Trp Glu Thr Ile Glu His Ala Gly Ile 2180 2185 2190 Asn Pro His Thr Leu His Gly Thr Pro Thr Gly Val Phe Thr Gly Thr 2195 2200 2205 Asn Gly Gln Asp Tyr Ala Leu Arg Val His Asn Ala Gly Gln Ser Thr 2210 2215 2220 Asp Gly Phe Ala Leu Thr Gly Thr Ala Gly Ser Val Ile Ser Gly Arg 2225 2230 2235 2240 Ile Ser Tyr Thr Phe Gly Phe Glu Gly Pro Ala Val Ser Val Asp Thr 2245 2250 2255 Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala Leu 2260 2265 2270 Arg Ala Gly Glu Cys Ser Met Ala Leu Ala Gly Gly Val Thr Val Met 2275 2280 2285 Ser Ser Pro Gly Ala Phe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala 2290 2295 2300 Ala Asp Gly His Cys Lys Ala Phe Ser Ala Ala Ala Asp Gly Thr Gly 2305 2310 2315 2320 Trp Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala 2325 2330 2335 His Arg Asn Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val 2340 2345 2350 Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ser 2355 2360 2365 Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu Ser Ala 2370 2375 2380 Gly Asp Val Asp Ala Val Glu Ala His Gly Thr Gly Thr Thr Leu Gly 2385 2390 2395 2400 Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Asp Arg 2405 2410 2415 Ala Gly Glu Gly Pro Leu Trp Leu Gly Ser Val Lys Ser Asn Val Gly 2420 2425 2430 His Thr Gln Ala Ala Ala Gly Val Ala Gly Val Ile Lys Met Val Met 2435 2440 2445 Ala Leu Arg His Gly Leu Leu Pro Arg Thr Leu His Val Asp Glu Pro 2450 2455 2460 Ser Pro His Val Asp Trp Ser Ala Gly Ala Val Gln Leu Leu Thr Glu 2465 2470 2475 2480 Thr Val Pro Trp Pro Gly Gly Glu Gly Arg Leu Arg Arg Ala Gly Val 2485 2490 2495 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Glu 2500 2505 2510 Ala Pro Ala Asp Asp Val Pro Gly Gly Pro Pro Ala Gly Glu Gly Asp 2515 2520 2525 Ala Gly Ser Asp Asp Glu Ala Ala Ala Gly Ser Pro Gly Val Trp Pro 2530 2535 2540 Trp Leu Val Ser Ala Lys Ser Gln Pro Ala Leu Arg Ala Gln Ala Gln 2545 2550 2555 2560 Ala Leu His Ala His Leu Thr Asp His Pro Gly Leu Asp Leu Ala Asp 2565 2570 2575 Val Gly Tyr Thr Leu Ala His Ala Arg Ala Val Phe Asp His Arg Ala 2580 2585 2590 Thr Leu Ile Ala Ala Asp Arg Asp Thr Phe Leu Gln Ala Leu Gln Ala 2595 2600 2605 Leu Ala Ala Gly Glu Pro His Pro Ala Val Ile His Ser Ser Ala Pro 2610 2615 2620 Gly Gly Thr Gly Thr Gly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys 2625 2630 2635 2640 Ser Gly Gln Gly Thr Gln Arg Pro Gly Met Ala His Gly Leu Tyr His 2645 2650 2655 Thr His Pro Val Phe Ala Ala Ala Leu Asn Asp Ile Cys Thr His Leu 2660 2665 2670 Asp Pro His Leu Asp His Pro Leu Leu Pro Leu Leu Thr Gln Asn Asp 2675 2680 2685 Asn Asp Asn Glu Asp Ala Ala Ala Leu Leu Gln Gln Thr Arg Tyr Ala 2690 2695 2700 Gln Pro Ala Leu Phe Ala Phe Gln Val Ala Leu His Arg Leu Leu Thr 2705 2710 2715 2720 Asp Gly Tyr His Ile Thr Pro His Tyr Tyr Ala Gly His Ser Leu Gly 2725 2730 2735 Glu Ile Thr Ala Ala His Leu Ala Gly Ile Leu Thr Leu Thr Asp Ala 2740 2745 2750 Thr Thr Leu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr Met Pro Pro 2755 2760 2765 Gly Thr Met Thr Thr Leu His Thr Thr Pro His His Ile Thr His His 2770 2775 2780 Leu Thr Ala His Glu Asn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro 2785 2790 2795 2800 Thr Ser Leu Val Ile Ser Gly Thr Pro His Thr Val Gln His Ile Thr 2805 2810 2815 Thr Leu Cys Gln Gln Gln Gly Ile Lys Thr Lys Thr Leu Pro Thr Asn 2820 2825 2830 His Ala Phe His Ser Pro His Thr Asn Pro Ile Leu Asn Gln Leu His 2835 2840 2845 Gln His Thr Gln Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu Ile 2850 2855 2860 Thr Ala Asn Thr Pro Pro Asp Gln Leu Leu Thr Pro His Tyr Trp Thr 2865 2870 2875 2880 Gln Gln Ala Arg Asn Thr Val Asp Tyr Ala Thr Thr Thr Gln Thr Leu 2885 2890 2895 His Gln His Gly Val Thr Thr Tyr Ile Glu Leu Gly Pro Asp Asn Thr 2900 2905 2910 Leu Thr Thr Leu Thr His His Asn Leu Pro Asn Pro Pro Thr Thr Thr 2915 2920 2925 Leu Thr Leu Thr His Pro His His His Pro Gln Thr His Leu Leu Thr 2930 2935 2940 Asn Leu Ala Lys Thr Thr Thr Thr Trp His Pro His His Tyr Thr His 2945 2950 2955 2960 His Asp Asn Gln Pro His Thr His Thr His Leu Asp Leu Pro Thr Tyr 2965 2970 2975 Pro Phe Gln His His His Tyr Trp Leu Glu Ser Thr Gln Pro Gly Ala 2980 2985 2990 Gly Asn Val Ser Ala Ala Gly Leu Asp Pro Thr Glu His Pro Leu Leu 2995 3000 3005 Gly Ala Thr Leu Glu Leu Ala Thr Asp Gly Gly Ala Leu Leu Ala Gly 3010 3015 3020 Arg Leu Ser Leu Arg Ser His Pro Trp Leu Ala Asp His Ala Val Gly 3025 3030 3035 3040 Gly Thr Val Leu Leu Ser Gly Ala Thr Phe Leu Glu Leu Ala Leu His 3045 3050 3055 Ala Gly Thr Tyr Val Gly Cys Asp Arg Val Asp Glu Leu Thr Leu His 3060 3065 3070 Ala Pro Leu Val Val Pro Val Asp Gly Gly Val Ser Val Gln Val Gly 3075 3080 3085 Val Ala Ala Ala Asp Gly Glu Gly Arg Arg Leu Val Ser Val Tyr Ala 3090 3095 3100 Arg Gly Gly Ser Ala Cys Gly Gly Gly Gly Ala Ser Gly Gly Val Trp 3105 3110 3115 3120 Thr Cys His Ala Ser Gly Val Leu Val Glu Ala Ala Ala Gly Gly Val 3125 3130 3135 Val Val Asp Gly Leu Ala Gly Val Trp Pro Pro Arg Gly Ala Val Ala 3140 3145 3150 Val Asp Val Asp Gly Val Arg Asp Arg Leu Ala Gly Ala Gly Cys Val 3155 3160 3165 Leu Gly Pro Val Phe Ser Gly Leu Arg Ala Val Trp Arg Asp Gly Gly 3170 3175 3180 Asp Leu Leu Ala Glu Val Cys Leu Pro Glu Glu Ala Trp Gly Asp Ala 3185 3190 3195 3200 Ala Gly Phe Gly Leu His Pro Ala Leu Leu Asp Gly Val Val Gln Pro 3205 3210 3215 Leu Ser Val Leu Leu Pro Gly Gly Thr Gly Phe Gly Glu Gly Ala Gly 3220 3225 3230 Phe Gly Glu Gly Val Arg Val Pro Ala Val Trp Gly Gly Val Ser Leu 3235 3240 3245 His Arg Ala Gly Val Thr Gly Val Arg Val Arg Val Ser Ala Val Gly 3250 3255 3260 Arg Gly Gly Gly Arg Glu Ala Val Ser Val Val Val Gly Asp Glu Ala 3265 3270 3275 3280 Gly Val Pro Val Ala Ser Val Asp Arg Leu Glu Leu Arg Pro Val Asp 3285 3290 3295 Met Gly Gln Leu Arg Ala Val Ser Val Ser Ala Gly Arg Arg Gly Ser 3300 3305 3310 Leu Tyr Ala Val Gln Trp Ala Glu Val Gly Pro Val Pro Val Cys Gly 3315 3320 3325 Gln Ala Trp Ala Trp His Glu Asp Val Gly Glu Ser Gly Gly Gly Pro 3330 3335 3340 Val Pro Gly Val Val Val Leu Arg Cys Pro Asp Ala Gly Ala Gly Gly 3345 3350 3355 3360 Gly Gly Gly Gly Gly Gly Gly Gly Gly Val Gly Glu Val Val Gly Gly 3365 3370 3375 Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu Glu Arg Phe Ala Gly 3380 3385 3390 Ser Arg Leu Val Val Val Thr Arg Gly Ala Val Val Ala Gly Pro Glu 3395 3400 3405 Asp Gly Pro Val Asp Val Val Gly Ala Ser Val Trp Gly Leu Val Arg 3410 3415 3420 Ser Ala Gln Ala Glu His Pro Asp Arg Phe Val Leu Leu Asp Leu Asp 3425 3430 3435 3440 Thr Asp Thr Gly Thr Asp Leu Asp Thr Gly Ala Gly Ala Gly Trp Gly 3445 3450 3455 Val Asp Gly Gly Arg Val Ala Ala Val Val Ala Cys Gly Glu Pro Gln 3460 3465 3470 Leu Ala Val Arg Gly Glu Arg Leu Leu Ala Ala Arg Leu Lys Arg Leu 3475 3480 3485 Glu Ser Ser Gly Asp Val Pro Ala Gln Arg Ser Gly Asp Thr Arg Ala 3490 3495 3500 Arg Arg Ser Asp Val Pro Ala Gln Arg Ser Gly Gly Val Pro Ala Arg 3505 3510 3515 3520 Arg Ser Val Asp Val Ser Gly Arg Glu Val Leu Pro Trp Leu Ser Gly 3525 3530 3535 Gly Ser Val Leu Val Thr Gly Gly Thr Gly Val Leu Gly Ala Ala Val 3540 3545 3550 Ala Arg His Leu Ala Gly Val Cys Gly Val Arg Asp Leu Leu Leu Val 3555 3560 3565 Ser Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu 3570 3575 3580 Leu Ala Ala Leu Gly Ala Glu Val Arg Ile Val Ala Cys Asp Val Gly 3585 3590 3595 3600 Glu Arg Arg Glu Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly Cys 3605 3610 3615 Pro Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp Asp Ala Thr 3620 3625 3630 Ile Ala Ser Leu Thr Pro Glu Arg Leu Gly Thr Val Phe Ala Ala Lys 3635 3640 3645 Val Asp Ala Ala Leu Leu Leu Asp Glu Leu Thr Arg Gly Met Glu Leu 3650 3655 3660 Ser Ala Phe Val Leu Phe Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala 3665 3670 3675 3680 Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala 3685 3690 3695 Tyr Arg Arg Arg Ala Ala Gly Leu Pro Gly Val Ser Leu Ala Trp Gly 3700 3705 3710 Leu Trp Glu Glu Ala Ser Gly Met Thr Gly His Leu Ala Gly Thr Asp 3715 3720 3725 His Arg Arg Ile Ile Arg Ser Gly Leu His Pro Met Ser Thr Pro Asp 3730 3735 3740 Ala Leu Ala Leu Phe Asp Ala Ala Leu Ala Leu Asp Arg Pro Val Leu 3745 3750 3755 3760 Leu Pro Ala Asp Leu Arg Pro Ala Pro Pro Leu Pro Pro Leu Leu Gln 3765 3770 3775 Asp Leu Leu Pro Ala Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr Thr 3780 3785 3790 Gly Gly Ala Asp Asn Gly Ala Gln Leu His Ala Arg Leu Ala Gly Gln 3795 3800 3805 Thr His Glu Gln Gln His Thr Thr Leu Leu Ala Leu Val Arg Ser His 3810 3815 3820 Ile Ala Thr Val Leu Gly His Thr Thr Pro Asp Thr Ile Pro Pro Asp 3825 3830 3835 3840 Arg Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu 3845 3850 3855 Arg Asn Arg Leu Ser Arg Thr Thr Gly Leu Arg Leu Pro Thr Thr Leu 3860 3865 3870 Ala Phe Asp His Pro Asn Pro Thr Thr Leu Thr His His Leu His Thr 3875 3880 3885 Gln Leu Gln Pro Gln Pro Asp Asn Ala Val Ala Pro Val Leu Ala Glu 3890 3895 3900 Leu Asp Lys Leu Glu Ser Ala Leu Ser Ala Leu Asp Lys Thr Asp Ser 3905 3910 3915 3920 Ala Ser Glu Arg Val Thr Leu Arg Leu Lys Ser Leu Met Leu Arg Trp 3925 3930 3935 Asn Ala Pro Gln His Pro Thr Ala Glu Ser Ala Asp Asp Asp Glu Lys 3940 3945 3950 Phe Thr Ser Ala Thr Glu Ala Glu Ile Phe Lys Phe Ile Asp Asn Asp 3955 3960 3965 Leu Gly Leu Ser 3970 <210> 3 <211> 13032 <212> DNA <213> Artificial Sequence <220> <223> milA1 gene of Streptomyces milbemycinicus <400> 3 ttgcccaaag cccagaacga gttcgcagtg gccggtcatc cgtggatcct ctccgggcac 60 accggaaccg cgctgcgggc ccaggcacgc cggctccacg accatgtcgc cgaccaccct 120 cggctccgtc cggaagacat cgcccacacg ctggcgagca gcggcccggc gctcacccat 180 cgcgcggcgg tgatcgcggc ggaccgggaa ggacatctcc gggggctcga cgcggtggcc 240 cggggtgagg acacccccgg tgtcgtacgg ggcacggcgg ccgcgggcgg cgacggggtc 300 gcgttcgtct tccccggcca gggcacccag tggcccggta tggccgccga tctgctgacg 360 gtctcccccg ccttcagccg ggcggtcgac gcctgcgccg aggcgttcga accgtatgtc 420 tcctggtcac cggaggccgt gctgcggggc gctccgggcg cgccgcccct ggaggggacc 480 gatgtggtgc agccgacgct gttcgccgtc atggtggggc tggccgagct gtggcggact 540 cttggggtga gcccgacgtc gatcgtgggc cactgcatcg gggagatcgc ggcagcccat 600 ctctgcggcg ccctgtcgct gtccgacgcg gcgcgcgtgg tgatcgagag cagccgggcc 660 caggcgacgc tctccgggtc gggtgcgctg atcgcggtcg cgcggtccga ggcgcagctg 720 cttccgttgc tgcggcggtg gccgggcagg ctgacgatcg ccgcggtcaa cggcccgatg 780 gccacggtcg tctccggcga tcggccggcc gccgacgagc tgttggcgga gttcgcccgt 840 gccggtgtcc gggcccgcga ggtggcgatc gacatccccg cgcactcgcc gttcatggcc 900 cccctcaggg acggtctgct cgactcgctg tcatcggtca ccgcgggtgc gtcgcggctg 960 ccgttccact cctcggtcat cggggggccg ctggagaccc aagggctcga cgcggcttac 1020 tggtaccgga acctcgccga cacggtccgc ttcgaaagcg tcgtcacggg gctgctgcgg 1080 cagggcacac gctgcttcgt ggagctgagc ccgcacccga tgctgaccat gtgtgtgcag 1140 gccaccgccg aggaggtggt cggcggtgag cgcgtcgtga tcctgccgac gctgcatcgc 1200 gggcaggccg ccgtcgagtc cgttcgcacc acgctggccg agctgtacgt acggggcgca 1260 ctggatgacc atcgggcggc gttctcggtg ccgggcggcc gcctgatcac cctgcctctc 1320 gagccgcccg cggacacgtc cgtagagctc gccgacgccc cggacccggc ggaggcctgc 1380 cggcccccct tggtggagcg gcttgcccgg ctctccaccg cggagcggaa gcggcggctg 1440 cgcgagctgg tgggcgtcga ggcggccaag gtcctcgagg acgtcgccgg ggcggacgcg 1500 ccgggccacg gcatcgcgga gcaggagcac ttcgtcactt cgggcttcga ctccgcggcc 1560 gcggtcgcgc tgcgcaaccg cctgaacgac gccaccggtt tgctgctgcc cttcaccctg 1620 gccttcgacc atccgacacc cgccgccgtc gccgaccatc tgcactcccg gctcttcgat 1680 caccagggcg gcgggcagcc gggcgccgac ggccggcccg accccgcggc ggcggccggt 1740 ccggccaggg ccgacgacga gccgatcgcc gtcatcggca tggcgggccg cttccccggg 1800 ggcgcccgta ccccggagga gctgtgggaa ctggtcgccg aaggcaccga cgccctctcg 1860 cccttcccgg agggccgggg ctgggatccg ctgcggctct acgatccgga ccccgcccgg 1920 cccggcacgt actaccagcg cgaagcggga ttcctccacg acgccgacaa gttcgacgcc 1980 gagttcttcg gcatcgcgcc acgcgaggcc accgcaatgg atccccagca gcggctgctc 2040 ctggagacct cctgggaggc gctcgaacgg gcgcggatcg acccgaccgc gctgcgcggc 2100 agccgcaccg gggtgttcgt cggcgtggcc ccgctggact acagcccccg aatgcaccag 2160 gcgtcgccgg agctggaggg ccatctgctg accggcaaca tcggcgccgc ggcctcgggg 2220 cggatctcct acgtactcgg gcttgagggg cccgcggtgt ccgtggacac ggcgtgctcg 2280 tcgtccctgg tcgccctgca tctggcggcc caggcgctgc gggccgggga gtgctcgctg 2340 gccctggtcg gcggggcgac ggtcctctcg acccccggca tgttcatcga gttctcgcgg 2400 cagcgcggtc tggctccgga cggccgctgc aaggcgtacg cggccgccgc ggacggcacc 2460 ggctggtccg agggtgtggg catgctgctc gtcgagcggc tgtccgacgc gcgacggctc 2520 ggacaccagg tgcttgcggt ggtacggggc tccgccgtca accaggacgg ggcgagcaac 2580 ggcttcacgg cgcccagcgg tccatcacag caacaggtca tccgggcggc cctggccaat 2640 gccggggtgt cggctccgga ggtcgacgcg gtggaggggc acggcaccgg cacccggttg 2700 ggcgatccga tcgaggcgca ggcgctgctg gccgcctacg ggcaggggcg ggcggccgac 2760 cggccgctgt ggctggggtc gatcaagtcg aacatcggac acacccagtg ggccgcgggt 2820 gtcatcgggg tcatcaaaat ggtgctcgcg ctccagcacg gtgtgctgcc gcgcacgctg 2880 cacgtggaca agccgtcgga ttacgtggac tggtcggccg gggccgtacg gctgttgacg 2940 gagccggtgc cctggccgga gcggggccac ccgcgccggg cgggggtgtc gtccttcggg 3000 gtgagcggca ccaacgccca tgtcatcctc gagcaggcaa cgccatcgtc cacggtggct 3060 cccggggggc ataccgccga ggccgggcct cccctgccgt gggtggtctc ggcgaagacg 3120 ccccaggcac tgcgcgacca ggcccgccgc ctgcacgaac acctcaccgc ccagccacag 3180 ctccaaccgg ccgacgtcgg ccacaccctc gccaccggcc gcgccacctt cgaccaccgg 3240 gccgtcctca tcggctccga ccgcgaacaa ctcctccacg gcctggacgc gctcgccacc 3300 ggccggcccg acccagcggt ccaccagacg tcggaccgtc ccgccaccgc cgacggccgt 3360 atcgtcttcg tcttccccgg acaaggcggt caatgggcgg gcatgggcct acggctgctg 3420 aacgcctcac ccgtcttcac cgagcggatg gccgcctgcg aacaggccct ctccccctac 3480 gtcgactggt cactcacgga catcctccac cggccggccg acgacgccgt atggcaacgc 3540 gccgacatcg tccagcccgc cctgttctcg atcatggtgt ccctggccgc gctctggcgc 3600 tcttgcggca tcgaaccgga cgccgtcctc ggccactccc aaggcgagat cgccgcggcc 3660 cacgtctgcg gcgccctgac gctccacgac gcggccaagg tcatcgccct gcgcagccag 3720 gccctccaag ccgtacgcgg cgccgggggc atggcctccg tacccctgcc cgcggaccag 3780 gtcaccgagg atctgcgcac ccactggccc gaccggctat gggtggccgc caccaactcc 3840 cccacggcaa ccgtcatctc gggaaacacc gacgcgcttg acgaagcgct cgaccactac 3900 cacgcccacg acgtacgggc caagcgcatc ccggtcgact acgcctccca ctgcccccat 3960 atcgacgcgg tggccgagcg actgcccgac ctgctgggcg gcatcgtccc gcgcgccgcc 4020 gacatcccct tctactccac ggttgacggc cgatgggccg agccgaccga gctcgacgcc 4080 gactactggt accgcaacct ccgcagcccg gtacggttcg cccacgccgt ccacgccctc 4140 accgagaccg accaccgcac ctttgtcgaa gtcagcccac accccacgct cacccccgcc 4200 atcacggcca ccaccgaaac caccgaccgc accaccaccg tcatcgcctc gctccaccgc 4260 gaccacgacg acacccacca catcctcacc aacctcgccc aggcccacat ccacggccac 4320 accatcgact ggcgacacca ctaccagact ctgcgcccca ccccacccca tatcgacctc 4380 cccacctacc ccttccaaca ccaccactac tggctccacg actccaccga ggacaaggcg 4440 gtgggtacgg acctcgccgc ggcccgcttc tgggaggcgg tccacggcga ggacaccaac 4500 gccgtcgccg cgctcctcga cgtcgagccg ggcacctcac tggacgcgct gctgccggcc 4560 ctgtccgcct ggcacggtcg gcgtcgcgac caggccatca ccgacacctg gtgttaccgc 4620 gacatctgga agccggccga cctcaccgcc gcgcgccccc ggccgtccgg ccgatggctt 4680 gtcgcgatct ccgcagggcg ggccgatcac ctccacgtca gtgccgtcct ggacgctctg 4740 gaacgccagg gtctgcccat cgccaccctc gtcctcgacg acacccacac cgaactcccc 4800 ctgctggagc ggcatctcgc acaggcgatc gcgagcgatg ggccggccat cggcggcgtg 4860 ctctcgctgc tcgccctcga cgaggggcca catccgcgcc acccggaggt gcccgtcggc 4920 accgccctca ccctcagcct gatccaggcg ctcatcgcac gcgaggacat ggcgccccgg 4980 ctgtggctgg ccacccacga ggccgtcgcc acctcgtccg cggatacgct cgatcacccc 5040 ctccaggcga tggtctgggg gctgggacgc accgccgcac tcgaacaccc cgatctgtgg 5100 ggcggcctca tcgaccttcc ggacactctc accgaacggg tcctccacgg cctcgtcacg 5160 gcgctgacca cctgtcacga cgaggacgaa ctcgcgctgc gcgccaccgg cccacgcacc 5220 cggcgcctga tccggacgcc gtccaccgcc gcagcggagg acaccccgcc gtggacgccc 5280 cgtggcaccg tcctcatcac cggcggcacc ggggccctgg gctcccgcgt cgcccaccgc 5340 atcgccgaac gccaccccga ctgccacttg ctgctggtga gccggcgagg gcccaaggcc 5400 cccggcgcca ccgcgctccg cgaccagctc atcgaactcg gcgccacggt gaccctcgcc 5460 gcatgtgaca ccgccgaccc cggcgcgctc gcggatctcc tcgccgatgt cccctcggac 5520 cgccccctca ccgcggtcgt ccacaccgcg ggcgtcctgg acgacagcac cctcgccgta 5580 cagaccccgg accacctcgc cgccgttctg gggcccaagt cccatgccgc acaccatctg 5640 cacgccctcg cccagcacca ccccctcgac gcgttcgtcc tcttctcgtc cgtcgcggcg 5700 cccttcggcg ccgcgggcca ggccaactac gcggccgcca acgcctacct cgacgccctc 5760 gcccagcacc gccgggccca ggggctggcc gccacctcca tcgcctgggg caactgggac 5820 ggcgacgggc tcgcgagcac acagtccgcg cagacgtacc tgcgcaaccg cggctttcct 5880 ccgatgccgc cacacctggc gctggccgcc ctggagcgag ccatcgtctc gccccacgcc 5940 cagctcgtcg tcgccgacgt cgactggaag aagctcaagc cggcgccgca cacccgcgac 6000 atcccgggaa gccgccgccc ggccccggcc gccaccgacg gcgcggacag gacggccgac 6060 gccaccgcga gcctccgtac ccgcctcgcg ggtcagagcc cggccgaacg gcaccagacg 6120 ctcctcgacc tcatcagctc tcatacagcc gccgtcctcg ggcacgccac gccccagacg 6180 atccccacgg accgggcctt ccgcgacctg ggtttcacct cgctgacggc catcgagctc 6240 cgcaaccgcc tcgcggcggc caccgggctc cgcctgccga ccaccgtcgc cttcgaccgt 6300 ccgacgccgg acaagctcgc ggccgacctg ctggcgcggt gcgcgccgac aggcccggac 6360 ggcatcgggg tgacgcccga cgcgacggcc acgagtggca gttcgcccgg tgcggcgcat 6420 ggcgcgccgg accccgccga gcccatcgcc atcgtcggct tggcctgccg ctaccccggc 6480 gggatcggct cccccgagga cctgtgggag ttcatcaccg cacaccggga cgccgtcgga 6540 gacttcccga ccgaccgggg ctgggacctg gcgaggctct tcgaccccga tccggaccgg 6600 ccgggcacct cgtacagccg acagggcgcc ttcctccgcg acgcgggcga cttcgacccg 6660 gagttcttcg ggatcagccc acgggaggcg acggcgacgg acccccagca gcgactgctc 6720 ctggaggcgt cctgggaagc cctcgaacga gccgggatca acccccacga tctccacggc 6780 agtccgacgg gcgtcttcac cggcagcaac gcgcaggact tcagcgcgcg gctgcggcag 6840 acgccgtcgg agctggcgga gctgtgcgag ggctatgcgc tgactggcag caacaacagc 6900 gtcgcctcgg ggcgcgtctc gtacgcgctc ggcctggaag gcccggcggt cagcatcgac 6960 accgcctgct cgtcctcgct cgtggcgctc catctggcct gccagtcgct ccgggccggc 7020 gaatgctcgc tggccctggc gggcggcgtc acggtcatga tgaccccgtt caacttcgtg 7080 gagttctccc ggcagcgggg cctggcggcg gacggccggt gcaaggcgtt ctccgccaca 7140 gccgatggca ccggctgggg cgagggcgtg ggcatggtgg tggtggagcg gctgtcggac 7200 gcgcggcgca acggccatcg tgtgctggcc ctcgtccgcg gcagcgccgt caaccaggac 7260 ggtgccagca atgggctgac tgccccgaac ggcccctcgc agcagcgggt catccgcgcc 7320 gccctggccg ccgccggggt cgccgcggca gaagtggacg cggtcgaggc gcacggcacg 7380 gggacgacgc tcggcgatcc gatcgaggcc caggccctgc tcgccaccta cgggcagggg 7440 cggccggcgg accgggcgct gtggctcggt acggtcaagt ccaacatcgg acacgcccag 7500 tcggccgccg gtatcgccgg ggtcatcaag atggtgctgg ccctgcggca cgggatgctg 7560 ccgcgtacgc tgcatgtgtc cgagccgtcg ccgcatgtgg actggtcggc gggtgcggta 7620 cggctgctga ccgaggacca gccgtggccg gacaccgggc gcccccggcg ggcgggggtg 7680 tcgtccttcg gcgtgagcgg caccaatgcc catgtgatcc tggagcaggc ggagccgggg 7740 ccggacccgg caccgacggc ctccgcgccc tccctgcccc cctggcccct ctccgccagg 7800 tcggcggagg ccctgcgggc ccaggcccgt aggttgctgg cgtacgtggc cgagcacccg 7860 gatgtcgacc ccgccgacgt ggggtactcc ctcgcgcgcg gacgggccgt gttcgagcac 7920 cgggccgtgc tcctcggcac cggccacgac gacttccggc gcgccctgga cgccctggcg 7980 tcgggcgcgc ccgacggcgc ggtcgtccag ggcgcggcgg tggggcggca gggcaaggtc 8040 gtctttgtgt gctcggggca gggcacccag cgccccggca tgggccgcgg gctctaccgc 8100 tcgtccacgg cgttcgccgg ggcgctggag gaggtgtgcg cccatctgga cccgtatctg 8160 gaacaccctc tgatggaggt gatgttcgcc gatgagaaga gcgatacgtc ggcgctgctg 8220 catctgaccg cctacgccca accggccctc ttcgccctcc agaccgcgct gcaccgcatg 8280 gtcaccgagg agttcgggct cacccccgac tatctggccg gccactccct gggcgagctg 8340 accgccgccc atctggcggg catcctcagc ctgcccgacg ccgcggcgct ggtggcggcc 8400 cgcgcccgcg ccatgcggga ccttccagcg accggagcca tggtcgccgt cgaggccacc 8460 gaggcggagc tgcggccccg gctcgccgag ttggcggacc gggtcggcat cgccgccgtc 8520 aacgcccccg cgtccctggt catcaccggc gaccacgacg ccgtgcacca gatcgccgac 8580 gacttccgcg ggcagggcag gaaggtcact cccctccagg tcagcggcgc cttccactct 8640 ccccatatgg agcccctgct cgacgagatc gggcgcaccg ccgaaaccct cacctaccac 8700 cggccccaca ctcccctcgt caccgcgtcg gccgacggcg gcgacgacac gaccgagccg 8760 cgggccgacg acgacccggg cacggccgcg ttctggcctc tccaggcccg gcgcaccgtc 8820 cactacgcgc gggccgtgga gcggctgcgc gcccgcggcg tcaccacgtt cctggaactc 8880 ggccccgact ccaccctcac taccctcgtc caccacaatc tcgccgcgca cgatcccgtg 8940 gccgtctccc tgctccatcc ggagcggtgc gagacgcaca gcgtcctcgg cgcactcgcc 9000 gcggtccacg cccacagccg ccccgtcgac tggacacgcc actacaccgc acggccgcgg 9060 ccgacgccac accagatcga cgtgcccacc tatgccttcc ggcaccggcg ctactggctg 9120 cccgccccgg cggcggtcgg cgatgtgacg gccgcggggc tcgacgcggc ggagcacccg 9180 ctgatcggcg ccgccgtgtg gctcgcggag ggcgacggct gtctgctgac cggcaggatc 9240 tcgccgcgta cgcacccgtg gctggccgac catgtcatcg ccggcactgt gctccttccg 9300 ggcaccgcgt tcgtggagct ggcgctgcgg gccggggcgt acgtgggctg cgaccgtgtg 9360 gaggagctga ccctgcacgc gccactcccg ctgcccgccg acggtgaggt ggtgctgcag 9420 gtggcggtgg gggccgccga cgagtccggc cgccgtgagc tgagcatcca cgcccggccg 9480 gcggacgacg gtacatggac acggcacgcc atcggcacgc tggcatcggc ccgcggcgtc 9540 ggcctcgacg atggcacggg gcacaatggc cacgccccgg cgggcgacga gccgttcggg 9600 tcgtgggcca cggcctggcc gccgcccggt gccgagccct tggacgtcac cggggtctac 9660 gaccggtttg ccgacgccga gttcacgtac ggggaggcat tccaggggct ggtcgcggct 9720 tggcggcacg gcgacgagac gctggcggag gtccgcctcc ccgaccagcc ggccggtgac 9780 gccctccgct tcgggctgca ccccgcgctg ctcgacgcgg cactgcagac catgtggctc 9840 gtggagcccg acggcacacg gccgagcggt ggcctgggcg gccccgatcg gggcctgccg 9900 ttcgcctggc agggggtctc gctgcgtacg gcgggcccgt cggccctgcg ggtacggctg 9960 cgacggccgg cgccggacac cgtggccgtc gccgtggccg acgcggccgg ccggccggtc 10020 gcgtcggtgg agtcgctgac gctgcggccg gtgccgcggg gcgccttgcg cggcaccgag 10080 acggcggtgc gcacctcgtt gtacggcctg gactggacgg atgtgccgct gccgacgccg 10140 cagacggccc tgccccggtg tgcgctgatc ggagcggaca cgctcgacct ggtccccgcg 10200 ctcgaggccg cggcgcccga ccgcatcacc gacggcgtgg agcgctacgc cgacctggag 10260 gagctggtgc gctccgtggc ggcgggcgcc cccgccccgg acctcgtcat cgccggctgc 10320 cacgcagccc ctgaagccga cggcgcgagc gaacagccac agcccgagac ggtgcgcaca 10380 aggacgggtc aggtgctgga gctgcttcag cggtggctcg gcgcggacgg gctcgccgac 10440 gcacacctgg tgctgttcac ctcaggcgcg gtcgccaccc ggccgggcga gccggtgcgg 10500 gacctggcgg gggcggcggt ctggggtctg gtgcgctccg gccagtcgga gcatccggag 10560 tgcttcaccg tggtggacat ggacggcgcc caggagtccc gcgcggcgct gctcggcgcg 10620 ctcggcctcg gcgagccgca actggcggtg cgcggcggcc gggcgctggc gccgcgcctg 10680 gtgcgcccgg gtgacgccga cgacgacagc ggcctggccc tgccgcaggg gccggaaggc 10740 tggcggttgg agtgtcccgg cacgggcagc ctggacgggt tgaccacgac cgagtccccg 10800 gccgcggcgg tgccgctcgg cccgggcgag gtacgggtcg cggtgcgggc cgcggggctg 10860 aacttccgcg atgtgctgat cgcgctgggc gtggtgcccg ggcggacggc gctgggcagt 10920 gagggggcgg ggatcgtcct cgaggtcggg gcggaggtcc gcgatctcgc gcccggggac 10980 cgggtggtgg gtatcttccc cgaggcgttc ggcccggtgg ccgtggccga gcgggcgacc 11040 ctggcgcggg tccccgacgg ctggtcgttc gcccaggccg cgtcggtccc catcgtgttc 11100 gccaccgcgt accacggcct ggtcgatctg gcgcgcctgc ggccggggga atcggtgctg 11160 atccatgccg cggccggcgg ggtgggcatg gccgccgtgc aactggcgcg ccatctgggg 11220 gccgaggtgt acgccacggc cggccccggc aagtggcaca tcctgcgttc ccaaggcatc 11280 gacgacgacc atctggcctc gtcgcgcacg ctggagttcg agcagcgctt cgccgcgacc 11340 cgcggcgggc gggggatcga tgtcgtcctg gactgtctgg cccatgagtt cgtcgacgcc 11400 tcgctgcgcc tggtggcgcg tgacggcggc cggttcctgg agatgggcaa gagcgacatc 11460 cgtgacccgc ggcaggtggc gctggaccat ccgggcgtgc tctaccgggc gttcgacctg 11520 ctggaggccg ggccggagcg ggtcgggcag atcctgcgca ccgtactgga cctgttcgag 11580 cgcggtgtcc tggcgcacct gccgacgacc tgctgggaca tccggcaggc ggagcacgcc 11640 ttccgccatc tgcagcaggg ccgtcacatc ggaaagaacg tgctcaccgt cccggccggc 11700 tggaacgccg agggcaccgt actgatcacc ggcggtatgg gcaccctggg cgccgccctc 11760 gcccgtcatc tggcgggtac cgggcgcgcc cgccatctgc tgctggccgg ccgacgcggc 11820 cccgacgccc cgggcgccga ggagctgcga gaggagctga ccgagctggg cgcgcgggtc 11880 accatcgccg catgcgatct cggcgaccgg gcggcggtcg cccggctcct gggggcgatc 11940 ccggccgagc ggccgctgac cgctgtcatc cacgcggcgg gtgtcgtcga cgatgccacc 12000 ctcgggtccc tcaccccccg ccacctggac gccgccctgg ccgccaaggc cgacgccgcc 12060 tggcatctgc acaccctcac ccgccacgcc gacgtggccg cgttcgtcct cttctcctcg 12120 gtcgcgggtc tgctcggctc gcccgggcag ggcaactacg ccgcggccaa cgccttcttg 12180 gacgcgctcg cccaccaccg gcgcggctct ggccttccgg cggtgtcgct ggcgtggggg 12240 ctgtgggagc agaccagcgg catgaccggg cacctggacc aggccgaccg cgcccggctg 12300 gcccggctcg gcatcagccc gctcacgacc gggcaggcgc tcggcctttt cgacgccgcc 12360 ctcggccacc accgccccgt gctcgtcccc gcccgcctcg acgtgcccga tccgcacccc 12420 ggctcgtcga ccgtgccgcc cctgtaccgg ggcctggtcg gatccaggac ccggcggaca 12480 ccccccgcgg ccgccgccac cgggccgttc cccctgcata cccgcctcgg cggtcacgcc 12540 ccggccgagc agcacgagat gctgctctcg ctggtccgct cccacgccgc cctcgtgctg 12600 ggccgcgacg atccggacac ggtccatccc ggcgcgcact tccgcggcct gggcttcgac 12660 tccctgaccg cggtcgagct ccgcaaccgg ctcaacgccg ccaccggcct ccggctctcc 12720 accaccctcg tcttcgacca ccccacgccc gacgaactcg cccgtcacgt ccgggagcag 12780 gtgctgggcg acggcgaagc ggcgcgggtg gccccggtgc tggccgagct cgacaggctg 12840 gaagcggcgc tgtcccgggt ggacggggac gatgcggtcc gggcgagggt gacggcccgg 12900 ttgcaggccc ttctcctgaa gtggaacgag tccgatggtc cggcgacggg cggtgacggt 12960 gcgggcaggc tggcgtccgc cacggccgcc gaggtgctgg atttcatcag gaacgacctc 13020 ggcctctcct ga 13032 <210> 4 <211> 4343 <212> PRT <213> Artificial Sequence <220> <223> milA1 of Streptomyces milbemycinicus <400> 4 Leu Pro Lys Ala Gln Asn Glu Phe Ala Val Ala Gly His Pro Trp Ile 1 5 10 15 Leu Ser Gly His Thr Gly Thr Ala Leu Arg Ala Gln Ala Arg Arg Leu 20 25 30 His Asp His Val Ala Asp His Pro Arg Leu Arg Pro Glu Asp Ile Ala 35 40 45 His Thr Leu Ala Ser Ser Gly Pro Ala Leu Thr His Arg Ala Ala Val 50 55 60 Ile Ala Ala Asp Arg Glu Gly His Leu Arg Gly Leu Asp Ala Val Ala 65 70 75 80 Arg Gly Glu Asp Thr Pro Gly Val Val Arg Gly Thr Ala Ala Ala Gly 85 90 95 Gly Asp Gly Val Ala Phe Val Phe Pro Gly Gln Gly Thr Gln Trp Pro 100 105 110 Gly Met Ala Ala Asp Leu Leu Thr Val Ser Pro Ala Phe Ser Arg Ala 115 120 125 Val Asp Ala Cys Ala Glu Ala Phe Glu Pro Tyr Val Ser Trp Ser Pro 130 135 140 Glu Ala Val Leu Arg Gly Ala Pro Gly Ala Pro Pro Leu Glu Gly Thr 145 150 155 160 Asp Val Val Gln Pro Thr Leu Phe Ala Val Met Val Gly Leu Ala Glu 165 170 175 Leu Trp Arg Thr Leu Gly Val Ser Pro Thr Ser Ile Val Gly His Cys 180 185 190 Ile Gly Glu Ile Ala Ala Ala His Leu Cys Gly Ala Leu Ser Leu Ser 195 200 205 Asp Ala Ala Arg Val Val Ile Glu Ser Ser Arg Ala Gln Ala Thr Leu 210 215 220 Ser Gly Ser Gly Ala Leu Ile Ala Val Ala Arg Ser Glu Ala Gln Leu 225 230 235 240 Leu Pro Leu Leu Arg Arg Trp Pro Gly Arg Leu Thr Ile Ala Ala Val 245 250 255 Asn Gly Pro Met Ala Thr Val Val Ser Gly Asp Arg Pro Ala Ala Asp 260 265 270 Glu Leu Leu Ala Glu Phe Ala Arg Ala Gly Val Arg Ala Arg Glu Val 275 280 285 Ala Ile Asp Ile Pro Ala His Ser Pro Phe Met Ala Pro Leu Arg Asp 290 295 300 Gly Leu Leu Asp Ser Leu Ser Ser Val Thr Ala Gly Ala Ser Arg Leu 305 310 315 320 Pro Phe His Ser Ser Val Ile Gly Gly Pro Leu Glu Thr Gln Gly Leu 325 330 335 Asp Ala Ala Tyr Trp Tyr Arg Asn Leu Ala Asp Thr Val Arg Phe Glu 340 345 350 Ser Val Val Thr Gly Leu Leu Arg Gln Gly Thr Arg Cys Phe Val Glu 355 360 365 Leu Ser Pro His Pro Met Leu Thr Met Cys Val Gln Ala Thr Ala Glu 370 375 380 Glu Val Val Gly Gly Glu Arg Val Val Ile Leu Pro Thr Leu His Arg 385 390 395 400 Gly Gln Ala Ala Val Glu Ser Val Arg Thr Thr Leu Ala Glu Leu Tyr 405 410 415 Val Arg Gly Ala Leu Asp Asp His Arg Ala Ala Phe Ser Val Pro Gly 420 425 430 Gly Arg Leu Ile Thr Leu Pro Leu Glu Pro Pro Ala Asp Thr Ser Val 435 440 445 Glu Leu Ala Asp Ala Pro Asp Pro Ala Glu Ala Cys Arg Pro Pro Leu 450 455 460 Val Glu Arg Leu Ala Arg Leu Ser Thr Ala Glu Arg Lys Arg Arg Leu 465 470 475 480 Arg Glu Leu Val Gly Val Glu Ala Ala Lys Val Leu Glu Asp Val Ala 485 490 495 Gly Ala Asp Ala Pro Gly His Gly Ile Ala Glu Gln Glu His Phe Val 500 505 510 Thr Ser Gly Phe Asp Ser Ala Ala Ala Val Ala Leu Arg Asn Arg Leu 515 520 525 Asn Asp Ala Thr Gly Leu Leu Leu Pro Phe Thr Leu Ala Phe Asp His 530 535 540 Pro Thr Pro Ala Ala Val Ala Asp His Leu His Ser Arg Leu Phe Asp 545 550 555 560 His Gln Gly Gly Gly Gln Pro Gly Ala Asp Gly Arg Pro Asp Pro Ala 565 570 575 Ala Ala Ala Gly Pro Ala Arg Ala Asp Asp Glu Pro Ile Ala Val Ile 580 585 590 Gly Met Ala Gly Arg Phe Pro Gly Gly Ala Arg Thr Pro Glu Glu Leu 595 600 605 Trp Glu Leu Val Ala Glu Gly Thr Asp Ala Leu Ser Pro Phe Pro Glu 610 615 620 Gly Arg Gly Trp Asp Pro Leu Arg Leu Tyr Asp Pro Asp Pro Ala Arg 625 630 635 640 Pro Gly Thr Tyr Tyr Gln Arg Glu Ala Gly Phe Leu His Asp Ala Asp 645 650 655 Lys Phe Asp Ala Glu Phe Phe Gly Ile Ala Pro Arg Glu Ala Thr Ala 660 665 670 Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser Trp Glu Ala Leu 675 680 685 Glu Arg Ala Arg Ile Asp Pro Thr Ala Leu Arg Gly Ser Arg Thr Gly 690 695 700 Val Phe Val Gly Val Ala Pro Leu Asp Tyr Ser Pro Arg Met His Gln 705 710 715 720 Ala Ser Pro Glu Leu Glu Gly His Leu Leu Thr Gly Asn Ile Gly Ala 725 730 735 Ala Ala Ser Gly Arg Ile Ser Tyr Val Leu Gly Leu Glu Gly Pro Ala 740 745 750 Val Ser Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu 755 760 765 Ala Ala Gln Ala Leu Arg Ala Gly Glu Cys Ser Leu Ala Leu Val Gly 770 775 780 Gly Ala Thr Val Leu Ser Thr Pro Gly Met Phe Ile Glu Phe Ser Arg 785 790 795 800 Gln Arg Gly Leu Ala Pro Asp Gly Arg Cys Lys Ala Tyr Ala Ala Ala 805 810 815 Ala Asp Gly Thr Gly Trp Ser Glu Gly Val Gly Met Leu Leu Val Glu 820 825 830 Arg Leu Ser Asp Ala Arg Arg Leu Gly His Gln Val Leu Ala Val Val 835 840 845 Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly Phe Thr Ala 850 855 860 Pro Ser Gly Pro Ser Gln Gln Gln Val Ile Arg Ala Ala Leu Ala Asn 865 870 875 880 Ala Gly Val Ser Ala Pro Glu Val Asp Ala Val Glu Gly His Gly Thr 885 890 895 Gly Thr Arg Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Ala 900 905 910 Tyr Gly Gln Gly Arg Ala Ala Asp Arg Pro Leu Trp Leu Gly Ser Ile 915 920 925 Lys Ser Asn Ile Gly His Thr Gln Trp Ala Ala Gly Val Ile Gly Val 930 935 940 Ile Lys Met Val Leu Ala Leu Gln His Gly Val Leu Pro Arg Thr Leu 945 950 955 960 His Val Asp Lys Pro Ser Asp Tyr Val Asp Trp Ser Ala Gly Ala Val 965 970 975 Arg Leu Leu Thr Glu Pro Val Pro Trp Pro Glu Arg Gly His Pro Arg 980 985 990 Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val 995 1000 1005 Ile Leu Glu Gln Ala Thr Pro Ser Ser Thr Val Ala Pro Gly Gly His 1010 1015 1020 Thr Ala Glu Ala Gly Pro Pro Leu Pro Trp Val Val Ser Ala Lys Thr 1025 1030 1035 1040 Pro Gln Ala Leu Arg Asp Gln Ala Arg Arg Leu His Glu His Leu Thr 1045 1050 1055 Ala Gln Pro Gln Leu Gln Pro Ala Asp Val Gly His Thr Leu Ala Thr 1060 1065 1070 Gly Arg Ala Thr Phe Asp His Arg Ala Val Leu Ile Gly Ser Asp Arg 1075 1080 1085 Glu Gln Leu Leu His Gly Leu Asp Ala Leu Ala Thr Gly Arg Pro Asp 1090 1095 1100 Pro Ala Val His Gln Thr Ser Asp Arg Pro Ala Thr Ala Asp Gly Arg 1105 1110 1115 1120 Ile Val Phe Val Phe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met Gly 1125 1130 1135 Leu Arg Leu Leu Asn Ala Ser Pro Val Phe Thr Glu Arg Met Ala Ala 1140 1145 1150 Cys Glu Gln Ala Leu Ser Pro Tyr Val Asp Trp Ser Leu Thr Asp Ile 1155 1160 1165 Leu His Arg Pro Ala Asp Asp Ala Val Trp Gln Arg Ala Asp Ile Val 1170 1175 1180 Gln Pro Ala Leu Phe Ser Ile Met Val Ser Leu Ala Ala Leu Trp Arg 1185 1190 1195 1200 Ser Cys Gly Ile Glu Pro Asp Ala Val Leu Gly His Ser Gln Gly Glu 1205 1210 1215 Ile Ala Ala Ala His Val Cys Gly Ala Leu Thr Leu His Asp Ala Ala 1220 1225 1230 Lys Val Ile Ala Leu Arg Ser Gln Ala Leu Gln Ala Val Arg Gly Ala 1235 1240 1245 Gly Gly Met Ala Ser Val Pro Leu Pro Ala Asp Gln Val Thr Glu Asp 1250 1255 1260 Leu Arg Thr His Trp Pro Asp Arg Leu Trp Val Ala Ala Thr Asn Ser 1265 1270 1275 1280 Pro Thr Ala Thr Val Ile Ser Gly Asn Thr Asp Ala Leu Asp Glu Ala 1285 1290 1295 Leu Asp His Tyr His Ala His Asp Val Arg Ala Lys Arg Ile Pro Val 1300 1305 1310 Asp Tyr Ala Ser His Cys Pro His Ile Asp Ala Val Ala Glu Arg Leu 1315 1320 1325 Pro Asp Leu Leu Gly Gly Ile Val Pro Arg Ala Ala Asp Ile Pro Phe 1330 1335 1340 Tyr Ser Thr Val Asp Gly Arg Trp Ala Glu Pro Thr Glu Leu Asp Ala 1345 1350 1355 1360 Asp Tyr Trp Tyr Arg Asn Leu Arg Ser Pro Val Arg Phe Ala His Ala 1365 1370 1375 Val His Ala Leu Thr Glu Thr Asp His Arg Thr Phe Val Glu Val Ser 1380 1385 1390 Pro His Pro Thr Leu Thr Pro Ala Ile Thr Ala Thr Thr Glu Thr Thr 1395 1400 1405 Asp Arg Thr Thr Thr Val Ile Ala Ser Leu His Arg Asp His Asp Asp 1410 1415 1420 Thr His His Ile Leu Thr Asn Leu Ala Gln Ala His Ile His Gly His 1425 1430 1435 1440 Thr Ile Asp Trp Arg His His Tyr Gln Thr Leu Arg Pro Thr Pro Pro 1445 1450 1455 His Ile Asp Leu Pro Thr Tyr Pro Phe Gln His His His Tyr Trp Leu 1460 1465 1470 His Asp Ser Thr Glu Asp Lys Ala Val Gly Thr Asp Leu Ala Ala Ala 1475 1480 1485 Arg Phe Trp Glu Ala Val His Gly Glu Asp Thr Asn Ala Val Ala Ala 1490 1495 1500 Leu Leu Asp Val Glu Pro Gly Thr Ser Leu Asp Ala Leu Leu Pro Ala 1505 1510 1515 1520 Leu Ser Ala Trp His Gly Arg Arg Arg Asp Gln Ala Ile Thr Asp Thr 1525 1530 1535 Trp Cys Tyr Arg Asp Ile Trp Lys Pro Ala Asp Leu Thr Ala Ala Arg 1540 1545 1550 Pro Arg Pro Ser Gly Arg Trp Leu Val Ala Ile Ser Ala Gly Arg Ala 1555 1560 1565 Asp His Leu His Val Ser Ala Val Leu Asp Ala Leu Glu Arg Gln Gly 1570 1575 1580 Leu Pro Ile Ala Thr Leu Val Leu Asp Asp Thr His Thr Glu Leu Pro 1585 1590 1595 1600 Leu Leu Glu Arg His Leu Ala Gln Ala Ile Ala Ser Asp Gly Pro Ala 1605 1610 1615 Ile Gly Gly Val Leu Ser Leu Leu Ala Leu Asp Glu Gly Pro His Pro 1620 1625 1630 Arg His Pro Glu Val Pro Val Gly Thr Ala Leu Thr Leu Ser Leu Ile 1635 1640 1645 Gln Ala Leu Ile Ala Arg Glu Asp Met Ala Pro Arg Leu Trp Leu Ala 1650 1655 1660 Thr His Glu Ala Val Ala Thr Ser Ser Ala Asp Thr Leu Asp His Pro 1665 1670 1675 1680 Leu Gln Ala Met Val Trp Gly Leu Gly Arg Thr Ala Ala Leu Glu His 1685 1690 1695 Pro Asp Leu Trp Gly Gly Leu Ile Asp Leu Pro Asp Thr Leu Thr Glu 1700 1705 1710 Arg Val Leu His Gly Leu Val Thr Ala Leu Thr Thr Cys His Asp Glu 1715 1720 1725 Asp Glu Leu Ala Leu Arg Ala Thr Gly Pro Arg Thr Arg Arg Leu Ile 1730 1735 1740 Arg Thr Pro Ser Thr Ala Ala Ala Glu Asp Thr Pro Pro Trp Thr Pro 1745 1750 1755 1760 Arg Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Ala Leu Gly Ser Arg 1765 1770 1775 Val Ala His Arg Ile Ala Glu Arg His Pro Asp Cys His Leu Leu Leu 1780 1785 1790 Val Ser Arg Arg Gly Pro Lys Ala Pro Gly Ala Thr Ala Leu Arg Asp 1795 1800 1805 Gln Leu Ile Glu Leu Gly Ala Thr Val Thr Leu Ala Ala Cys Asp Thr 1810 1815 1820 Ala Asp Pro Gly Ala Leu Ala Asp Leu Leu Ala Asp Val Pro Ser Asp 1825 1830 1835 1840 Arg Pro Leu Thr Ala Val Val His Thr Ala Gly Val Leu Asp Asp Ser 1845 1850 1855 Thr Leu Ala Val Gln Thr Pro Asp His Leu Ala Ala Val Leu Gly Pro 1860 1865 1870 Lys Ser His Ala Ala His His Leu His Ala Leu Ala Gln His His Pro 1875 1880 1885 Leu Asp Ala Phe Val Leu Phe Ser Ser Val Ala Ala Pro Phe Gly Ala 1890 1895 1900 Ala Gly Gln Ala Asn Tyr Ala Ala Ala Asn Ala Tyr Leu Asp Ala Leu 1905 1910 1915 1920 Ala Gln His Arg Arg Ala Gln Gly Leu Ala Ala Thr Ser Ile Ala Trp 1925 1930 1935 Gly Asn Trp Asp Gly Asp Gly Leu Ala Ser Thr Gln Ser Ala Gln Thr 1940 1945 1950 Tyr Leu Arg Asn Arg Gly Phe Pro Pro Met Pro Pro His Leu Ala Leu 1955 1960 1965 Ala Ala Leu Glu Arg Ala Ile Val Ser Pro His Ala Gln Leu Val Val 1970 1975 1980 Ala Asp Val Asp Trp Lys Lys Leu Lys Pro Ala Pro His Thr Arg Asp 1985 1990 1995 2000 Ile Pro Gly Ser Arg Arg Pro Ala Pro Ala Ala Thr Asp Gly Ala Asp 2005 2010 2015 Arg Thr Ala Asp Ala Thr Ala Ser Leu Arg Thr Arg Leu Ala Gly Gln 2020 2025 2030 Ser Pro Ala Glu Arg His Gln Thr Leu Leu Asp Leu Ile Ser Ser His 2035 2040 2045 Thr Ala Ala Val Leu Gly His Ala Thr Pro Gln Thr Ile Pro Thr Asp 2050 2055 2060 Arg Ala Phe Arg Asp Leu Gly Phe Thr Ser Leu Thr Ala Ile Glu Leu 2065 2070 2075 2080 Arg Asn Arg Leu Ala Ala Ala Thr Gly Leu Arg Leu Pro Thr Thr Val 2085 2090 2095 Ala Phe Asp Arg Pro Thr Pro Asp Lys Leu Ala Ala Asp Leu Leu Ala 2100 2105 2110 Arg Cys Ala Pro Thr Gly Pro Asp Gly Ile Gly Val Thr Pro Asp Ala 2115 2120 2125 Thr Ala Thr Ser Gly Ser Ser Pro Gly Ala Ala His Gly Ala Pro Asp 2130 2135 2140 Pro Ala Glu Pro Ile Ala Ile Val Gly Leu Ala Cys Arg Tyr Pro Gly 2145 2150 2155 2160 Gly Ile Gly Ser Pro Glu Asp Leu Trp Glu Phe Ile Thr Ala His Arg 2165 2170 2175 Asp Ala Val Gly Asp Phe Pro Thr Asp Arg Gly Trp Asp Leu Ala Arg 2180 2185 2190 Leu Phe Asp Pro Asp Pro Asp Arg Pro Gly Thr Ser Tyr Ser Arg Gln 2195 2200 2205 Gly Ala Phe Leu Arg Asp Ala Gly Asp Phe Asp Pro Glu Phe Phe Gly 2210 2215 2220 Ile Ser Pro Arg Glu Ala Thr Ala Thr Asp Pro Gln Gln Arg Leu Leu 2225 2230 2235 2240 Leu Glu Ala Ser Trp Glu Ala Leu Glu Arg Ala Gly Ile Asn Pro His 2245 2250 2255 Asp Leu His Gly Ser Pro Thr Gly Val Phe Thr Gly Ser Asn Ala Gln 2260 2265 2270 Asp Phe Ser Ala Arg Leu Arg Gln Thr Pro Ser Glu Leu Ala Glu Leu 2275 2280 2285 Cys Glu Gly Tyr Ala Leu Thr Gly Ser Asn Asn Ser Val Ala Ser Gly 2290 2295 2300 Arg Val Ser Tyr Ala Leu Gly Leu Glu Gly Pro Ala Val Ser Ile Asp 2305 2310 2315 2320 Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ser 2325 2330 2335 Leu Arg Ala Gly Glu Cys Ser Leu Ala Leu Ala Gly Gly Val Thr Val 2340 2345 2350 Met Met Thr Pro Phe Asn Phe Val Glu Phe Ser Arg Gln Arg Gly Leu 2355 2360 2365 Ala Ala Asp Gly Arg Cys Lys Ala Phe Ser Ala Thr Ala Asp Gly Thr 2370 2375 2380 Gly Trp Gly Glu Gly Val Gly Met Val Val Val Glu Arg Leu Ser Asp 2385 2390 2395 2400 Ala Arg Arg Asn Gly His Arg Val Leu Ala Leu Val Arg Gly Ser Ala 2405 2410 2415 Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro 2420 2425 2430 Ser Gln Gln Arg Val Ile Arg Ala Ala Leu Ala Ala Ala Gly Val Ala 2435 2440 2445 Ala Ala Glu Val Asp Ala Val Glu Ala His Gly Thr Gly Thr Thr Leu 2450 2455 2460 Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gly 2465 2470 2475 2480 Arg Pro Ala Asp Arg Ala Leu Trp Leu Gly Thr Val Lys Ser Asn Ile 2485 2490 2495 Gly His Ala Gln Ser Ala Ala Gly Ile Ala Gly Val Ile Lys Met Val 2500 2505 2510 Leu Ala Leu Arg His Gly Met Leu Pro Arg Thr Leu His Val Ser Glu 2515 2520 2525 Pro Ser Pro His Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr 2530 2535 2540 Glu Asp Gln Pro Trp Pro Asp Thr Gly Arg Pro Arg Arg Ala Gly Val 2545 2550 2555 2560 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Gln 2565 2570 2575 Ala Glu Pro Gly Pro Asp Pro Ala Pro Thr Ala Ser Ala Pro Ser Leu 2580 2585 2590 Pro Pro Trp Pro Leu Ser Ala Arg Ser Ala Glu Ala Leu Arg Ala Gln 2595 2600 2605 Ala Arg Arg Leu Leu Ala Tyr Val Ala Glu His Pro Asp Val Asp Pro 2610 2615 2620 Ala Asp Val Gly Tyr Ser Leu Ala Arg Gly Arg Ala Val Phe Glu His 2625 2630 2635 2640 Arg Ala Val Leu Leu Gly Thr Gly His Asp Asp Phe Arg Arg Ala Leu 2645 2650 2655 Asp Ala Leu Ala Ser Gly Ala Pro Asp Gly Ala Val Val Gln Gly Ala 2660 2665 2670 Ala Val Gly Arg Gln Gly Lys Val Val Phe Val Cys Ser Gly Gln Gly 2675 2680 2685 Thr Gln Arg Pro Gly Met Gly Arg Gly Leu Tyr Arg Ser Ser Thr Ala 2690 2695 2700 Phe Ala Gly Ala Leu Glu Glu Val Cys Ala His Leu Asp Pro Tyr Leu 2705 2710 2715 2720 Glu His Pro Leu Met Glu Val Met Phe Ala Asp Glu Lys Ser Asp Thr 2725 2730 2735 Ser Ala Leu Leu His Leu Thr Ala Tyr Ala Gln Pro Ala Leu Phe Ala 2740 2745 2750 Leu Gln Thr Ala Leu His Arg Met Val Thr Glu Glu Phe Gly Leu Thr 2755 2760 2765 Pro Asp Tyr Leu Ala Gly His Ser Leu Gly Glu Leu Thr Ala Ala His 2770 2775 2780 Leu Ala Gly Ile Leu Ser Leu Pro Asp Ala Ala Ala Leu Val Ala Ala 2785 2790 2795 2800 Arg Ala Arg Ala Met Arg Asp Leu Pro Ala Thr Gly Ala Met Val Ala 2805 2810 2815 Val Glu Ala Thr Glu Ala Glu Leu Arg Pro Arg Leu Ala Glu Leu Ala 2820 2825 2830 Asp Arg Val Gly Ile Ala Ala Val Asn Ala Pro Ala Ser Leu Val Ile 2835 2840 2845 Thr Gly Asp His Asp Ala Val His Gln Ile Ala Asp Asp Phe Arg Gly 2850 2855 2860 Gln Gly Arg Lys Val Thr Pro Leu Gln Val Ser Gly Ala Phe His Ser 2865 2870 2875 2880 Pro His Met Glu Pro Leu Leu Asp Glu Ile Gly Arg Thr Ala Glu Thr 2885 2890 2895 Leu Thr Tyr His Arg Pro His Thr Pro Leu Val Thr Ala Ser Ala Asp 2900 2905 2910 Gly Gly Asp Asp Thr Thr Glu Pro Arg Ala Asp Asp Asp Pro Gly Thr 2915 2920 2925 Ala Ala Phe Trp Pro Leu Gln Ala Arg Arg Thr Val His Tyr Ala Arg 2930 2935 2940 Ala Val Glu Arg Leu Arg Ala Arg Gly Val Thr Thr Phe Leu Glu Leu 2945 2950 2955 2960 Gly Pro Asp Ser Thr Leu Thr Thr Leu Val His His Asn Leu Ala Ala 2965 2970 2975 His Asp Pro Val Ala Val Ser Leu Leu His Pro Glu Arg Cys Glu Thr 2980 2985 2990 His Ser Val Leu Gly Ala Leu Ala Ala Val His Ala His Ser Arg Pro 2995 3000 3005 Val Asp Trp Thr Arg His Tyr Thr Ala Arg Pro Arg Pro Thr Pro His 3010 3015 3020 Gln Ile Asp Val Pro Thr Tyr Ala Phe Arg His Arg Arg Tyr Trp Leu 3025 3030 3035 3040 Pro Ala Pro Ala Ala Val Gly Asp Val Thr Ala Ala Gly Leu Asp Ala 3045 3050 3055 Ala Glu His Pro Leu Ile Gly Ala Ala Val Trp Leu Ala Glu Gly Asp 3060 3065 3070 Gly Cys Leu Leu Thr Gly Arg Ile Ser Pro Arg Thr His Pro Trp Leu 3075 3080 3085 Ala Asp His Val Ile Ala Gly Thr Val Leu Leu Pro Gly Thr Ala Phe 3090 3095 3100 Val Glu Leu Ala Leu Arg Ala Gly Ala Tyr Val Gly Cys Asp Arg Val 3105 3110 3115 3120 Glu Glu Leu Thr Leu His Ala Pro Leu Pro Leu Pro Ala Asp Gly Glu 3125 3130 3135 Val Val Leu Gln Val Ala Val Gly Ala Ala Asp Glu Ser Gly Arg Arg 3140 3145 3150 Glu Leu Ser Ile His Ala Arg Pro Ala Asp Asp Gly Thr Trp Thr Arg 3155 3160 3165 His Ala Ile Gly Thr Leu Ala Ser Ala Arg Gly Val Gly Leu Asp Asp 3170 3175 3180 Gly Thr Gly His Asn Gly His Ala Pro Ala Gly Asp Glu Pro Phe Gly 3185 3190 3195 3200 Ser Trp Ala Thr Ala Trp Pro Pro Pro Gly Ala Glu Pro Leu Asp Val 3205 3210 3215 Thr Gly Val Tyr Asp Arg Phe Ala Asp Ala Glu Phe Thr Tyr Gly Glu 3220 3225 3230 Ala Phe Gln Gly Leu Val Ala Ala Trp Arg His Gly Asp Glu Thr Leu 3235 3240 3245 Ala Glu Val Arg Leu Pro Asp Gln Pro Ala Gly Asp Ala Leu Arg Phe 3250 3255 3260 Gly Leu His Pro Ala Leu Leu Asp Ala Ala Leu Gln Thr Met Trp Leu 3265 3270 3275 3280 Val Glu Pro Asp Gly Thr Arg Pro Ser Gly Gly Leu Gly Gly Pro Asp 3285 3290 3295 Arg Gly Leu Pro Phe Ala Trp Gln Gly Val Ser Leu Arg Thr Ala Gly 3300 3305 3310 Pro Ser Ala Leu Arg Val Arg Leu Arg Arg Pro Ala Pro Asp Thr Val 3315 3320 3325 Ala Val Ala Val Ala Asp Ala Ala Gly Arg Pro Val Ala Ser Val Glu 3330 3335 3340 Ser Leu Thr Leu Arg Pro Val Pro Arg Gly Ala Leu Arg Gly Thr Glu 3345 3350 3355 3360 Thr Ala Val Arg Thr Ser Leu Tyr Gly Leu Asp Trp Thr Asp Val Pro 3365 3370 3375 Leu Pro Thr Pro Gln Thr Ala Leu Pro Arg Cys Ala Leu Ile Gly Ala 3380 3385 3390 Asp Thr Leu Asp Leu Val Pro Ala Leu Glu Ala Ala Ala Pro Asp Arg 3395 3400 3405 Ile Thr Asp Gly Val Glu Arg Tyr Ala Asp Leu Glu Glu Leu Val Arg 3410 3415 3420 Ser Val Ala Ala Gly Ala Pro Ala Pro Asp Leu Val Ile Ala Gly Cys 3425 3430 3435 3440 His Ala Ala Pro Glu Ala Asp Gly Ala Ser Glu Gln Pro Gln Pro Glu 3445 3450 3455 Thr Val Arg Thr Arg Thr Gly Gln Val Leu Glu Leu Leu Gln Arg Trp 3460 3465 3470 Leu Gly Ala Asp Gly Leu Ala Asp Ala His Leu Val Leu Phe Thr Ser 3475 3480 3485 Gly Ala Val Ala Thr Arg Pro Gly Glu Pro Val Arg Asp Leu Ala Gly 3490 3495 3500 Ala Ala Val Trp Gly Leu Val Arg Ser Gly Gln Ser Glu His Pro Glu 3505 3510 3515 3520 Cys Phe Thr Val Val Asp Met Asp Gly Ala Gln Glu Ser Arg Ala Ala 3525 3530 3535 Leu Leu Gly Ala Leu Gly Leu Gly Glu Pro Gln Leu Ala Val Arg Gly 3540 3545 3550 Gly Arg Ala Leu Ala Pro Arg Leu Val Arg Pro Gly Asp Ala Asp Asp 3555 3560 3565 Asp Ser Gly Leu Ala Leu Pro Gln Gly Pro Glu Gly Trp Arg Leu Glu 3570 3575 3580 Cys Pro Gly Thr Gly Ser Leu Asp Gly Leu Thr Thr Thr Glu Ser Pro 3585 3590 3595 3600 Ala Ala Ala Val Pro Leu Gly Pro Gly Glu Val Arg Val Ala Val Arg 3605 3610 3615 Ala Ala Gly Leu Asn Phe Arg Asp Val Leu Ile Ala Leu Gly Val Val 3620 3625 3630 Pro Gly Arg Thr Ala Leu Gly Ser Glu Gly Ala Gly Ile Val Leu Glu 3635 3640 3645 Val Gly Ala Glu Val Arg Asp Leu Ala Pro Gly Asp Arg Val Val Gly 3650 3655 3660 Ile Phe Pro Glu Ala Phe Gly Pro Val Ala Val Ala Glu Arg Ala Thr 3665 3670 3675 3680 Leu Ala Arg Val Pro Asp Gly Trp Ser Phe Ala Gln Ala Ala Ser Val 3685 3690 3695 Pro Ile Val Phe Ala Thr Ala Tyr His Gly Leu Val Asp Leu Ala Arg 3700 3705 3710 Leu Arg Pro Gly Glu Ser Val Leu Ile His Ala Ala Ala Gly Gly Val 3715 3720 3725 Gly Met Ala Ala Val Gln Leu Ala Arg His Leu Gly Ala Glu Val Tyr 3730 3735 3740 Ala Thr Ala Gly Pro Gly Lys Trp His Ile Leu Arg Ser Gln Gly Ile 3745 3750 3755 3760 Asp Asp Asp His Leu Ala Ser Ser Arg Thr Leu Glu Phe Glu Gln Arg 3765 3770 3775 Phe Ala Ala Thr Arg Gly Gly Arg Gly Ile Asp Val Val Leu Asp Cys 3780 3785 3790 Leu Ala His Glu Phe Val Asp Ala Ser Leu Arg Leu Val Ala Arg Asp 3795 3800 3805 Gly Gly Arg Phe Leu Glu Met Gly Lys Ser Asp Ile Arg Asp Pro Arg 3810 3815 3820 Gln Val Ala Leu Asp His Pro Gly Val Leu Tyr Arg Ala Phe Asp Leu 3825 3830 3835 3840 Leu Glu Ala Gly Pro Glu Arg Val Gly Gln Ile Leu Arg Thr Val Leu 3845 3850 3855 Asp Leu Phe Glu Arg Gly Val Leu Ala His Leu Pro Thr Thr Cys Trp 3860 3865 3870 Asp Ile Arg Gln Ala Glu His Ala Phe Arg His Leu Gln Gln Gly Arg 3875 3880 3885 His Ile Gly Lys Asn Val Leu Thr Val Pro Ala Gly Trp Asn Ala Glu 3890 3895 3900 Gly Thr Val Leu Ile Thr Gly Gly Met Gly Thr Leu Gly Ala Ala Leu 3905 3910 3915 3920 Ala Arg His Leu Ala Gly Thr Gly Arg Ala Arg His Leu Leu Leu Ala 3925 3930 3935 Gly Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Glu Leu Arg Glu Glu 3940 3945 3950 Leu Thr Glu Leu Gly Ala Arg Val Thr Ile Ala Ala Cys Asp Leu Gly 3955 3960 3965 Asp Arg Ala Ala Val Ala Arg Leu Leu Gly Ala Ile Pro Ala Glu Arg 3970 3975 3980 Pro Leu Thr Ala Val Ile His Ala Ala Gly Val Val Asp Asp Ala Thr 3985 3990 3995 4000 Leu Gly Ser Leu Thr Pro Arg His Leu Asp Ala Ala Leu Ala Ala Lys 4005 4010 4015 Ala Asp Ala Ala Trp His Leu His Thr Leu Thr Arg His Ala Asp Val 4020 4025 4030 Ala Ala Phe Val Leu Phe Ser Ser Val Ala Gly Leu Leu Gly Ser Pro 4035 4040 4045 Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Phe Leu Asp Ala Leu Ala 4050 4055 4060 His His Arg Arg Gly Ser Gly Leu Pro Ala Val Ser Leu Ala Trp Gly 4065 4070 4075 4080 Leu Trp Glu Gln Thr Ser Gly Met Thr Gly His Leu Asp Gln Ala Asp 4085 4090 4095 Arg Ala Arg Leu Ala Arg Leu Gly Ile Ser Pro Leu Thr Thr Gly Gln 4100 4105 4110 Ala Leu Gly Leu Phe Asp Ala Ala Leu Gly His His Arg Pro Val Leu 4115 4120 4125 Val Pro Ala Arg Leu Asp Val Pro Asp Pro His Pro Gly Ser Ser Thr 4130 4135 4140 Val Pro Pro Leu Tyr Arg Gly Leu Val Gly Ser Arg Thr Arg Arg Thr 4145 4150 4155 4160 Pro Pro Ala Ala Ala Ala Thr Gly Pro Phe Pro Leu His Thr Arg Leu 4165 4170 4175 Gly Gly His Ala Pro Ala Glu Gln His Glu Met Leu Leu Ser Leu Val 4180 4185 4190 Arg Ser His Ala Ala Leu Val Leu Gly Arg Asp Asp Pro Asp Thr Val 4195 4200 4205 His Pro Gly Ala His Phe Arg Gly Leu Gly Phe Asp Ser Leu Thr Ala 4210 4215 4220 Val Glu Leu Arg Asn Arg Leu Asn Ala Ala Thr Gly Leu Arg Leu Ser 4225 4230 4235 4240 Thr Thr Leu Val Phe Asp His Pro Thr Pro Asp Glu Leu Ala Arg His 4245 4250 4255 Val Arg Glu Gln Val Leu Gly Asp Gly Glu Ala Ala Arg Val Ala Pro 4260 4265 4270 Val Leu Ala Glu Leu Asp Arg Leu Glu Ala Ala Leu Ser Arg Val Asp 4275 4280 4285 Gly Asp Asp Ala Val Arg Ala Arg Val Thr Ala Arg Leu Gln Ala Leu 4290 4295 4300 Leu Leu Lys Trp Asn Glu Ser Asp Gly Pro Ala Thr Gly Gly Asp Gly 4305 4310 4315 4320 Ala Gly Arg Leu Ala Ser Ala Thr Ala Ala Glu Val Leu Asp Phe Ile 4325 4330 4335 Arg Asn Asp Leu Gly Leu Ser 4340 <210> 5 <211> 13032 <212> DNA <213> Artificial Sequence <220> <223> milA1 gene of S. bingchenggensis BCW-1 (Accession no. CP002047) <400> 5 ttgcccaaag cccagaacga gttcgcagtg gccggtcatc cgtggatcct ctccgggcac 60 accggaaccg cgctgcgggc ccaggcacgc cggctccacg accatgtcgc cgaccaccct 120 cggctccgtc cggaagacat cgcccacacg ctggcgagca gcggcccggc gctcacccat 180 cgcgcggcgg tgatcgcggc ggaccgggaa ggacatctcc gggggctcga cgcggtggcc 240 cggggtgagg acacccccgg tgtcgtacgg ggcacggcgg ccgcgggcgg cgacggggtc 300 gcgttcgtct tccccggcca gggcacccag tggcccggta tggccgccga tctgctgacg 360 gtctcccccg ccttcagccg ggcggtcgac gcctgcgccg aggcgttcga accgtatgtc 420 tcctggtcac cggaggccgt gctgcggggc gctccgggcg cgccgcccct ggaggggacc 480 gatgtggtgc agccgacgct gttcgccgtc atggtggggc tggccgagct gtggcggact 540 cttggggtga gcccgacgtc gatcgtgggc cactgcatcg gggagatcgc ggcagcccat 600 ctctgcggcg ccctgtcgct gtccgacgcg gcgcgcgtgg tgatcgagag cagccgggcc 660 caggcgacgc tctccgggtc gggtgcgctg atcgcggtcg cgcggtccga ggcgcagctg 720 cttccgttgc tgcggcggtg gccgggcagg ctgacgatcg ccgcggtcaa cggcccgatg 780 gccacggtcg tctccggcga tcggccggcc gccgacgagc tgttggcgga gttcgcccgt 840 gccggtgtcc gggcccgcga ggtggcgatc gacatccccg cgcactcgcc gttcatggcc 900 cccctcaggg acggtctgct cgactcgctg tcatcggtca ccgcgggtgc gtcgcggctg 960 ccgttccact cctcggtcat cggggggccg ctggagaccc aagggctcga cgcggcttac 1020 tggtaccgga acctcgccga cacggtccgc ttcgaaagcg tcgtcacggg gctgctgcgg 1080 cagggcacac gctgcttcgt ggagctgagc ccgcacccga tgctgaccat gtgtgtgcag 1140 gccaccgccg aggaggtggt cggcggtgag cgcgtcgtga tcctgccgac gctgcatcgc 1200 gggcaggccg ccgtcgagtc cgttcgcacc acgctggccg agctgtacgt acggggcgca 1260 ctggatgacc atcgggcggc gttctcggtg ccgggcggcc gcctgatcac cctgcctctc 1320 gagccgcccg cggacacgtc cgtagagctc gccgacgccc cggacccggc ggaggcctgc 1380 cggcccccct tggtggagcg gcttgcccgg ctctccaccg cggagcggaa gcggcggctg 1440 cgcgagctgg tgggcgtcga ggcggccaag gtcctcgagg acgtcgccgg ggcggacgcg 1500 ccgggccacg gcatcgcgga gcaggagcac ttcgtcactt cgggcttcga ctccgcggcc 1560 gcggtcgcgc tgcgcaaccg cctgaacgac gccaccggtt tgctgctgcc cttcaccctg 1620 gccttcgacc atccgacacc cgccgccgtc gccgaccatc tgcactcccg gctcttcgat 1680 caccagggcg gcgggcagcc gggcgccgac ggccggcccg accccgcggc ggcggccggt 1740 ccggccaggg ccgacgacga gccgatcgcc gtcatcggca tggcgggccg cttccccggg 1800 ggcgcccgta ccccggagga gctgtgggaa ctggtcgccg aaggcaccga cgccctctcg 1860 cccttcccgg agggccgggg ctgggatccg ctgcggctct acgatccgga ccccgcccgg 1920 cccggcacgt actaccagcg cgaagcggga ttcctccacg acgccgacaa gttcgacgcc 1980 gagttcttcg gcatcgcgcc acgcgaggcc accgcaatgg atccccagca gcggctgctc 2040 ctggagacct cctgggaggc gctcgaacgg gcgcggatcg acccgaccgc gctgcgcggc 2100 agccgcaccg gggtgttcgt cggcgtggcc ccgctggact acagcccccg aatgcaccag 2160 gcgtcgccgg agctggaggg ccatctgctg accggcaaca tcggcgccgc ggcctcgggg 2220 cggatctcct acgtactcgg gcttgagggg cccgcggtgt ccgtggacac ggcgtgctcg 2280 tcgtccctgg tcgccctgca tctggcggcc caggcgctgc gggccgggga gtgctcgctg 2340 gccctggtcg gcggggcgac ggtcctctcg acccccggca tgttcatcga gttctcgcgg 2400 cagcgcggtc tggctccgga cggccgctgc aaggcgtacg cggccgccgc ggacggcacc 2460 ggctggtccg agggtgtggg catgctgctc gtcgagcggc tgtccgacgc gcgacggctc 2520 ggacaccagg tgcttgcggt ggtacggggc tccgccgtca accaggacgg ggcgagcaac 2580 ggcttcacgg cgcccagcgg tccatcacag caacaggtca tccgggcggc cctggccaat 2640 gccggggtgt cggctccgga ggtcgacgcg gtggaggggc acggcaccgg cacccggttg 2700 ggcgatccga tcgaggcgca ggcgctgctg gccgcctacg ggcaggggcg ggcggccgac 2760 cggccgctgt ggctggggtc gatcaagtcg aacatcggac acacccagtg ggccgcgggt 2820 gtcatcgggg tcatcaaaat ggtgctcgcg ctccagcacg gtgtgctgcc gcgcacgctg 2880 cacgtggaca agccgtcgga ttacgtggac tggtcggccg gggccgtacg gctgttgacg 2940 gagccggtgc cctggccgga gcggggccac ccgcgccggg cgggggtgtc gtccttcggg 3000 gtgagcggca ccaacgccca tgtcatcctc gagcaggcaa cgccatcgtc cacggtggct 3060 cccggggggc ataccgccga ggccgggcct cccctgccgt gggtggtctc ggcgaagacg 3120 ccccaggcac tgcgcgacca ggcccgccgc ctgcacgaac acctcaccgc ccagccacag 3180 ctccaaccgg ccgacgtcgg ccacaccctc gccaccggcc gcgccacctt cgaccaccgg 3240 gccgtcctca tcggctccga ccgcgaacaa ctcctccacg gcctggacgc gctcgccacc 3300 ggccggcccg acccagcggt ccaccagacg tcggaccgtc ccgccaccgc cgacggccgt 3360 atcgtcttcg tcttccccgg acaaggcggt caatgggcgg gcatgggcct acggctgctg 3420 aacgcctcac ccgtcttcac cgagcggatg gccgcctgcg aacaggccct ctccccctac 3480 gtcgactggt cactcacgga catcctccac cggccggccg acgacgccgt atggcaacgc 3540 gccgacatcg tccagcccgc cctgttctcg atcatggtgt ccctggccgc gctctggcgc 3600 tcttgcggca tcgaaccgga cgccgtcctc ggccactccc aaggcgagat cgccgcggcc 3660 cacgtctgcg gcgccctgac gctccacgac gcggccaagg tcatcgccct gcgcagccag 3720 gccctccaag ccgtacgcgg cgccgggggc atggcctccg tacccctgcc cgcggaccag 3780 gtcaccgagg atctgcgcac ccactggccc gaccggctat gggtggccgc caccaactcc 3840 cccacggcaa ccgtcatctc gggaaacacc gacgcgcttg acgaagcgct cgaccactac 3900 cacgcccacg acgtacgggc caagcgcatc ccggtcgact acgcctccca ctgcccccat 3960 atcgacgcgg tggccgagcg actgcccgac ctgctgggcg gcatcgtccc gcgcgccgcc 4020 gacatcccct tctactccac ggttgacggc cgatgggccg agccgaccga gctcgacgcc 4080 gactactggt accgcaacct ccgcagcccg gtacggttcg cccacgccgt ccacgccctc 4140 accgagaccg accaccgcac ctttgtcgaa gtcagcccac accccacgct cacccccgcc 4200 atcacggcca ccaccgaaac caccgaccgc accaccaccg tcatcgcctc gctccaccgc 4260 gaccacgacg acacccacca catcctcacc aacctcgccc aggcccacat ccacggccac 4320 accatcgact ggcgacacca ctaccagact ctgcgcccca ccccacccca tatcgacctc 4380 cccacctacc ccttccaaca ccaccactac tggctccacg actccaccga ggacaaggcg 4440 gtgggtacgg acctcgccgc ggcccgcttc tgggaggcgg tccacggcga ggacaccaac 4500 gccgtcgccg cgctcctcga cgtcgagccg ggcacctcac tggacgcgct gctgccggcc 4560 ctgtccgcct ggcacggtcg gcgtcgcgac caggccatca ccgacacctg gtgttaccgc 4620 gacatctgga agccggccga cctcaccgcc gcgcgccccc ggccgtccgg ccgatggctt 4680 gtcgcgatct ccgcagggcg ggccgatcac ctccacgtca gtgccgtcct ggacgctctg 4740 gaacgccagg gtctgcccat cgccaccctc gtcctcgacg acacccacac cgaactcccc 4800 ctgctggagc ggcatctcgc acaggcgatc gcgagcgatg ggccggccat cggcggcgtg 4860 ctctcgctgc tcgccctcga cgaggggcca catccgcgcc acccggaggt gcccgtcggc 4920 accgccctca ccctcagcct gatccaggcg ctcatcgcac gcgaggacat ggcgccccgg 4980 ctgtggctgg ccacccacga ggccgtcgcc acctcgtccg cggatacgct cgatcacccc 5040 ctccaggcga tggtctgggg gctgggacgc accgccgcac tcgaacaccc cgatctgtgg 5100 ggcggcctca tcgaccttcc ggacactctc accgaacggg tcctccacgg cctcgtcacg 5160 gcgctgacca cctgtcacga cgaggacgaa ctcgcgctgc gcgccaccgg cccacgcacc 5220 cggcgcctga tccggacgcc gtccaccgcc gcagcggagg acaccccgcc gtggacgccc 5280 cgtggcaccg tcctcatcac cggcggcacc ggggccctgg gctcccgcgt cgcccaccgc 5340 atcgccgaac gccaccccga ctgccacttg ctgctggtga gccggcgagg gcccaaggcc 5400 cccggcgcca ccgcgctccg cgaccagctc atcgaactcg gcgccacggt gaccctcgcc 5460 gcatgtgaca ccgccgaccc cggcgcgctc gcggatctcc tcgccgatgt cccctcggac 5520 cgccccctca ccgcggtcgt ccacaccgcg ggcgtcctgg acgacagcac cctcgccgta 5580 cagaccccgg accacctcgc cgccgttctg gggcccaagt cccatgccgc acaccatctg 5640 cacgccctcg cccagcacca ccccctcgac gcgttcgtcc tcttctcgtc cgtcgcggcg 5700 cccttcggcg ccgcgggcca ggccaactac gcggccgcca acgcctacct cgacgccctc 5760 gcccagcacc gccgggccca ggggctggcc gccacctcca tcgcctgggg caactgggac 5820 ggcgacgggc tcgcgagcac acagtccgcg cagacgtacc tgcgcaaccg cggctttcct 5880 ccgatgccgc cacacctggc gctggccgcc ctggagcgag ccatcgtctc gccccacgcc 5940 cagctcgtcg tcgccgacgt cgactggaag aagctcaagc cggcgccgca cacccgcgac 6000 atcccgggaa gccgccgccc ggccccggcc gccaccgacg gcgcggacag gacggccgac 6060 gccaccgcga gcctccgtac ccgcctcgcg ggtcagagcc cggccgaacg gcaccagacg 6120 ctcctcgacc tcatcagctc tcatacagcc gccgtcctcg ggcacgccac gccccagacg 6180 atccccacgg accgggcctt ccgcgacctg ggtttcacct cgctgacggc catcgagctc 6240 cgcaaccgcc tcgcggcggc caccgggctc cgcctgccga ccaccgtcgc cttcgaccgt 6300 ccgacgccgg acaagctcgc ggccgacctg ctggcgcggt gcgcgccgac aggcccggac 6360 ggcatcgggg tgacgcccga cgcgacggcc acgagtggca gttcgcccgg tgcggcgcat 6420 ggcgcgccgg accccgccga gcccatcgcc atcgtcggct tggcctgccg ctaccccggc 6480 gggatcggct cccccgagga cctgtgggag ttcatcaccg cacaccggga cgccgtcgga 6540 gacttcccga ccgaccgggg ctgggacctg gcgaggctct tcgaccccga tccggaccgg 6600 ccgggcacct cgtacagccg acagggcgcc ttcctccgcg acgcgggcga cttcgacccg 6660 gagttcttcg ggatcagccc acgggaggcg acggcgacgg acccccagca gcgactgctc 6720 ctggaggcgt cctgggaagc cctcgaacga gccgggatca acccccacga tctccacggc 6780 agtccgacgg gcgtcttcac cggcagcaac gcgcaggact tcagcgcgcg gctgcggcag 6840 acgccgtcgg agctggcgga gctgtgcgag ggctatgcgc tgactggcag caacaacagc 6900 gtcgcctcgg ggcgcgtctc gtacgcgctc ggcctggaag gcccggcggt cagcatcgac 6960 accgcctgct cgtcctcgct cgtggcgctc catctggcct gccagtcgct ccgggccggc 7020 gaatgctcgc tggccctggc gggcggcgtc acggtcatga tgaccccgtt caacttcgtg 7080 gagttctccc ggcagcgggg cctggcggcg gacggccggt gcaaggcgtt ctccgccaca 7140 gccgatggca ccggctgggg cgagggcgtg ggcatggtgg tggtggagcg gctgtcggac 7200 gcgcggcgca acggccatcg tgtgctggcc ctcgtccgcg gcagcgccgt caaccaggac 7260 ggtgccagca atgggctgac tgccccgaac ggcccctcgc agcagcgggt catccgcgcc 7320 gccctggccg ccgccggggt cgccgcggca gaagtggacg cggtcgaggc gcacggcacg 7380 gggacgacgc tcggcgatcc gatcgaggcc caggccctgc tcgccaccta cgggcagggg 7440 cggccggcgg accgggcgct gtggctcggt acggtcaagt ccaacatcgg acacgcccag 7500 tcggccgccg gtatcgccgg ggtcatcaag atggtgctgg ccctgcggca cgggatgctg 7560 ccgcgtacgc tgcatgtgtc cgagccgtcg ccgcatgtgg actggtcggc gggtgcggta 7620 cggctgctga ccgaggacca gccgtggccg gacaccgggc gcccccggcg ggcgggggtg 7680 tcgtccttcg gcgtgagcgg caccaatgcc catgtgatcc tggagcaggc ggagccgggg 7740 ccggacccgg caccgacggc ctccgcgccc tccctgcccc cctggcccct ctccgccagg 7800 tcggcggagg ccctgcgggc ccaggcccgt aggttgctgg cgtacgtggc cgagcacccg 7860 gatgtcgacc ccgccgacgt ggggtactcc ctcgcgcgcg gacgggccgt gttcgagcac 7920 cgggccgtgc tcctcggcac cggccacgac gacttccggc gcgccctgga cgccctggcg 7980 tcgggcgcgc ccgacggcgc ggtcgtccag ggcgcggcgg tggggcggca gggcaaggtc 8040 gtctttgtgt gctcggggca gggcacccag cgccccggca tgggccgcgg gctctaccgc 8100 tcgtccacgg cgttcgccgg ggcgctggag gaggtgtgcg cccatctgga cccgtatctg 8160 gaacaccctc tgatggaggt gatgttcgcc gatgagaaga gcgatacgtc ggcgctgctg 8220 catctgaccg cctacgccca accggccctc ttcgccctcc agaccgcgct gcaccgcatg 8280 gtcaccgagg agttcgggct cacccccgac tatctggccg gccactccct gggcgagctg 8340 accgccgccc atctggcggg catcctcagc ctgcccgacg ccgcggcgct ggtggcggcc 8400 cgcgcccgcg ccatgcggga ccttccagcg accggagcca tggtcgccgt cgaggccacc 8460 gaggcggagc tgcggccccg gctcgccgag ttggcggacc gggtcggcat cgccgccgtc 8520 aacgcccccg cgtccctggt catcaccggc gaccacgacg ccgtgcacca gatcgccgac 8580 gacttccgcg ggcagggcag gaaggtcact cccctccagg tcagcggcgc cttccactct 8640 ccccatatgg agcccctgct cgacgagatc gggcgcaccg ccgaaaccct cacctaccac 8700 cggccccaca ctcccctcgt caccgcgtcg gccgacggcg gcgacgacac gaccgagccg 8760 cgggccgacg acgacccggg cacggccgcg ttctggcctc tccaggcccg gcgcaccgtc 8820 cactacgcgc gggccgtgga gcggctgcgc gcccgcggcg tcaccacgtt cctggaactc 8880 ggccccgact ccaccctcac taccctcgtc caccacaatc tcgccgcgca cgatcccgtg 8940 gccgtctccc tgctccatcc ggagcggtgc gagacgcaca gcgtcctcgg cgcactcgcc 9000 gcggtccacg cccacagccg ccccgtcgac tggacacgcc actacaccgc acggccgcgg 9060 ccgacgccac accagatcga cgtgcccacc tatgccttcc ggcaccggcg ctactggctg 9120 cccgccccgg cggcggtcgg cgatgtgacg gccgcggggc tcgacgcggc ggagcacccg 9180 ctgatcggcg ccgccgtgtg gctcgcggag ggcgacggct gtctgctgac cggcaggatc 9240 tcgccgcgta cgcacccgtg gctggccgac catgtcatcg ccggcactgt gctccttccg 9300 ggcaccgcgt tcgtggagct ggcgctgcgg gccggggcgt acgtgggctg cgaccgtgtg 9360 gaggagctga ccctgcacgc gccactcccg ctgcccgccg acggtgaggt ggtgctgcag 9420 gtggcggtgg gggccgccga cgagtccggc cgccgtgagc tgagcatcca cgcccggccg 9480 gcggacgacg gtacatggac acggcacgcc atcggcacgc tggcatcggc ccgcggcgtc 9540 ggcctcgacg atggcacggg gcacaatggc cacgccccgg cgggcgacga gccgttcggg 9600 tcgtgggcca cggcctggcc gccgcccggt gccgagccct tggacgtcac cggggtctac 9660 gaccggtttg ccgacgccga gttcacgtac ggggaggcat tccaggggct ggtcgcggct 9720 tggcggcacg gcgacgagac gctggcggag gtccgcctcc ccgaccagcc ggccggtgac 9780 gccctccgct tcgggctgca ccccgcgctg ctcgacgcgg cactgcagac catgtggctc 9840 gtggagcccg acggcacacg gccgagcggt ggcctgggcg gccccgatcg gggcctgccg 9900 ttcgcctggc agggggtctc gctgcgtacg gcgggcccgt cggccctgcg ggtacggctg 9960 cgacggccgg cgccggacac cgtggccgtc gccgtggccg acgcggccgg ccggccggtc 10020 gcgtcggtgg agtcgctgac gctgcggccg gtgccgcggg gcgccttgcg cggcaccgag 10080 acggcggtgc gcacctcgtt gtacggcctg gactggacgg atgtgccgct gccgacgccg 10140 cagacggccc tgccccggtg tgcgctgatc ggagcggaca cgctcgacct ggtccccgcg 10200 ctcgaggccg cggcgcccga ccgcatcacc gacggcgtgg agcgctacgc cgacctggag 10260 gagctggtgc gctccgtggc ggcgggcgcc cccgccccgg acctcgtcat cgccggctgc 10320 cacgcagccc ctgaagccga cggcgcgagc gaacagccac agcccgagac ggtgcgcaca 10380 aggacgggtc aggtgctgga gctgcttcag cggtggctcg gcgcggacgg gctcgccgac 10440 gcacacctgg tgctgttcac ctcaggcgcg gtcgccaccc ggccgggcga gccggtgcgg 10500 gacctggcgg gggcggcggt ctggggtctg gtgcgctccg gccagtcgga gcatccggag 10560 tgcttcaccg tggtggacat ggacggcgcc caggagtccc gcgcggcgct gctcggcgcg 10620 ctcggcctcg gcgagccgca actggcggtg cgcggcggcc gggcgctggc gccgcgcctg 10680 gtgcgcccgg gtgacgccga cgacgacagc ggcctggccc tgccgcaggg gccggaaggc 10740 tggcggttgg agtgtcccgg cacgggcagc ctggacgggt tgaccacgac cgagtccccg 10800 gccgcggcgg tgccgctcgg cccgggcgag gtacgggtcg cggtgcgggc cgcggggctg 10860 aacttccgcg atgtgctgat cgcgctgggc gtggtgcccg ggcggacggc gctgggcagt 10920 gagggggcgg ggatcgtcct cgaggtcggg gcggaggtcc gcgatctcgc gcccggggac 10980 cgggtggtgg gtatcttccc cgaggcgttc ggcccggtgg ccgtggccga gcgggcgacc 11040 ctggcgcggg tccccgacgg ctggtcgttc gcccaggccg cgtcggtccc catcgtgttc 11100 gccaccgcgt accacggcct ggtcgatctg gcgcgcctgc ggccggggga atcggtgctg 11160 atccatgccg cggccggcgg ggtgggcatg gccgccgtgc aactggcgcg ccatctgggg 11220 gccgaggtgt acgccacggc cggccccggc aagtggcaca tcctgcgttc ccaaggcatc 11280 gacgacgacc atctggcctc gtcgcgcacg ctggagttcg agcagcgctt cgccgcgacc 11340 cgcggcgggc gggggatcga tgtcgtcctg gactgtctgg cccatgagtt cgtcgacgcc 11400 tcgctgcgcc tggtggcgcg tgacggcggc cggttcctgg agatgggcaa gagcgacatc 11460 cgtgacccgc ggcaggtggc gctggaccat ccgggcgtgc tctaccgggc gttcgacctg 11520 ctggaggccg ggccggagcg ggtcgggcag atcctgcgca ccgtactgga cctgttcgag 11580 cgcggtgtcc tggcgcacct gccgacgacc tgctgggaca tccggcaggc ggagcacgcc 11640 ttccgccatc tgcagcaggg ccgtcacatc ggaaagaacg tgctcaccgt cccggccggc 11700 tggaacgccg agggcaccgt actgatcacc ggcggtatgg gcaccctggg cgccgccctc 11760 gcccgtcatc tggcgggtac cgggcgcgcc cgccatctgc tgctggccgg ccgacgcggc 11820 cccgacgccc cgggcgccga ggagctgcga gaggagctga ccgagctggg cgcgcgggtc 11880 accatcgccg catgcgatct cggcgaccgg gcggcggtcg cccggctcct gggggcgatc 11940 ccggccgagc ggccgctgac cgctgtcatc cacgcggcgg gtgtcgtcga cgatgccacc 12000 ctcgggtccc tcaccccccg ccacctggac gccgccctgg ccgccaaggc cgacgccgcc 12060 tggcatctgc acaccctcac ccgccacgcc gacgtggccg cgttcgtcct cttctcctcg 12120 gtcgcgggtc tgctcggctc gcccgggcag ggcaactacg ccgcggccaa cgccttcttg 12180 gacgcgctcg cccaccaccg gcgcggctct ggccttccgg cggtgtcgct ggcgtggggg 12240 ctgtgggagc agaccagcgg catgaccggg cacctggacc aggccgaccg cgcccggctg 12300 gcccggctcg gcatcagccc gctcacgacc gggcaggcgc tcggcctttt cgacgccgcc 12360 ctcggccacc accgccccgt gctcgtcccc gcccgcctcg acgtgcccga tccgcacccc 12420 ggctcgtcga ccgtgccgcc cctgtaccgg ggcctggtcg gatccaggac ccggcggaca 12480 ccccccgcgg ccgccgccac cgggccgttc cccctgcata cccgcctcgg cggtcacgcc 12540 ccggccgagc agcacgagat gctgctctcg ctggtccgct cccacgccgc cctcgtgctg 12600 ggccgcgacg atccggacac ggtccatccc ggcgcgcact tccgcggcct gggcttcgac 12660 tccctgaccg cggtcgagct ccgcaaccgg ctcaacgccg ccaccggcct ccggctctcc 12720 accaccctcg tcttcgacca ccccacgccc gacgaactcg cccgtcacgt ccgggagcag 12780 gtgctgggcg acggcgaagc ggcgcgggtg gccccggtgc tggccgagct cgacaggctg 12840 gaagcggcgc tgtcccgggt ggacggggac gatgcggtcc gggcgagggt gacggcccgg 12900 ttgcaggccc ttctcctgaa gtggaacgag tccgatggtc cggcgacggg cggtgacggt 12960 gcgggcaggc tggcgtccgc cacggccgcc gaggtgctgg atttcatcag gaacgacctc 13020 ggcctctcct ga 13032 <210> 6 <211> 4343 <212> PRT <213> Artificial Sequence <220> <223> milA1 of S. bingchenggensis BCW-1 (ADI03910.) <400> 6 Leu Pro Lys Ala Gln Asn Glu Phe Ala Val Ala Gly His Pro Trp Ile 1 5 10 15 Leu Ser Gly His Thr Gly Thr Ala Leu Arg Ala Gln Ala Arg Arg Leu 20 25 30 His Asp His Val Ala Asp His Pro Arg Leu Arg Pro Glu Asp Ile Ala 35 40 45 His Thr Leu Ala Ser Ser Gly Pro Ala Leu Thr His Arg Ala Ala Val 50 55 60 Ile Ala Ala Asp Arg Glu Gly His Leu Arg Gly Leu Asp Ala Val Ala 65 70 75 80 Arg Gly Glu Asp Thr Pro Gly Val Val Arg Gly Thr Ala Ala Ala Gly 85 90 95 Gly Asp Gly Val Ala Phe Val Phe Pro Gly Gln Gly Thr Gln Trp Pro 100 105 110 Gly Met Ala Ala Asp Leu Leu Thr Val Ser Pro Ala Phe Ser Arg Ala 115 120 125 Val Asp Ala Cys Ala Glu Ala Phe Glu Pro Tyr Val Ser Trp Ser Pro 130 135 140 Glu Ala Val Leu Arg Gly Ala Pro Gly Ala Pro Pro Leu Glu Gly Thr 145 150 155 160 Asp Val Val Gln Pro Thr Leu Phe Ala Val Met Val Gly Leu Ala Glu 165 170 175 Leu Trp Arg Thr Leu Gly Val Ser Pro Thr Ser Ile Val Gly His Cys 180 185 190 Ile Gly Glu Ile Ala Ala Ala His Leu Cys Gly Ala Leu Ser Leu Ser 195 200 205 Asp Ala Ala Arg Val Val Ile Glu Ser Ser Arg Ala Gln Ala Thr Leu 210 215 220 Ser Gly Ser Gly Ala Leu Ile Ala Val Ala Arg Ser Glu Ala Gln Leu 225 230 235 240 Leu Pro Leu Leu Arg Arg Trp Pro Gly Arg Leu Thr Ile Ala Ala Val 245 250 255 Asn Gly Pro Met Ala Thr Val Val Ser Gly Asp Arg Pro Ala Ala Asp 260 265 270 Glu Leu Leu Ala Glu Phe Ala Arg Ala Gly Val Arg Ala Arg Glu Val 275 280 285 Ala Ile Asp Ile Pro Ala His Ser Pro Phe Met Ala Pro Leu Arg Asp 290 295 300 Gly Leu Leu Asp Ser Leu Ser Ser Val Thr Ala Gly Ala Ser Arg Leu 305 310 315 320 Pro Phe His Ser Ser Val Ile Gly Gly Pro Leu Glu Thr Gln Gly Leu 325 330 335 Asp Ala Ala Tyr Trp Tyr Arg Asn Leu Ala Asp Thr Val Arg Phe Glu 340 345 350 Ser Val Val Thr Gly Leu Leu Arg Gln Gly Thr Arg Cys Phe Val Glu 355 360 365 Leu Ser Pro His Pro Met Leu Thr Met Cys Val Gln Ala Thr Ala Glu 370 375 380 Glu Val Val Gly Gly Glu Arg Val Val Ile Leu Pro Thr Leu His Arg 385 390 395 400 Gly Gln Ala Ala Val Glu Ser Val Arg Thr Thr Leu Ala Glu Leu Tyr 405 410 415 Val Arg Gly Ala Leu Asp Asp His Arg Ala Ala Phe Ser Val Pro Gly 420 425 430 Gly Arg Leu Ile Thr Leu Pro Leu Glu Pro Pro Ala Asp Thr Ser Val 435 440 445 Glu Leu Ala Asp Ala Pro Asp Pro Ala Glu Ala Cys Arg Pro Pro Leu 450 455 460 Val Glu Arg Leu Ala Arg Leu Ser Thr Ala Glu Arg Lys Arg Arg Leu 465 470 475 480 Arg Glu Leu Val Gly Val Glu Ala Ala Lys Val Leu Glu Asp Val Ala 485 490 495 Gly Ala Asp Ala Pro Gly His Gly Ile Ala Glu Gln Glu His Phe Val 500 505 510 Thr Ser Gly Phe Asp Ser Ala Ala Ala Val Ala Leu Arg Asn Arg Leu 515 520 525 Asn Asp Ala Thr Gly Leu Leu Leu Pro Phe Thr Leu Ala Phe Asp His 530 535 540 Pro Thr Pro Ala Ala Val Ala Asp His Leu His Ser Arg Leu Phe Asp 545 550 555 560 His Gln Gly Gly Gly Gln Pro Gly Ala Asp Gly Arg Pro Asp Pro Ala 565 570 575 Ala Ala Ala Gly Pro Ala Arg Ala Asp Asp Glu Pro Ile Ala Val Ile 580 585 590 Gly Met Ala Gly Arg Phe Pro Gly Gly Ala Arg Thr Pro Glu Glu Leu 595 600 605 Trp Glu Leu Val Ala Glu Gly Thr Asp Ala Leu Ser Pro Phe Pro Glu 610 615 620 Gly Arg Gly Trp Asp Pro Leu Arg Leu Tyr Asp Pro Asp Pro Ala Arg 625 630 635 640 Pro Gly Thr Tyr Tyr Gln Arg Glu Ala Gly Phe Leu His Asp Ala Asp 645 650 655 Lys Phe Asp Ala Glu Phe Phe Gly Ile Ala Pro Arg Glu Ala Thr Ala 660 665 670 Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser Trp Glu Ala Leu 675 680 685 Glu Arg Ala Arg Ile Asp Pro Thr Ala Leu Arg Gly Ser Arg Thr Gly 690 695 700 Val Phe Val Gly Val Ala Pro Leu Asp Tyr Ser Pro Arg Met His Gln 705 710 715 720 Ala Ser Pro Glu Leu Glu Gly His Leu Leu Thr Gly Asn Ile Gly Ala 725 730 735 Ala Ala Ser Gly Arg Ile Ser Tyr Val Leu Gly Leu Glu Gly Pro Ala 740 745 750 Val Ser Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu 755 760 765 Ala Ala Gln Ala Leu Arg Ala Gly Glu Cys Ser Leu Ala Leu Val Gly 770 775 780 Gly Ala Thr Val Leu Ser Thr Pro Gly Met Phe Ile Glu Phe Ser Arg 785 790 795 800 Gln Arg Gly Leu Ala Pro Asp Gly Arg Cys Lys Ala Tyr Ala Ala Ala 805 810 815 Ala Asp Gly Thr Gly Trp Ser Glu Gly Val Gly Met Leu Leu Val Glu 820 825 830 Arg Leu Ser Asp Ala Arg Arg Leu Gly His Gln Val Leu Ala Val Val 835 840 845 Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly Phe Thr Ala 850 855 860 Pro Ser Gly Pro Ser Gln Gln Gln Val Ile Arg Ala Ala Leu Ala Asn 865 870 875 880 Ala Gly Val Ser Ala Pro Glu Val Asp Ala Val Glu Gly His Gly Thr 885 890 895 Gly Thr Arg Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Ala 900 905 910 Tyr Gly Gln Gly Arg Ala Ala Asp Arg Pro Leu Trp Leu Gly Ser Ile 915 920 925 Lys Ser Asn Ile Gly His Thr Gln Trp Ala Ala Gly Val Ile Gly Val 930 935 940 Ile Lys Met Val Leu Ala Leu Gln His Gly Val Leu Pro Arg Thr Leu 945 950 955 960 His Val Asp Lys Pro Ser Asp Tyr Val Asp Trp Ser Ala Gly Ala Val 965 970 975 Arg Leu Leu Thr Glu Pro Val Pro Trp Pro Glu Arg Gly His Pro Arg 980 985 990 Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val 995 1000 1005 Ile Leu Glu Gln Ala Thr Pro Ser Ser Thr Val Ala Pro Gly Gly His 1010 1015 1020 Thr Ala Glu Ala Gly Pro Pro Leu Pro Trp Val Val Ser Ala Lys Thr 1025 1030 1035 1040 Pro Gln Ala Leu Arg Asp Gln Ala Arg Arg Leu His Glu His Leu Thr 1045 1050 1055 Ala Gln Pro Gln Leu Gln Pro Ala Asp Val Gly His Thr Leu Ala Thr 1060 1065 1070 Gly Arg Ala Thr Phe Asp His Arg Ala Val Leu Ile Gly Ser Asp Arg 1075 1080 1085 Glu Gln Leu Leu His Gly Leu Asp Ala Leu Ala Thr Gly Arg Pro Asp 1090 1095 1100 Pro Ala Val His Gln Thr Ser Asp Arg Pro Ala Thr Ala Asp Gly Arg 1105 1110 1115 1120 Ile Val Phe Val Phe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met Gly 1125 1130 1135 Leu Arg Leu Leu Asn Ala Ser Pro Val Phe Thr Glu Arg Met Ala Ala 1140 1145 1150 Cys Glu Gln Ala Leu Ser Pro Tyr Val Asp Trp Ser Leu Thr Asp Ile 1155 1160 1165 Leu His Arg Pro Ala Asp Asp Ala Val Trp Gln Arg Ala Asp Ile Val 1170 1175 1180 Gln Pro Ala Leu Phe Ser Ile Met Val Ser Leu Ala Ala Leu Trp Arg 1185 1190 1195 1200 Ser Cys Gly Ile Glu Pro Asp Ala Val Leu Gly His Ser Gln Gly Glu 1205 1210 1215 Ile Ala Ala Ala His Val Cys Gly Ala Leu Thr Leu His Asp Ala Ala 1220 1225 1230 Lys Val Ile Ala Leu Arg Ser Gln Ala Leu Gln Ala Val Arg Gly Ala 1235 1240 1245 Gly Gly Met Ala Ser Val Pro Leu Pro Ala Asp Gln Val Thr Glu Asp 1250 1255 1260 Leu Arg Thr His Trp Pro Asp Arg Leu Trp Val Ala Ala Thr Asn Ser 1265 1270 1275 1280 Pro Thr Ala Thr Val Ile Ser Gly Asn Thr Asp Ala Leu Asp Glu Ala 1285 1290 1295 Leu Asp His Tyr His Ala His Asp Val Arg Ala Lys Arg Ile Pro Val 1300 1305 1310 Asp Tyr Ala Ser His Cys Pro His Ile Asp Ala Val Ala Glu Arg Leu 1315 1320 1325 Pro Asp Leu Leu Gly Gly Ile Val Pro Arg Ala Ala Asp Ile Pro Phe 1330 1335 1340 Tyr Ser Thr Val Asp Gly Arg Trp Ala Glu Pro Thr Glu Leu Asp Ala 1345 1350 1355 1360 Asp Tyr Trp Tyr Arg Asn Leu Arg Ser Pro Val Arg Phe Ala His Ala 1365 1370 1375 Val His Ala Leu Thr Glu Thr Asp His Arg Thr Phe Val Glu Val Ser 1380 1385 1390 Pro His Pro Thr Leu Thr Pro Ala Ile Thr Ala Thr Thr Glu Thr Thr 1395 1400 1405 Asp Arg Thr Thr Thr Val Ile Ala Ser Leu His Arg Asp His Asp Asp 1410 1415 1420 Thr His His Ile Leu Thr Asn Leu Ala Gln Ala His Ile His Gly His 1425 1430 1435 1440 Thr Ile Asp Trp Arg His His Tyr Gln Thr Leu Arg Pro Thr Pro Pro 1445 1450 1455 His Ile Asp Leu Pro Thr Tyr Pro Phe Gln His His His Tyr Trp Leu 1460 1465 1470 His Asp Ser Thr Glu Asp Lys Ala Val Gly Thr Asp Leu Ala Ala Ala 1475 1480 1485 Arg Phe Trp Glu Ala Val His Gly Glu Asp Thr Asn Ala Val Ala Ala 1490 1495 1500 Leu Leu Asp Val Glu Pro Gly Thr Ser Leu Asp Ala Leu Leu Pro Ala 1505 1510 1515 1520 Leu Ser Ala Trp His Gly Arg Arg Arg Asp Gln Ala Ile Thr Asp Thr 1525 1530 1535 Trp Cys Tyr Arg Asp Ile Trp Lys Pro Ala Asp Leu Thr Ala Ala Arg 1540 1545 1550 Pro Arg Pro Ser Gly Arg Trp Leu Val Ala Ile Ser Ala Gly Arg Ala 1555 1560 1565 Asp His Leu His Val Ser Ala Val Leu Asp Ala Leu Glu Arg Gln Gly 1570 1575 1580 Leu Pro Ile Ala Thr Leu Val Leu Asp Asp Thr His Thr Glu Leu Pro 1585 1590 1595 1600 Leu Leu Glu Arg His Leu Ala Gln Ala Ile Ala Ser Asp Gly Pro Ala 1605 1610 1615 Ile Gly Gly Val Leu Ser Leu Leu Ala Leu Asp Glu Gly Pro His Pro 1620 1625 1630 Arg His Pro Glu Val Pro Val Gly Thr Ala Leu Thr Leu Ser Leu Ile 1635 1640 1645 Gln Ala Leu Ile Ala Arg Glu Asp Met Ala Pro Arg Leu Trp Leu Ala 1650 1655 1660 Thr His Glu Ala Val Ala Thr Ser Ser Ala Asp Thr Leu Asp His Pro 1665 1670 1675 1680 Leu Gln Ala Met Val Trp Gly Leu Gly Arg Thr Ala Ala Leu Glu His 1685 1690 1695 Pro Asp Leu Trp Gly Gly Leu Ile Asp Leu Pro Asp Thr Leu Thr Glu 1700 1705 1710 Arg Val Leu His Gly Leu Val Thr Ala Leu Thr Thr Cys His Asp Glu 1715 1720 1725 Asp Glu Leu Ala Leu Arg Ala Thr Gly Pro Arg Thr Arg Arg Leu Ile 1730 1735 1740 Arg Thr Pro Ser Thr Ala Ala Ala Glu Asp Thr Pro Pro Trp Thr Pro 1745 1750 1755 1760 Arg Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Ala Leu Gly Ser Arg 1765 1770 1775 Val Ala His Arg Ile Ala Glu Arg His Pro Asp Cys His Leu Leu Leu 1780 1785 1790 Val Ser Arg Arg Gly Pro Lys Ala Pro Gly Ala Thr Ala Leu Arg Asp 1795 1800 1805 Gln Leu Ile Glu Leu Gly Ala Thr Val Thr Leu Ala Ala Cys Asp Thr 1810 1815 1820 Ala Asp Pro Gly Ala Leu Ala Asp Leu Leu Ala Asp Val Pro Ser Asp 1825 1830 1835 1840 Arg Pro Leu Thr Ala Val Val His Thr Ala Gly Val Leu Asp Asp Ser 1845 1850 1855 Thr Leu Ala Val Gln Thr Pro Asp His Leu Ala Ala Val Leu Gly Pro 1860 1865 1870 Lys Ser His Ala Ala His His Leu His Ala Leu Ala Gln His His Pro 1875 1880 1885 Leu Asp Ala Phe Val Leu Phe Ser Ser Val Ala Ala Pro Phe Gly Ala 1890 1895 1900 Ala Gly Gln Ala Asn Tyr Ala Ala Ala Asn Ala Tyr Leu Asp Ala Leu 1905 1910 1915 1920 Ala Gln His Arg Arg Ala Gln Gly Leu Ala Ala Thr Ser Ile Ala Trp 1925 1930 1935 Gly Asn Trp Asp Gly Asp Gly Leu Ala Ser Thr Gln Ser Ala Gln Thr 1940 1945 1950 Tyr Leu Arg Asn Arg Gly Phe Pro Pro Met Pro Pro His Leu Ala Leu 1955 1960 1965 Ala Ala Leu Glu Arg Ala Ile Val Ser Pro His Ala Gln Leu Val Val 1970 1975 1980 Ala Asp Val Asp Trp Lys Lys Leu Lys Pro Ala Pro His Thr Arg Asp 1985 1990 1995 2000 Ile Pro Gly Ser Arg Arg Pro Ala Pro Ala Ala Thr Asp Gly Ala Asp 2005 2010 2015 Arg Thr Ala Asp Ala Thr Ala Ser Leu Arg Thr Arg Leu Ala Gly Gln 2020 2025 2030 Ser Pro Ala Glu Arg His Gln Thr Leu Leu Asp Leu Ile Ser Ser His 2035 2040 2045 Thr Ala Ala Val Leu Gly His Ala Thr Pro Gln Thr Ile Pro Thr Asp 2050 2055 2060 Arg Ala Phe Arg Asp Leu Gly Phe Thr Ser Leu Thr Ala Ile Glu Leu 2065 2070 2075 2080 Arg Asn Arg Leu Ala Ala Ala Thr Gly Leu Arg Leu Pro Thr Thr Val 2085 2090 2095 Ala Phe Asp Arg Pro Thr Pro Asp Lys Leu Ala Ala Asp Leu Leu Ala 2100 2105 2110 Arg Cys Ala Pro Thr Gly Pro Asp Gly Ile Gly Val Thr Pro Asp Ala 2115 2120 2125 Thr Ala Thr Ser Gly Ser Ser Pro Gly Ala Ala His Gly Ala Pro Asp 2130 2135 2140 Pro Ala Glu Pro Ile Ala Ile Val Gly Leu Ala Cys Arg Tyr Pro Gly 2145 2150 2155 2160 Gly Ile Gly Ser Pro Glu Asp Leu Trp Glu Phe Ile Thr Ala His Arg 2165 2170 2175 Asp Ala Val Gly Asp Phe Pro Thr Asp Arg Gly Trp Asp Leu Ala Arg 2180 2185 2190 Leu Phe Asp Pro Asp Pro Asp Arg Pro Gly Thr Ser Tyr Ser Arg Gln 2195 2200 2205 Gly Ala Phe Leu Arg Asp Ala Gly Asp Phe Asp Pro Glu Phe Phe Gly 2210 2215 2220 Ile Ser Pro Arg Glu Ala Thr Ala Thr Asp Pro Gln Gln Arg Leu Leu 2225 2230 2235 2240 Leu Glu Ala Ser Trp Glu Ala Leu Glu Arg Ala Gly Ile Asn Pro His 2245 2250 2255 Asp Leu His Gly Ser Pro Thr Gly Val Phe Thr Gly Ser Asn Ala Gln 2260 2265 2270 Asp Phe Ser Ala Arg Leu Arg Gln Thr Pro Ser Glu Leu Ala Glu Leu 2275 2280 2285 Cys Glu Gly Tyr Ala Leu Thr Gly Ser Asn Asn Ser Val Ala Ser Gly 2290 2295 2300 Arg Val Ser Tyr Ala Leu Gly Leu Glu Gly Pro Ala Val Ser Ile Asp 2305 2310 2315 2320 Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ser 2325 2330 2335 Leu Arg Ala Gly Glu Cys Ser Leu Ala Leu Ala Gly Gly Val Thr Val 2340 2345 2350 Met Met Thr Pro Phe Asn Phe Val Glu Phe Ser Arg Gln Arg Gly Leu 2355 2360 2365 Ala Ala Asp Gly Arg Cys Lys Ala Phe Ser Ala Thr Ala Asp Gly Thr 2370 2375 2380 Gly Trp Gly Glu Gly Val Gly Met Val Val Val Glu Arg Leu Ser Asp 2385 2390 2395 2400 Ala Arg Arg Asn Gly His Arg Val Leu Ala Leu Val Arg Gly Ser Ala 2405 2410 2415 Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro 2420 2425 2430 Ser Gln Gln Arg Val Ile Arg Ala Ala Leu Ala Ala Ala Gly Val Ala 2435 2440 2445 Ala Ala Glu Val Asp Ala Val Glu Ala His Gly Thr Gly Thr Thr Leu 2450 2455 2460 Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gly 2465 2470 2475 2480 Arg Pro Ala Asp Arg Ala Leu Trp Leu Gly Thr Val Lys Ser Asn Ile 2485 2490 2495 Gly His Ala Gln Ser Ala Ala Gly Ile Ala Gly Val Ile Lys Met Val 2500 2505 2510 Leu Ala Leu Arg His Gly Met Leu Pro Arg Thr Leu His Val Ser Glu 2515 2520 2525 Pro Ser Pro His Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr 2530 2535 2540 Glu Asp Gln Pro Trp Pro Asp Thr Gly Arg Pro Arg Arg Ala Gly Val 2545 2550 2555 2560 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Gln 2565 2570 2575 Ala Glu Pro Gly Pro Asp Pro Ala Pro Thr Ala Ser Ala Pro Ser Leu 2580 2585 2590 Pro Pro Trp Pro Leu Ser Ala Arg Ser Ala Glu Ala Leu Arg Ala Gln 2595 2600 2605 Ala Arg Arg Leu Leu Ala Tyr Val Ala Glu His Pro Asp Val Asp Pro 2610 2615 2620 Ala Asp Val Gly Tyr Ser Leu Ala Arg Gly Arg Ala Val Phe Glu His 2625 2630 2635 2640 Arg Ala Val Leu Leu Gly Thr Gly His Asp Asp Phe Arg Arg Ala Leu 2645 2650 2655 Asp Ala Leu Ala Ser Gly Ala Pro Asp Gly Ala Val Val Gln Gly Ala 2660 2665 2670 Ala Val Gly Arg Gln Gly Lys Val Val Phe Val Cys Ser Gly Gln Gly 2675 2680 2685 Thr Gln Arg Pro Gly Met Gly Arg Gly Leu Tyr Arg Ser Ser Thr Ala 2690 2695 2700 Phe Ala Gly Ala Leu Glu Glu Val Cys Ala His Leu Asp Pro Tyr Leu 2705 2710 2715 2720 Glu His Pro Leu Met Glu Val Met Phe Ala Asp Glu Lys Ser Asp Thr 2725 2730 2735 Ser Ala Leu Leu His Leu Thr Ala Tyr Ala Gln Pro Ala Leu Phe Ala 2740 2745 2750 Leu Gln Thr Ala Leu His Arg Met Val Thr Glu Glu Phe Gly Leu Thr 2755 2760 2765 Pro Asp Tyr Leu Ala Gly His Ser Leu Gly Glu Leu Thr Ala Ala His 2770 2775 2780 Leu Ala Gly Ile Leu Ser Leu Pro Asp Ala Ala Ala Leu Val Ala Ala 2785 2790 2795 2800 Arg Ala Arg Ala Met Arg Asp Leu Pro Ala Thr Gly Ala Met Val Ala 2805 2810 2815 Val Glu Ala Thr Glu Ala Glu Leu Arg Pro Arg Leu Ala Glu Leu Ala 2820 2825 2830 Asp Arg Val Gly Ile Ala Ala Val Asn Ala Pro Ala Ser Leu Val Ile 2835 2840 2845 Thr Gly Asp His Asp Ala Val His Gln Ile Ala Asp Asp Phe Arg Gly 2850 2855 2860 Gln Gly Arg Lys Val Thr Pro Leu Gln Val Ser Gly Ala Phe His Ser 2865 2870 2875 2880 Pro His Met Glu Pro Leu Leu Asp Glu Ile Gly Arg Thr Ala Glu Thr 2885 2890 2895 Leu Thr Tyr His Arg Pro His Thr Pro Leu Val Thr Ala Ser Ala Asp 2900 2905 2910 Gly Gly Asp Asp Thr Thr Glu Pro Arg Ala Asp Asp Asp Pro Gly Thr 2915 2920 2925 Ala Ala Phe Trp Pro Leu Gln Ala Arg Arg Thr Val His Tyr Ala Arg 2930 2935 2940 Ala Val Glu Arg Leu Arg Ala Arg Gly Val Thr Thr Phe Leu Glu Leu 2945 2950 2955 2960 Gly Pro Asp Ser Thr Leu Thr Thr Leu Val His His Asn Leu Ala Ala 2965 2970 2975 His Asp Pro Val Ala Val Ser Leu Leu His Pro Glu Arg Cys Glu Thr 2980 2985 2990 His Ser Val Leu Gly Ala Leu Ala Ala Val His Ala His Ser Arg Pro 2995 3000 3005 Val Asp Trp Thr Arg His Tyr Thr Ala Arg Pro Arg Pro Thr Pro His 3010 3015 3020 Gln Ile Asp Val Pro Thr Tyr Ala Phe Arg His Arg Arg Tyr Trp Leu 3025 3030 3035 3040 Pro Ala Pro Ala Ala Val Gly Asp Val Thr Ala Ala Gly Leu Asp Ala 3045 3050 3055 Ala Glu His Pro Leu Ile Gly Ala Ala Val Trp Leu Ala Glu Gly Asp 3060 3065 3070 Gly Cys Leu Leu Thr Gly Arg Ile Ser Pro Arg Thr His Pro Trp Leu 3075 3080 3085 Ala Asp His Val Ile Ala Gly Thr Val Leu Leu Pro Gly Thr Ala Phe 3090 3095 3100 Val Glu Leu Ala Leu Arg Ala Gly Ala Tyr Val Gly Cys Asp Arg Val 3105 3110 3115 3120 Glu Glu Leu Thr Leu His Ala Pro Leu Pro Leu Pro Ala Asp Gly Glu 3125 3130 3135 Val Val Leu Gln Val Ala Val Gly Ala Ala Asp Glu Ser Gly Arg Arg 3140 3145 3150 Glu Leu Ser Ile His Ala Arg Pro Ala Asp Asp Gly Thr Trp Thr Arg 3155 3160 3165 His Ala Ile Gly Thr Leu Ala Ser Ala Arg Gly Val Gly Leu Asp Asp 3170 3175 3180 Gly Thr Gly His Asn Gly His Ala Pro Ala Gly Asp Glu Pro Phe Gly 3185 3190 3195 3200 Ser Trp Ala Thr Ala Trp Pro Pro Pro Gly Ala Glu Pro Leu Asp Val 3205 3210 3215 Thr Gly Val Tyr Asp Arg Phe Ala Asp Ala Glu Phe Thr Tyr Gly Glu 3220 3225 3230 Ala Phe Gln Gly Leu Val Ala Ala Trp Arg His Gly Asp Glu Thr Leu 3235 3240 3245 Ala Glu Val Arg Leu Pro Asp Gln Pro Ala Gly Asp Ala Leu Arg Phe 3250 3255 3260 Gly Leu His Pro Ala Leu Leu Asp Ala Ala Leu Gln Thr Met Trp Leu 3265 3270 3275 3280 Val Glu Pro Asp Gly Thr Arg Pro Ser Gly Gly Leu Gly Gly Pro Asp 3285 3290 3295 Arg Gly Leu Pro Phe Ala Trp Gln Gly Val Ser Leu Arg Thr Ala Gly 3300 3305 3310 Pro Ser Ala Leu Arg Val Arg Leu Arg Arg Pro Ala Pro Asp Thr Val 3315 3320 3325 Ala Val Ala Val Ala Asp Ala Ala Gly Arg Pro Val Ala Ser Val Glu 3330 3335 3340 Ser Leu Thr Leu Arg Pro Val Pro Arg Gly Ala Leu Arg Gly Thr Glu 3345 3350 3355 3360 Thr Ala Val Arg Thr Ser Leu Tyr Gly Leu Asp Trp Thr Asp Val Pro 3365 3370 3375 Leu Pro Thr Pro Gln Thr Ala Leu Pro Arg Cys Ala Leu Ile Gly Ala 3380 3385 3390 Asp Thr Leu Asp Leu Val Pro Ala Leu Glu Ala Ala Ala Pro Asp Arg 3395 3400 3405 Ile Thr Asp Gly Val Glu Arg Tyr Ala Asp Leu Glu Glu Leu Val Arg 3410 3415 3420 Ser Val Ala Ala Gly Ala Pro Ala Pro Asp Leu Val Ile Ala Gly Cys 3425 3430 3435 3440 His Ala Ala Pro Glu Ala Asp Gly Ala Ser Glu Gln Pro Gln Pro Glu 3445 3450 3455 Thr Val Arg Thr Arg Thr Gly Gln Val Leu Glu Leu Leu Gln Arg Trp 3460 3465 3470 Leu Gly Ala Asp Gly Leu Ala Asp Ala His Leu Val Leu Phe Thr Ser 3475 3480 3485 Gly Ala Val Ala Thr Arg Pro Gly Glu Pro Val Arg Asp Leu Ala Gly 3490 3495 3500 Ala Ala Val Trp Gly Leu Val Arg Ser Gly Gln Ser Glu His Pro Glu 3505 3510 3515 3520 Cys Phe Thr Val Val Asp Met Asp Gly Ala Gln Glu Ser Arg Ala Ala 3525 3530 3535 Leu Leu Gly Ala Leu Gly Leu Gly Glu Pro Gln Leu Ala Val Arg Gly 3540 3545 3550 Gly Arg Ala Leu Ala Pro Arg Leu Val Arg Pro Gly Asp Ala Asp Asp 3555 3560 3565 Asp Ser Gly Leu Ala Leu Pro Gln Gly Pro Glu Gly Trp Arg Leu Glu 3570 3575 3580 Cys Pro Gly Thr Gly Ser Leu Asp Gly Leu Thr Thr Thr Glu Ser Pro 3585 3590 3595 3600 Ala Ala Ala Val Pro Leu Gly Pro Gly Glu Val Arg Val Ala Val Arg 3605 3610 3615 Ala Ala Gly Leu Asn Phe Arg Asp Val Leu Ile Ala Leu Gly Val Val 3620 3625 3630 Pro Gly Arg Thr Ala Leu Gly Ser Glu Gly Ala Gly Ile Val Leu Glu 3635 3640 3645 Val Gly Ala Glu Val Arg Asp Leu Ala Pro Gly Asp Arg Val Val Gly 3650 3655 3660 Ile Phe Pro Glu Ala Phe Gly Pro Val Ala Val Ala Glu Arg Ala Thr 3665 3670 3675 3680 Leu Ala Arg Val Pro Asp Gly Trp Ser Phe Ala Gln Ala Ala Ser Val 3685 3690 3695 Pro Ile Val Phe Ala Thr Ala Tyr His Gly Leu Val Asp Leu Ala Arg 3700 3705 3710 Leu Arg Pro Gly Glu Ser Val Leu Ile His Ala Ala Ala Gly Gly Val 3715 3720 3725 Gly Met Ala Ala Val Gln Leu Ala Arg His Leu Gly Ala Glu Val Tyr 3730 3735 3740 Ala Thr Ala Gly Pro Gly Lys Trp His Ile Leu Arg Ser Gln Gly Ile 3745 3750 3755 3760 Asp Asp Asp His Leu Ala Ser Ser Arg Thr Leu Glu Phe Glu Gln Arg 3765 3770 3775 Phe Ala Ala Thr Arg Gly Gly Arg Gly Ile Asp Val Val Leu Asp Cys 3780 3785 3790 Leu Ala His Glu Phe Val Asp Ala Ser Leu Arg Leu Val Ala Arg Asp 3795 3800 3805 Gly Gly Arg Phe Leu Glu Met Gly Lys Ser Asp Ile Arg Asp Pro Arg 3810 3815 3820 Gln Val Ala Leu Asp His Pro Gly Val Leu Tyr Arg Ala Phe Asp Leu 3825 3830 3835 3840 Leu Glu Ala Gly Pro Glu Arg Val Gly Gln Ile Leu Arg Thr Val Leu 3845 3850 3855 Asp Leu Phe Glu Arg Gly Val Leu Ala His Leu Pro Thr Thr Cys Trp 3860 3865 3870 Asp Ile Arg Gln Ala Glu His Ala Phe Arg His Leu Gln Gln Gly Arg 3875 3880 3885 His Ile Gly Lys Asn Val Leu Thr Val Pro Ala Gly Trp Asn Ala Glu 3890 3895 3900 Gly Thr Val Leu Ile Thr Gly Gly Met Gly Thr Leu Gly Ala Ala Leu 3905 3910 3915 3920 Ala Arg His Leu Ala Gly Thr Gly Arg Ala Arg His Leu Leu Leu Ala 3925 3930 3935 Gly Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Glu Leu Arg Glu Glu 3940 3945 3950 Leu Thr Glu Leu Gly Ala Arg Val Thr Ile Ala Ala Cys Asp Leu Gly 3955 3960 3965 Asp Arg Ala Ala Val Ala Arg Leu Leu Gly Ala Ile Pro Ala Glu Arg 3970 3975 3980 Pro Leu Thr Ala Val Ile His Ala Ala Gly Val Val Asp Asp Ala Thr 3985 3990 3995 4000 Leu Gly Ser Leu Thr Pro Arg His Leu Asp Ala Ala Leu Ala Ala Lys 4005 4010 4015 Ala Asp Ala Ala Trp His Leu His Thr Leu Thr Arg His Ala Asp Val 4020 4025 4030 Ala Ala Phe Val Leu Phe Ser Ser Val Ala Gly Leu Leu Gly Ser Pro 4035 4040 4045 Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Phe Leu Asp Ala Leu Ala 4050 4055 4060 His His Arg Arg Gly Ser Gly Leu Pro Ala Val Ser Leu Ala Trp Gly 4065 4070 4075 4080 Leu Trp Glu Gln Thr Ser Gly Met Thr Gly His Leu Asp Gln Ala Asp 4085 4090 4095 Arg Ala Arg Leu Ala Arg Leu Gly Ile Ser Pro Leu Thr Thr Gly Gln 4100 4105 4110 Ala Leu Gly Leu Phe Asp Ala Ala Leu Gly His His Arg Pro Val Leu 4115 4120 4125 Val Pro Ala Arg Leu Asp Val Pro Asp Pro His Pro Gly Ser Ser Thr 4130 4135 4140 Val Pro Pro Leu Tyr Arg Gly Leu Val Gly Ser Arg Thr Arg Arg Thr 4145 4150 4155 4160 Pro Pro Ala Ala Ala Ala Thr Gly Pro Phe Pro Leu His Thr Arg Leu 4165 4170 4175 Gly Gly His Ala Pro Ala Glu Gln His Glu Met Leu Leu Ser Leu Val 4180 4185 4190 Arg Ser His Ala Ala Leu Val Leu Gly Arg Asp Asp Pro Asp Thr Val 4195 4200 4205 His Pro Gly Ala His Phe Arg Gly Leu Gly Phe Asp Ser Leu Thr Ala 4210 4215 4220 Val Glu Leu Arg Asn Arg Leu Asn Ala Ala Thr Gly Leu Arg Leu Ser 4225 4230 4235 4240 Thr Thr Leu Val Phe Asp His Pro Thr Pro Asp Glu Leu Ala Arg His 4245 4250 4255 Val Arg Glu Gln Val Leu Gly Asp Gly Glu Ala Ala Arg Val Ala Pro 4260 4265 4270 Val Leu Ala Glu Leu Asp Arg Leu Glu Ala Ala Leu Ser Arg Val Asp 4275 4280 4285 Gly Asp Asp Ala Val Arg Ala Arg Val Thr Ala Arg Leu Gln Ala Leu 4290 4295 4300 Leu Leu Lys Trp Asn Glu Ser Asp Gly Pro Ala Thr Gly Gly Asp Gly 4305 4310 4315 4320 Ala Gly Arg Leu Ala Ser Ala Thr Ala Ala Glu Val Leu Asp Phe Ile 4325 4330 4335 Arg Asn Asp Leu Gly Leu Ser 4340 <210> 7 <211> 12993 <212> DNA <213> Artificial Sequence <220> <223> meilingmycin biosynthetic gene cluster (meiA1) of Streptomyces nanchangensis strain NS3226 <400> 7 gtggccggac atccgtggat cctctccgga cacaccggaa ccgcgctgcg ggcccaggcg 60 cgccggctcc acgaccatgt cgccgaccac cccctgctcc gtccggaaga catcgcgcac 120 acgctggcga gcggcggccc ggcgctcacc catcgcgcgg cggtgatcgc ggcggaccgg 180 gagggatatc tccgggggct cgacgcggtg gcccgaggtg aggacgcccc cggtgtcgta 240 cggggcacgg cgaccgcggt cggcgacggg gtcgcgttcg tcttccccgg ccagggcacc 300 cagtggcccg gtatggccgc ggatctgctg acggtctccc ctgccttcag ccgggcggtc 360 gacgcctgcg ccgaggcgtt cgaaccgtat gtcccctggt caccggaggc ggtgctgcgg 420 ggcgctccgg gcgcgccgcc cctggagggg accgatgtgg tgcagccgac gctgttcgcc 480 gtcatggtgg ggctggccga gctgtggcgg actcttgggg tgagcccgac gacgatcgtg 540 gggcactgca tcggggagat cgcggcggcc catctctgcg gcgccctgtc gctgtccgac 600 gcggcgcgcg tggtgatcga gagcagccgg gcccaggcga cgctctccgg gtcgggtgcg 660 ctgatcgcgg tcgcgcggtc cgaggcgcag ctgcttccgc tactgcggcg gtggccgggc 720 aggctgacga tcgccgcggt caacggcccg atggccacgg tcgtctccgg cgatcggccg 780 gccgccgacg agctgttggc ggagttggcc cgtgccggtg tccgggcccg cgaggtggcg 840 atcgacatcc ccgcgcactc ggcgttcatg gcccccctca gggacggtct gctcgactcg 900 ctgtcatcgg tcaccgcggg tgcgtcgcgg ctgccgttcc actcctcggt catcgggggg 960 ccgctggaga cccaagggct cgacgcggct tactggtacc ggaacctcgc cgacacggtc 1020 cgcttcgaaa gcgtggtcac ggggctgctg cggcagggca cgcgctgctt cgtggagctg 1080 agcccgcatc cgatgctgac catgtgtgtg caggccaccg ccgaggaggt ggtcggcggt 1140 gagcgcgtcg tgatcctgcc gacgctgcat cgcgggcaag ccgccgtcga gtccgttcgc 1200 accacgctgg ccgagctgta cgtacggggg gcgctggatg accctcgggc ggcgttctcg 1260 gtgccgggcg gccgactgat caccctgccc ctcgagccgc tcgcggacac gtccgtagag 1320 ctcgccgacg ccccggatcc tgcggaggcc tgccggcccc cttgggcgga gcggcttgcc 1380 cggctctcca ccgcggagcg gaagcggcgg ctgtgcgagc tggtgggcgt cgaggcggcc 1440 aaggtcctcg aggacgtcgc cggggcggac gcgccgcgcc acggcatcgc tgagcaggag 1500 cacttcgtcg cttcgggctt cgactccgcg gccgcggtcg cgctgcgcaa ccgcctgaac 1560 gacgccaccg gactgctgct gcccttcacc ctggccttcg accatccgac acccgccgcc 1620 gtcgccgacc atctgcactc ccggctcttc gatcaccggg gcggtgggca gccgggcgcc 1680 gacggctggc ccgaccccgc ggcggcggcc ggtccggcca gggccgacga cgagccgatc 1740 gccgtcatcg gcatggcggg ccgcttcccc gggggcgctc gtaccccgga ggagctgtgg 1800 gatctggtcg ccgaaggcac cgacgccctc tcccccttcc cggagggccg gggctgggat 1860 ccgctgcggc tctacgatcc ggaccccgcc cggcccggca cgtactacca gcgcgaagcg 1920 ggattcctcc acgacgccga caagttcgac gccgagttct tcggcatcgc gccacgcgag 1980 gccacggcca tggatcccca gcagcggctg ctcctggaga cctcctggga ggcgctcgaa 2040 cgggcgcgga tcgacccgac cgcgctgcgc ggcagccgca ccggggtgtt cgtcggcgtg 2100 gccccgctgg actacagccc ccgtatgcac caggcgtcgc cggagctgga gggccatctg 2160 ctgaccggca acatcggcgc cgcggcctcg gggcggatct cctacgtact cgggctcgag 2220 gggcccgcgg tgtccgtgga cacggcgtgc tcgtcgtccc tggtagccct gcatctggcg 2280 gctcaggcgc tgcgggccgg ggagtgctcg ctggccctgg tcggcggggc gacggtcctc 2340 tcgacccccg gcatgttcat cgagttctcg cggcagcgcg gtctggctcc ggacggccgc 2400 tgcaaggcgt acgcggccgc cgcggacggc accggctggt ccgagggcgt gggcatgctg 2460 ctcgtcgagc ggctgtccga cgcacgacgg ctcggacacc aggtgctggc ggtggtacgg 2520 ggctccgccg tcaaccagga cggggcgagc aacggcttca cggcgcccag cggtccatca 2580 cagcaacagg tcatccgggc ggccctggcc aatgcggggg tgtcggctcc ggaggtcgac 2640 gcggtggagg ggcacggcac cggcacccgg ttgggcgatc cgatcgaggc gcaggcgctg 2700 ctggcggcgt acgggcaggg gcgggcggcc gaccggccgc tgtggctggg ctcgatcaag 2760 tcgaacatcg gacacaccca gtgggccgcg ggcgtcatcg gggtcatcaa aatggtgctc 2820 gcgctccagc gcggtgtgct gccgcgcacg ctgcacgtgg acaagccgtc ggattacgtg 2880 gactggtcgg cgggggccgt acggctgttg acggagccgg tgccctggcc ggagaggggc 2940 cacccgcgcc gggcgggggt gtcgtccttc ggcgtgagcg gcaccaacgc ccatgtcatc 3000 ctcgagcagg caacgccatc gtccacggtg gctcccgagg ggcctaccgc cgaggccggg 3060 cctcccctgc cgtgggtgat ctcggcgaag accccccagg cactgcgcga ccaggcccgc 3120 cgcctgcacg aacacctcac cgcccagcca cagctccaac cggccgacgt cggccacacc 3180 ctcgccaccg gccgcgccac cttcgaccac cgggccgtcc tcatcggctc cgaccgcgaa 3240 caactcctcc acggcctgga cgcgctcgcc accggccggc ccgacccagc ggtccaccag 3300 acagcggacc gtcccgccac cgccgacggc cgtatcgtct tcgtcttccc cggacaaggc 3360 ggtcaatggg cgggcatggg tctacggctg ctgaacgcct cacccgtctt caccgagcgg 3420 atggccgcct gcgaacaggc cctctccccc tacgtcgact ggtcactcac ggacatcctc 3480 caccggccgg ccgacgacgc cgcatggcaa cgcgccgaca tcgtccagcc cgccctgttc 3540 tcgatcatgg tgtccctggc cgcgctctgg cgctcttgcg gcatcgaacc ggacgcggtc 3600 ctcggccact cccaaggcga gatcgccgcg gcccacgtct gcggcgcact gacgctccac 3660 gacgcggcca aggtcatcgc cctgcgcagc caggccctcc aagccgtacg cggcgccggg 3720 ggcatggcct ccgtacccct gtccgcggac caggtcaccg aggatctgca cacccactgg 3780 cccgaccggc tctgggtggc cgccaccaac tcccccacgg caaccgtcat ctcgggaaac 3840 accgacgcac tcgacgaagc gctcgaccac taccacgccc acgacgtacg ggccaaacgc 3900 atcccggtcg actacgcctc ccactgcccc catatcgacg cggtggccga gcgactgccc 3960 gatctgctgg gcggcatcgt cccgcgcgcc gccgacatcc ccttctactc cacggttgac 4020 ggccgatggg ccgagccgac cgagctcgac gccgactact ggtaccgcaa cctccgcagc 4080 cccgtacggt tcgcccacgc cgtccacgcc ctcaccgagg ccgaacaccg caccttcgtc 4140 gaagtcagcc cacaccccac gctcaccccc gccatcacgg ccaccgccga aaccaccgac 4200 cgcaccacca ccgtcatcgc ctcgctccac cgcgaccacg aagacgctca ccacatcctc 4260 accaacctcg cccaggccca catccacggc cacaccgtcg cctggcgaca ccactaccgg 4320 actctgcgcc ccaccccgcc ccacatcgac ctccccacct accccttcca acaccagcac 4380 tactggctcc acgactccac cgaggacaag gcggtgggta cggacctcgc tgcggcccgc 4440 ttctgggagg cagtcgacgg cgaggacacc aacgccgtcg ccgcgctcct cgacgtcgag 4500 ccgggcacct cgctggacgc gctgctgccg gccctgtccg cctggcacgg tcggcgtcgc 4560 gaccaggcca tcaccgacac ctggtgttac cgggacatct ggaagccggt cgacctcacc 4620 gccgcgcgcc cccgaccgtc cagccgatgg cttgtcgcga tctccgcagg gcgggccgat 4680 cacctccacg tcagtgccgt cctggacgct ctggaacgcc agggtctgcc catcgccacc 4740 ctcgtcctcg acgacaccca catcgaactc cccctgctgg agcggcatct cgcacaggtg 4800 atcgcgagcg atgggccggc catcggcggc gtgctctcgc tgctcgccct cgacgagggg 4860 ccacatccgc gccacccgga ggtgcccgtc ggcaccgccc tcaccctcag cctgatccag 4920 gcgctcatcg cacgtgagga catcgcgccc cggctctggc tggccaccca cgaggccgtc 4980 gccacctcgt ccgcggatac gctcgatcac cccctccagg cgatggtctg ggggctggga 5040 cgcaccgccg ccctcgaaca ccccgatctg tggggcggac tcatcgacct tccggacact 5100 ctcaccgaac gggtcctccg cggcctcgtc acggcgctga ccacctgtca cgacgaggac 5160 gagctcgcgc tgcgcgccac cggcccacgc acccggcggc tggtccggac gccgtccacc 5220 gccgcggcgg aggacacccc gccgtggacg ccccgtggca ccgtcctcat caccggcggc 5280 accggggccc tcggctcccg cgtcgcccac cgcatcgccg aacgtcaccc cggctgccac 5340 ttgctgctgg tgagccggcg aggggccaac gcccccggcg ccaccgcgct ccgcgaccag 5400 ctcatcgaac tcggcgccac ggtgaccctc gccgtatgtg acaccgccga ccccggcgcg 5460 ctcgcggatc tcctcgccga tgtcccctcg ggccgccctc tcaccgcggt cgtccacacc 5520 gcgggcgtcc tggacgacag caccctcgcc gtacagaccc cggaccacct cgccgccgtt 5580 ctggggccca agtcccatgc cgcacaccat ctgcacgccc tcgcccagca ccaccccctc 5640 gacgcgttcg tcctcttctc gtccgtcgcg gcgcccttcg gtgccgcggg ccaggccaac 5700 tacgcggccg ccaacgccta cctcgacgcc ctcgcccggc accgccgggc ccaggggctg 5760 gccgccacct ccatcgcctg gggcaactgg gacggcgacg ggctcgcgag cacccagtcc 5820 gcgcagacgt acctgcgcaa ccgcggcttt cctcccatgc cgccacacct ggcgctggcc 5880 gccatggagc gagcggtcgt ctcgccccac gcccagctcg tcgtcgccga cgtcgactgg 5940 aagaagctca agccgacgcc gcacacccgc gacatcccgg aaagccgccg cccggccccg 6000 gccgccaccg acggcgcaga caggaccgcc gacgccaccg cgagcctccg tacccgcctc 6060 gcgggtcaga gcccggccga acggcaccag acgctcctcg acctcatcag ctctcataca 6120 gccgccgtcc tcgggcacgc cacgccccag acgatcccca cggaccgggc cttccgcgac 6180 ctgggtttca cctcgctgac ggccatcgag ctccgcaacc gcctcgcggc ggccaccggg 6240 ctccgcctgc cgaccaccgt cgccttcgac cgcccgacgc cggacaagct cgcggcggac 6300 ctgctggcgc ggtgcgcgcc gacgggcccg gacggcatcg gagtgacagc cgacgcgacg 6360 gccgcgagcg gcagttcgcc cggtccggcg catggcgcgc tggaccccgc cgagcccatc 6420 gccatcgtcg gctgggcctg ccgctacccc ggcgggatcg gctcccccga ggacctgtgg 6480 gagttcgtca ccgcacaccg ggacgccgtc ggagacttcc cgaccgaccg gggctgggac 6540 ctggcgaggc tcttcgaccc cgatccggac cggccgggca cctcgtacag ccgacagggc 6600 gccttcctcc acgacgcggg cgacttcgac ccggagttct tcgggatcag cccacgggag 6660 gcgacggcga cggaccccca gcagcggctg ctcctggaga cgtcctggga agccctcgaa 6720 cgagccggga tcaacccgca cgatctccac ggcagtccga cgggcgtctt caccggcagc 6780 aacgcgcagg acttcagcgc acggctgcgg cagacgccgt cggagctggc ggagctgtgc 6840 gagggctatg cgctgacggg cagcaacaac agcgtcgcct cggggcgcgt ctcgtacgcg 6900 ctcggcctgg aaggcccggc ggtcagcatc gacaccgcct gctcgtcctc gctcgtggcg 6960 ctccatctgg cctgccagtc gctccgggcc ggcgaatgct cgcttgccct ggcgggcggc 7020 gtcacggtca tgatgacccc gttcaacttc gtggagttct cccggcagcg gggcctggcg 7080 gcggacggcc ggtgcaaggc gttctccgcc accgccgatg gcaccggctg gggcgagggc 7140 gtgggcatgg tggtggtgga gcggctgtcg gacgcgcggc gcaacggcca tcgtgtgctg 7200 gccctggtcc gcggcagcgc cgtcaaccag gacggtgcca gcaatgggct gactgccccg 7260 aacggcccct cgcagcagcg ggtcatccgc gccgccctgg ccgccgccgg ggtcaccgcg 7320 gcagaggtgg acgcggtcga ggcgcacggc acggggacga cgctcggcga tccgatcgag 7380 gcccaggccc tgctcgccac ctatgggcag gggcggccgg cggaccgggc gctgtggctc 7440 ggtacggtca agtccaacat cggacacgcc cagtcggccg ccggtatcgc cggggtcatc 7500 aagatggtgc tggccctgcg gcacgggatg ctgccgcgta cgctgcatgt gtccgagccg 7560 tcgccgcatg tggactggtc ggcgggtgcg gtacggctgc tgaccgagga ccagccgtgg 7620 ccggacaccg ggcgcccccg gcgggcgggg gtgtcgtcct tcggcgtgag cggcaccaac 7680 gcccatgtga tcctggagca ggcggagccg gggccggacc cggacccggc gccgacggcc 7740 tccgcgcact ccgtgctccc ctggcccctc tccgccaggt cggcggaggc cctgcgggcc 7800 caggcccgta ggttgcgggc gtacgtggcc gagcacccgg atgtcgaccc cgccgacgtg 7860 gggtactccc tcgcgcgcgg acgggccacc ttcgagcacc gggccgtgct cctcggcacc 7920 ggccacgacg acttccggcg cggcttggac gccctggtgt cgggcgcgcc cgacggcgcg 7980 gtcgtccagg gcgcggcggt ggggcggcag ggcaaggtcg tctttgtgtg ctcggggcag 8040 ggcacccagc gccccggcat gggccgcggg ctctaccgct cgtccacggc gttcgccggg 8100 gcgctggagg aggtgtgcgc ccatctggac ccgtatctgg aacaccctct gatggaggtg 8160 atgttcgccg acgagaagag cgatacgtcg gcgctgctgc atctgaccgc ctacgcccaa 8220 ccggccctct tcgccctcca gaccgcgctg catcgcatgg tcaccgagga gttcgggctc 8280 acccccgact atctggccgg ccactccctg ggcgagctga ccgccgccca tctggcgggc 8340 atcctcagcc tgcccgacgc cgcggcgctg gttgcggccc gcgcccgcgc catgcgggac 8400 cttccggcgg ccggagccat ggtcgccgtc gaggccaccg aggccgaact gcggcctcgg 8460 ctcgccgagt tggcggagcg ggtcgacatc gccgccgtca acgcccccgc gtccctggtc 8520 atcaccggcg accacggcgc cgtgcaccag atcgccgacg acttccgcgc gcagggcagg 8580 aaggtcacct ccctccaggt cagcggcgcc ttccactccc cccatatgga gcccctgctc 8640 gacgagatcg ggcgcaccgc cgaaaccctc acctaccacc ggccccacac tctcctcgtc 8700 accgcatcgg cggacggcgg cgacgacacg atcgagccgc gggccgacga cgacccgggc 8760 acggccgcgt tctggcctct ccaggcccgg cgcaccgtgc actacgcacg ggccgtggag 8820 cggctgcacg cccgcggcgt caccacgttc ctggaactcg gccccgacgc caccctcacc 8880 gccctcgtcc accacaacct cgccgcgcac gatcccgtgg ctgtctccct gctccatccg 8940 gagcggtgcg agacgcacag cgtcctcggc gcgctcgccg cggtccacgc ccacagccgc 9000 cccgtcgact ggacgcgcca ctacaccgca cggccgcggc cgacgccaca ccagatcgac 9060 gtgcccacct atgccttccg gcaccggcgc tactggctgc ccgccccggc ggcggtcggc 9120 gatgtgacgg ccgcggggct cgacgcggcg gagcacccgc tgatcggcgc cgccgtgggg 9180 ctcgcggagg gcgacggctg tctgctgacc ggcaggatct cgccgcgtac gcacccgtgg 9240 ctggccgacc atgtcatcgt cggcaccgtg ctgcttccgg gcaccgcgtt cgtggagctg 9300 gcgctgcggg ccggggcgta tgtgggctgc ggccgtgtgg aggagctgac cctgcacgcg 9360 ccgctccccg ccgacggtga ggtggtgctc caggtgacgg tgggggccgc cgacgagtcc 9420 ggccgccgtg agctgagcat tcacgcccgg ccggcggacg acggtacatg gacacggcac 9480 gccatcggca cgctggcacc ggcccacgac gtcgacgcgg gtcaagatgg ccacgccccg 9540 gcggatgacg ggcagttcgg gtcgtgggcc acggcctggc cgccgcccgg tgcggagccc 9600 ttggacgtca ccggggtcta cgcccggttt gccgacgccg agttcacgta cggggaggcc 9660 ttccaggggc tggtcgcggc ttggcggcac ggcgacgaga cgctggcgga ggtccgcctc 9720 cccgaccagc cggccggtga cgcccaccgc ttcgggctgc accccgcgct gctcgacgcg 9780 gcactgcaga ccatgtggct cgtggagccc gacggcacac ggccgacggg tggcctgggc 9840 ggccccgatc ggggcctgcc gttcgcctgg cagggggtct cgctgcgtac ggcgggcccg 9900 tcggccctgc gggtacggct gcgacggccg gcgccggaca ccgtggccgt cgccgtggct 9960 gacccggccg gccgaccggt cgcgtcggtg gagtcgctga cgctgcggcc ggtgccgcgg 10020 ggcgccttgc gcggcgccga ggcggcggtg cgcacctcgt tgcacggcct ggactggacg 10080 gatgtgccgc tgccgacgcc gcccccggcc cggccccggt gtgcgctgat cggagcggac 10140 acgctcggcc tgggccccgc gctcgaggcc gcggcgcccg accgcatcac cgacggcgtg 10200 gagcgctacg ccgacctgga ggagctggtg cgctccgtgg cggcgggcgc ccccgccccg 10260 gacctcgtca tcgccacctg ccacacagcc cctgaagccg acggcgcgag cgaacagcca 10320 cagcccgaga cggtgcgcac aaggacgggt caggtgctgg agctgcttca gcggtggctc 10380 ggcgcggacg ggctcgccga cgcacacctg gtgctgttca cctcaggcgc ggtcgccacc 10440 cggccgggcg agctggtgcg tgacctggcg ggggcggccg tctggggtct ggtgcgctcc 10500 ggccagtcgg agcatccgga gtgcttcacc gtggtggaca tggacggcgc ccaggagtcc 10560 cgcgcggcgc tgctcggcgc gctcggcctc ggcgagcctc aactggcggt gcgcggcggc 10620 cgggcgctgg cgccgcgcct ggtgcgcccg ggtgccgcag ccgacgacag cggcctggcc 10680 ctgccgcggg ggccggaagg ctggcggttg gagtgtcccg gcacgggcag cctggacggg 10740 ttgaccacga ccgagtcccc ggccgcggcg gtgccgctcg gcccgggcga ggtacgggtc 10800 gcggtgcggg ccgcggggct gaacttccgc gatgtgctga tcgcgctggg cgtggtgccc 10860 gggcggacgg cgctgggcag tgagggggcg gggatcgtcc tcgaggtcgg ggcggaggtc 10920 cgcgatctca cgcccgggga ccgggtggtg ggtatcttcc ccgaggcgtt cggcccggtg 10980 gccgtggccg agcgggcgac cttggcgcgg atccccgacg gctggtcgtt cgcccaggcc 11040 gcgtcggtcc ccatcgtgtt cgccaccgcg taccacggcc tggtcgatct ggcgcgcctg 11100 cggccggggg aatcggtgct gatccatgcc gcggccggcg gggtgggcat ggccgccgtg 11160 caactggcgc gccatctggg ggccgaggtg tacgccacag ccggccccgg caagtggcac 11220 atcctgcgct cccaaggcat cgacgacgac catctggcgt cgtcgcgcac gctggagttc 11280 gagcagcgct tcgccgcgac ccacggcggg cggggcatcg atgtcgtcct ggactgtctg 11340 gcccatgagt tcgtcgacgc ctcgctgcgc ctggtggcgc gtgacggcgg ccggttcctg 11400 gagatgggca agagcgacat ccgtgacccg cggcaggtgg cgctggacca tccgggcgtg 11460 ctctaccggg cgttcgacct gttggaggcc gggccggagc gggtcgggca gatcctgcgc 11520 accgtactgg acctgttcga gcgcggtgtc ctggcgcacc tgccgacgac ctgctgggac 11580 atccggcagg cggagcaggc cttccgccat ctgcagcagg gccgccacat cggaaagaac 11640 gtgctcaccg tcccggccgg ctggaacgcc gagggcaccg tactgatcac cggcggtacg 11700 ggcaccctgg gtgccgccct cgctcgccat ctggcgggta ccgggcgcgc ccgccatctg 11760 ctgctggtcg gccgacgcgg ccccgacgcc ccgggcgccg aggagctgcg agaggagctg 11820 accgagctgg gcgcgcgggt caccatcgcc gcatgcgatc tcggcgaccg ggcggcggtc 11880 gcccggctcc tgggggcgat cccggccgag cggccgctga ccgccgtcat ccacgcggcg 11940 ggtgtcgtcg acgatgccac cctcgggtcc ctcacccccc gccacctgga cgccgccctg 12000 gccgccaagg ccgacgccgc ctggcatctg cacaccctca cccgccacgc cgacgtggcc 12060 gcgttcgtcc tcttctcctc ggtcgccggt ctgctcggct cgcccgggca gggcaactac 12120 gccgcggcca acgccttctt ggacgcgctc gcccaccacc ggcgctgctc tggccttccg 12180 gcggtgtcgc tggcgtgggg gctgtgggag cagaccagcg gcatgaccgg agacctggac 12240 caggccgacc gcgcccggct ggcccggctc ggcatcagcc cgctcacgac cgggcaggcg 12300 ctcgaacttt tcgacaccgc cctcggccac caccgccccg tgctcgtccc cgcccgcctc 12360 gacgtgcccg acccgcaccc cggctcgtcg accgtgccgc ccctgtaccg gggcctggtc 12420 ggatccagga cccggcggac accccccgcg tccgccgcca ccgggccgtt ccccctgcat 12480 acccgcctcg acggtcacgc cccggccgag cagcacgaga tgctgctctc gctggtccgc 12540 tcgcacgccg ctctcgtgct gggccgcgac gatccggaca cggtccatcc cggcgcgcac 12600 ttccgcggtc tgggcttcga ctccctgacc gcggtcgagc tccgcaatcg gctcaacgcc 12660 gccaccggcc tccggctctc caccaccctc gtcttcgacc accccacgcc cgacgaactc 12720 gcccgtcacg tccgggagca ggtgctgggc gacggcgaag cggcgcgggt ggccccggtg 12780 ctggccgagc tcgacaggct ggaggccgcg ctgtcccggg tgaacgggga cgatgcgctc 12840 cgggcgaggg tgacggcccg gctgcaggcc cttctcctga agtggaacga gtccgatggt 12900 ccggcgacgg gcgcagacgg tgcgggcagg ctggcgtccg ccacggccgc cgaggtgctg 12960 gatttcatca ggaacgacct cggcctctcc tga 12993 <210> 8 <211> 4330 <212> PRT <213> Artificial Sequence <220> <223> meiA1 of Streptomyces nanchangensis strain NS3226 <400> 8 Val Ala Gly His Pro Trp Ile Leu Ser Gly His Thr Gly Thr Ala Leu 1 5 10 15 Arg Ala Gln Ala Arg Arg Leu His Asp His Val Ala Asp His Pro Leu 20 25 30 Leu Arg Pro Glu Asp Ile Ala His Thr Leu Ala Ser Gly Gly Pro Ala 35 40 45 Leu Thr His Arg Ala Ala Val Ile Ala Ala Asp Arg Glu Gly Tyr Leu 50 55 60 Arg Gly Leu Asp Ala Val Ala Arg Gly Glu Asp Ala Pro Gly Val Val 65 70 75 80 Arg Gly Thr Ala Thr Ala Val Gly Asp Gly Val Ala Phe Val Phe Pro 85 90 95 Gly Gln Gly Thr Gln Trp Pro Gly Met Ala Ala Asp Leu Leu Thr Val 100 105 110 Ser Pro Ala Phe Ser Arg Ala Val Asp Ala Cys Ala Glu Ala Phe Glu 115 120 125 Pro Tyr Val Pro Trp Ser Pro Glu Ala Val Leu Arg Gly Ala Pro Gly 130 135 140 Ala Pro Pro Leu Glu Gly Thr Asp Val Val Gln Pro Thr Leu Phe Ala 145 150 155 160 Val Met Val Gly Leu Ala Glu Leu Trp Arg Thr Leu Gly Val Ser Pro 165 170 175 Thr Thr Ile Val Gly His Cys Ile Gly Glu Ile Ala Ala Ala His Leu 180 185 190 Cys Gly Ala Leu Ser Leu Ser Asp Ala Ala Arg Val Val Ile Glu Ser 195 200 205 Ser Arg Ala Gln Ala Thr Leu Ser Gly Ser Gly Ala Leu Ile Ala Val 210 215 220 Ala Arg Ser Glu Ala Gln Leu Leu Pro Leu Leu Arg Arg Trp Pro Gly 225 230 235 240 Arg Leu Thr Ile Ala Ala Val Asn Gly Pro Met Ala Thr Val Val Ser 245 250 255 Gly Asp Arg Pro Ala Ala Asp Glu Leu Leu Ala Glu Leu Ala Arg Ala 260 265 270 Gly Val Arg Ala Arg Glu Val Ala Ile Asp Ile Pro Ala His Ser Ala 275 280 285 Phe Met Ala Pro Leu Arg Asp Gly Leu Leu Asp Ser Leu Ser Ser Val 290 295 300 Thr Ala Gly Ala Ser Arg Leu Pro Phe His Ser Ser Val Ile Gly Gly 305 310 315 320 Pro Leu Glu Thr Gln Gly Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu 325 330 335 Ala Asp Thr Val Arg Phe Glu Ser Val Val Thr Gly Leu Leu Arg Gln 340 345 350 Gly Thr Arg Cys Phe Val Glu Leu Ser Pro His Pro Met Leu Thr Met 355 360 365 Cys Val Gln Ala Thr Ala Glu Glu Val Val Gly Gly Glu Arg Val Val 370 375 380 Ile Leu Pro Thr Leu His Arg Gly Gln Ala Ala Val Glu Ser Val Arg 385 390 395 400 Thr Thr Leu Ala Glu Leu Tyr Val Arg Gly Ala Leu Asp Asp Pro Arg 405 410 415 Ala Ala Phe Ser Val Pro Gly Gly Arg Leu Ile Thr Leu Pro Leu Glu 420 425 430 Pro Leu Ala Asp Thr Ser Val Glu Leu Ala Asp Ala Pro Asp Pro Ala 435 440 445 Glu Ala Cys Arg Pro Pro Trp Ala Glu Arg Leu Ala Arg Leu Ser Thr 450 455 460 Ala Glu Arg Lys Arg Arg Leu Cys Glu Leu Val Gly Val Glu Ala Ala 465 470 475 480 Lys Val Leu Glu Asp Val Ala Gly Ala Asp Ala Pro Arg His Gly Ile 485 490 495 Ala Glu Gln Glu His Phe Val Ala Ser Gly Phe Asp Ser Ala Ala Ala 500 505 510 Val Ala Leu Arg Asn Arg Leu Asn Asp Ala Thr Gly Leu Leu Leu Pro 515 520 525 Phe Thr Leu Ala Phe Asp His Pro Thr Pro Ala Ala Val Ala Asp His 530 535 540 Leu His Ser Arg Leu Phe Asp His Arg Gly Gly Gly Gln Pro Gly Ala 545 550 555 560 Asp Gly Trp Pro Asp Pro Ala Ala Ala Ala Gly Pro Ala Arg Ala Asp 565 570 575 Asp Glu Pro Ile Ala Val Ile Gly Met Ala Gly Arg Phe Pro Gly Gly 580 585 590 Ala Arg Thr Pro Glu Glu Leu Trp Asp Leu Val Ala Glu Gly Thr Asp 595 600 605 Ala Leu Ser Pro Phe Pro Glu Gly Arg Gly Trp Asp Pro Leu Arg Leu 610 615 620 Tyr Asp Pro Asp Pro Ala Arg Pro Gly Thr Tyr Tyr Gln Arg Glu Ala 625 630 635 640 Gly Phe Leu His Asp Ala Asp Lys Phe Asp Ala Glu Phe Phe Gly Ile 645 650 655 Ala Pro Arg Glu Ala Thr Ala Met Asp Pro Gln Gln Arg Leu Leu Leu 660 665 670 Glu Thr Ser Trp Glu Ala Leu Glu Arg Ala Arg Ile Asp Pro Thr Ala 675 680 685 Leu Arg Gly Ser Arg Thr Gly Val Phe Val Gly Val Ala Pro Leu Asp 690 695 700 Tyr Ser Pro Arg Met His Gln Ala Ser Pro Glu Leu Glu Gly His Leu 705 710 715 720 Leu Thr Gly Asn Ile Gly Ala Ala Ala Ser Gly Arg Ile Ser Tyr Val 725 730 735 Leu Gly Leu Glu Gly Pro Ala Val Ser Val Asp Thr Ala Cys Ser Ser 740 745 750 Ser Leu Val Ala Leu His Leu Ala Ala Gln Ala Leu Arg Ala Gly Glu 755 760 765 Cys Ser Leu Ala Leu Val Gly Gly Ala Thr Val Leu Ser Thr Pro Gly 770 775 780 Met Phe Ile Glu Phe Ser Arg Gln Arg Gly Leu Ala Pro Asp Gly Arg 785 790 795 800 Cys Lys Ala Tyr Ala Ala Ala Ala Asp Gly Thr Gly Trp Ser Glu Gly 805 810 815 Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Leu Gly 820 825 830 His Gln Val Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp Gly 835 840 845 Ala Ser Asn Gly Phe Thr Ala Pro Ser Gly Pro Ser Gln Gln Gln Val 850 855 860 Ile Arg Ala Ala Leu Ala Asn Ala Gly Val Ser Ala Pro Glu Val Asp 865 870 875 880 Ala Val Glu Gly His Gly Thr Gly Thr Arg Leu Gly Asp Pro Ile Glu 885 890 895 Ala Gln Ala Leu Leu Ala Ala Tyr Gly Gln Gly Arg Ala Ala Asp Arg 900 905 910 Pro Leu Trp Leu Gly Ser Ile Lys Ser Asn Ile Gly His Thr Gln Trp 915 920 925 Ala Ala Gly Val Ile Gly Val Ile Lys Met Val Leu Ala Leu Gln Arg 930 935 940 Gly Val Leu Pro Arg Thr Leu His Val Asp Lys Pro Ser Asp Tyr Val 945 950 955 960 Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr Glu Pro Val Pro Trp 965 970 975 Pro Glu Arg Gly His Pro Arg Arg Ala Gly Val Ser Ser Phe Gly Val 980 985 990 Ser Gly Thr Asn Ala His Val Ile Leu Glu Gln Ala Thr Pro Ser Ser 995 1000 1005 Thr Val Ala Pro Glu Gly Pro Thr Ala Glu Ala Gly Pro Pro Leu Pro 1010 1015 1020 Trp Val Ile Ser Ala Lys Thr Pro Gln Ala Leu Arg Asp Gln Ala Arg 1025 1030 1035 1040 Arg Leu His Glu His Leu Thr Ala Gln Pro Gln Leu Gln Pro Ala Asp 1045 1050 1055 Val Gly His Thr Leu Ala Thr Gly Arg Ala Thr Phe Asp His Arg Ala 1060 1065 1070 Val Leu Ile Gly Ser Asp Arg Glu Gln Leu Leu His Gly Leu Asp Ala 1075 1080 1085 Leu Ala Thr Gly Arg Pro Asp Pro Ala Val His Gln Thr Ala Asp Arg 1090 1095 1100 Pro Ala Thr Ala Asp Gly Arg Ile Val Phe Val Phe Pro Gly Gln Gly 1105 1110 1115 1120 Gly Gln Trp Ala Gly Met Gly Leu Arg Leu Leu Asn Ala Ser Pro Val 1125 1130 1135 Phe Thr Glu Arg Met Ala Ala Cys Glu Gln Ala Leu Ser Pro Tyr Val 1140 1145 1150 Asp Trp Ser Leu Thr Asp Ile Leu His Arg Pro Ala Asp Asp Ala Ala 1155 1160 1165 Trp Gln Arg Ala Asp Ile Val Gln Pro Ala Leu Phe Ser Ile Met Val 1170 1175 1180 Ser Leu Ala Ala Leu Trp Arg Ser Cys Gly Ile Glu Pro Asp Ala Val 1185 1190 1195 1200 Leu Gly His Ser Gln Gly Glu Ile Ala Ala Ala His Val Cys Gly Ala 1205 1210 1215 Leu Thr Leu His Asp Ala Ala Lys Val Ile Ala Leu Arg Ser Gln Ala 1220 1225 1230 Leu Gln Ala Val Arg Gly Ala Gly Gly Met Ala Ser Val Pro Leu Ser 1235 1240 1245 Ala Asp Gln Val Thr Glu Asp Leu His Thr His Trp Pro Asp Arg Leu 1250 1255 1260 Trp Val Ala Ala Thr Asn Ser Pro Thr Ala Thr Val Ile Ser Gly Asn 1265 1270 1275 1280 Thr Asp Ala Leu Asp Glu Ala Leu Asp His Tyr His Ala His Asp Val 1285 1290 1295 Arg Ala Lys Arg Ile Pro Val Asp Tyr Ala Ser His Cys Pro His Ile 1300 1305 1310 Asp Ala Val Ala Glu Arg Leu Pro Asp Leu Leu Gly Gly Ile Val Pro 1315 1320 1325 Arg Ala Ala Asp Ile Pro Phe Tyr Ser Thr Val Asp Gly Arg Trp Ala 1330 1335 1340 Glu Pro Thr Glu Leu Asp Ala Asp Tyr Trp Tyr Arg Asn Leu Arg Ser 1345 1350 1355 1360 Pro Val Arg Phe Ala His Ala Val His Ala Leu Thr Glu Ala Glu His 1365 1370 1375 Arg Thr Phe Val Glu Val Ser Pro His Pro Thr Leu Thr Pro Ala Ile 1380 1385 1390 Thr Ala Thr Ala Glu Thr Thr Asp Arg Thr Thr Thr Val Ile Ala Ser 1395 1400 1405 Leu His Arg Asp His Glu Asp Ala His His Ile Leu Thr Asn Leu Ala 1410 1415 1420 Gln Ala His Ile His Gly His Thr Val Ala Trp Arg His His Tyr Arg 1425 1430 1435 1440 Thr Leu Arg Pro Thr Pro Pro His Ile Asp Leu Pro Thr Tyr Pro Phe 1445 1450 1455 Gln His Gln His Tyr Trp Leu His Asp Ser Thr Glu Asp Lys Ala Val 1460 1465 1470 Gly Thr Asp Leu Ala Ala Ala Arg Phe Trp Glu Ala Val Asp Gly Glu 1475 1480 1485 Asp Thr Asn Ala Val Ala Ala Leu Leu Asp Val Glu Pro Gly Thr Ser 1490 1495 1500 Leu Asp Ala Leu Leu Pro Ala Leu Ser Ala Trp His Gly Arg Arg Arg 1505 1510 1515 1520 Asp Gln Ala Ile Thr Asp Thr Trp Cys Tyr Arg Asp Ile Trp Lys Pro 1525 1530 1535 Val Asp Leu Thr Ala Ala Arg Pro Arg Pro Ser Ser Arg Trp Leu Val 1540 1545 1550 Ala Ile Ser Ala Gly Arg Ala Asp His Leu His Val Ser Ala Val Leu 1555 1560 1565 Asp Ala Leu Glu Arg Gln Gly Leu Pro Ile Ala Thr Leu Val Leu Asp 1570 1575 1580 Asp Thr His Ile Glu Leu Pro Leu Leu Glu Arg His Leu Ala Gln Val 1585 1590 1595 1600 Ile Ala Ser Asp Gly Pro Ala Ile Gly Gly Val Leu Ser Leu Leu Ala 1605 1610 1615 Leu Asp Glu Gly Pro His Pro Arg His Pro Glu Val Pro Val Gly Thr 1620 1625 1630 Ala Leu Thr Leu Ser Leu Ile Gln Ala Leu Ile Ala Arg Glu Asp Ile 1635 1640 1645 Ala Pro Arg Leu Trp Leu Ala Thr His Glu Ala Val Ala Thr Ser Ser 1650 1655 1660 Ala Asp Thr Leu Asp His Pro Leu Gln Ala Met Val Trp Gly Leu Gly 1665 1670 1675 1680 Arg Thr Ala Ala Leu Glu His Pro Asp Leu Trp Gly Gly Leu Ile Asp 1685 1690 1695 Leu Pro Asp Thr Leu Thr Glu Arg Val Leu Arg Gly Leu Val Thr Ala 1700 1705 1710 Leu Thr Thr Cys His Asp Glu Asp Glu Leu Ala Leu Arg Ala Thr Gly 1715 1720 1725 Pro Arg Thr Arg Arg Leu Val Arg Thr Pro Ser Thr Ala Ala Ala Glu 1730 1735 1740 Asp Thr Pro Pro Trp Thr Pro Arg Gly Thr Val Leu Ile Thr Gly Gly 1745 1750 1755 1760 Thr Gly Ala Leu Gly Ser Arg Val Ala His Arg Ile Ala Glu Arg His 1765 1770 1775 Pro Gly Cys His Leu Leu Leu Val Ser Arg Arg Gly Ala Asn Ala Pro 1780 1785 1790 Gly Ala Thr Ala Leu Arg Asp Gln Leu Ile Glu Leu Gly Ala Thr Val 1795 1800 1805 Thr Leu Ala Val Cys Asp Thr Ala Asp Pro Gly Ala Leu Ala Asp Leu 1810 1815 1820 Leu Ala Asp Val Pro Ser Gly Arg Pro Leu Thr Ala Val Val His Thr 1825 1830 1835 1840 Ala Gly Val Leu Asp Asp Ser Thr Leu Ala Val Gln Thr Pro Asp His 1845 1850 1855 Leu Ala Ala Val Leu Gly Pro Lys Ser His Ala Ala His His Leu His 1860 1865 1870 Ala Leu Ala Gln His His Pro Leu Asp Ala Phe Val Leu Phe Ser Ser 1875 1880 1885 Val Ala Ala Pro Phe Gly Ala Ala Gly Gln Ala Asn Tyr Ala Ala Ala 1890 1895 1900 Asn Ala Tyr Leu Asp Ala Leu Ala Arg His Arg Arg Ala Gln Gly Leu 1905 1910 1915 1920 Ala Ala Thr Ser Ile Ala Trp Gly Asn Trp Asp Gly Asp Gly Leu Ala 1925 1930 1935 Ser Thr Gln Ser Ala Gln Thr Tyr Leu Arg Asn Arg Gly Phe Pro Pro 1940 1945 1950 Met Pro Pro His Leu Ala Leu Ala Ala Met Glu Arg Ala Val Val Ser 1955 1960 1965 Pro His Ala Gln Leu Val Val Ala Asp Val Asp Trp Lys Lys Leu Lys 1970 1975 1980 Pro Thr Pro His Thr Arg Asp Ile Pro Glu Ser Arg Arg Pro Ala Pro 1985 1990 1995 2000 Ala Ala Thr Asp Gly Ala Asp Arg Thr Ala Asp Ala Thr Ala Ser Leu 2005 2010 2015 Arg Thr Arg Leu Ala Gly Gln Ser Pro Ala Glu Arg His Gln Thr Leu 2020 2025 2030 Leu Asp Leu Ile Ser Ser His Thr Ala Ala Val Leu Gly His Ala Thr 2035 2040 2045 Pro Gln Thr Ile Pro Thr Asp Arg Ala Phe Arg Asp Leu Gly Phe Thr 2050 2055 2060 Ser Leu Thr Ala Ile Glu Leu Arg Asn Arg Leu Ala Ala Ala Thr Gly 2065 2070 2075 2080 Leu Arg Leu Pro Thr Thr Val Ala Phe Asp Arg Pro Thr Pro Asp Lys 2085 2090 2095 Leu Ala Ala Asp Leu Leu Ala Arg Cys Ala Pro Thr Gly Pro Asp Gly 2100 2105 2110 Ile Gly Val Thr Ala Asp Ala Thr Ala Ala Ser Gly Ser Ser Pro Gly 2115 2120 2125 Pro Ala His Gly Ala Leu Asp Pro Ala Glu Pro Ile Ala Ile Val Gly 2130 2135 2140 Trp Ala Cys Arg Tyr Pro Gly Gly Ile Gly Ser Pro Glu Asp Leu Trp 2145 2150 2155 2160 Glu Phe Val Thr Ala His Arg Asp Ala Val Gly Asp Phe Pro Thr Asp 2165 2170 2175 Arg Gly Trp Asp Leu Ala Arg Leu Phe Asp Pro Asp Pro Asp Arg Pro 2180 2185 2190 Gly Thr Ser Tyr Ser Arg Gln Gly Ala Phe Leu His Asp Ala Gly Asp 2195 2200 2205 Phe Asp Pro Glu Phe Phe Gly Ile Ser Pro Arg Glu Ala Thr Ala Thr 2210 2215 2220 Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser Trp Glu Ala Leu Glu 2225 2230 2235 2240 Arg Ala Gly Ile Asn Pro His Asp Leu His Gly Ser Pro Thr Gly Val 2245 2250 2255 Phe Thr Gly Ser Asn Ala Gln Asp Phe Ser Ala Arg Leu Arg Gln Thr 2260 2265 2270 Pro Ser Glu Leu Ala Glu Leu Cys Glu Gly Tyr Ala Leu Thr Gly Ser 2275 2280 2285 Asn Asn Ser Val Ala Ser Gly Arg Val Ser Tyr Ala Leu Gly Leu Glu 2290 2295 2300 Gly Pro Ala Val Ser Ile Asp Thr Ala Cys Ser Ser Ser Leu Val Ala 2305 2310 2315 2320 Leu His Leu Ala Cys Gln Ser Leu Arg Ala Gly Glu Cys Ser Leu Ala 2325 2330 2335 Leu Ala Gly Gly Val Thr Val Met Met Thr Pro Phe Asn Phe Val Glu 2340 2345 2350 Phe Ser Arg Gln Arg Gly Leu Ala Ala Asp Gly Arg Cys Lys Ala Phe 2355 2360 2365 Ser Ala Thr Ala Asp Gly Thr Gly Trp Gly Glu Gly Val Gly Met Val 2370 2375 2380 Val Val Glu Arg Leu Ser Asp Ala Arg Arg Asn Gly His Arg Val Leu 2385 2390 2395 2400 Ala Leu Val Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly 2405 2410 2415 Leu Thr Ala Pro Asn Gly Pro Ser Gln Gln Arg Val Ile Arg Ala Ala 2420 2425 2430 Leu Ala Ala Ala Gly Val Thr Ala Ala Glu Val Asp Ala Val Glu Ala 2435 2440 2445 His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu 2450 2455 2460 Leu Ala Thr Tyr Gly Gln Gly Arg Pro Ala Asp Arg Ala Leu Trp Leu 2465 2470 2475 2480 Gly Thr Val Lys Ser Asn Ile Gly His Ala Gln Ser Ala Ala Gly Ile 2485 2490 2495 Ala Gly Val Ile Lys Met Val Leu Ala Leu Arg His Gly Met Leu Pro 2500 2505 2510 Arg Thr Leu His Val Ser Glu Pro Ser Pro His Val Asp Trp Ser Ala 2515 2520 2525 Gly Ala Val Arg Leu Leu Thr Glu Asp Gln Pro Trp Pro Asp Thr Gly 2530 2535 2540 Arg Pro Arg Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr Asn 2545 2550 2555 2560 Ala His Val Ile Leu Glu Gln Ala Glu Pro Gly Pro Asp Pro Asp Pro 2565 2570 2575 Ala Pro Thr Ala Ser Ala His Ser Val Leu Pro Trp Pro Leu Ser Ala 2580 2585 2590 Arg Ser Ala Glu Ala Leu Arg Ala Gln Ala Arg Arg Leu Arg Ala Tyr 2595 2600 2605 Val Ala Glu His Pro Asp Val Asp Pro Ala Asp Val Gly Tyr Ser Leu 2610 2615 2620 Ala Arg Gly Arg Ala Thr Phe Glu His Arg Ala Val Leu Leu Gly Thr 2625 2630 2635 2640 Gly His Asp Asp Phe Arg Arg Gly Leu Asp Ala Leu Val Ser Gly Ala 2645 2650 2655 Pro Asp Gly Ala Val Val Gln Gly Ala Ala Val Gly Arg Gln Gly Lys 2660 2665 2670 Val Val Phe Val Cys Ser Gly Gln Gly Thr Gln Arg Pro Gly Met Gly 2675 2680 2685 Arg Gly Leu Tyr Arg Ser Ser Thr Ala Phe Ala Gly Ala Leu Glu Glu 2690 2695 2700 Val Cys Ala His Leu Asp Pro Tyr Leu Glu His Pro Leu Met Glu Val 2705 2710 2715 2720 Met Phe Ala Asp Glu Lys Ser Asp Thr Ser Ala Leu Leu His Leu Thr 2725 2730 2735 Ala Tyr Ala Gln Pro Ala Leu Phe Ala Leu Gln Thr Ala Leu His Arg 2740 2745 2750 Met Val Thr Glu Glu Phe Gly Leu Thr Pro Asp Tyr Leu Ala Gly His 2755 2760 2765 Ser Leu Gly Glu Leu Thr Ala Ala His Leu Ala Gly Ile Leu Ser Leu 2770 2775 2780 Pro Asp Ala Ala Ala Leu Val Ala Ala Arg Ala Arg Ala Met Arg Asp 2785 2790 2795 2800 Leu Pro Ala Ala Gly Ala Met Val Ala Val Glu Ala Thr Glu Ala Glu 2805 2810 2815 Leu Arg Pro Arg Leu Ala Glu Leu Ala Glu Arg Val Asp Ile Ala Ala 2820 2825 2830 Val Asn Ala Pro Ala Ser Leu Val Ile Thr Gly Asp His Gly Ala Val 2835 2840 2845 His Gln Ile Ala Asp Asp Phe Arg Ala Gln Gly Arg Lys Val Thr Ser 2850 2855 2860 Leu Gln Val Ser Gly Ala Phe His Ser Pro His Met Glu Pro Leu Leu 2865 2870 2875 2880 Asp Glu Ile Gly Arg Thr Ala Glu Thr Leu Thr Tyr His Arg Pro His 2885 2890 2895 Thr Leu Leu Val Thr Ala Ser Ala Asp Gly Gly Asp Asp Thr Ile Glu 2900 2905 2910 Pro Arg Ala Asp Asp Asp Pro Gly Thr Ala Ala Phe Trp Pro Leu Gln 2915 2920 2925 Ala Arg Arg Thr Val His Tyr Ala Arg Ala Val Glu Arg Leu His Ala 2930 2935 2940 Arg Gly Val Thr Thr Phe Leu Glu Leu Gly Pro Asp Ala Thr Leu Thr 2945 2950 2955 2960 Ala Leu Val His His Asn Leu Ala Ala His Asp Pro Val Ala Val Ser 2965 2970 2975 Leu Leu His Pro Glu Arg Cys Glu Thr His Ser Val Leu Gly Ala Leu 2980 2985 2990 Ala Ala Val His Ala His Ser Arg Pro Val Asp Trp Thr Arg His Tyr 2995 3000 3005 Thr Ala Arg Pro Arg Pro Thr Pro His Gln Ile Asp Val Pro Thr Tyr 3010 3015 3020 Ala Phe Arg His Arg Arg Tyr Trp Leu Pro Ala Pro Ala Ala Val Gly 3025 3030 3035 3040 Asp Val Thr Ala Ala Gly Leu Asp Ala Ala Glu His Pro Leu Ile Gly 3045 3050 3055 Ala Ala Val Gly Leu Ala Glu Gly Asp Gly Cys Leu Leu Thr Gly Arg 3060 3065 3070 Ile Ser Pro Arg Thr His Pro Trp Leu Ala Asp His Val Ile Val Gly 3075 3080 3085 Thr Val Leu Leu Pro Gly Thr Ala Phe Val Glu Leu Ala Leu Arg Ala 3090 3095 3100 Gly Ala Tyr Val Gly Cys Gly Arg Val Glu Glu Leu Thr Leu His Ala 3105 3110 3115 3120 Pro Leu Pro Ala Asp Gly Glu Val Val Leu Gln Val Thr Val Gly Ala 3125 3130 3135 Ala Asp Glu Ser Gly Arg Arg Glu Leu Ser Ile His Ala Arg Pro Ala 3140 3145 3150 Asp Asp Gly Thr Trp Thr Arg His Ala Ile Gly Thr Leu Ala Pro Ala 3155 3160 3165 His Asp Val Asp Ala Gly Gln Asp Gly His Ala Pro Ala Asp Asp Gly 3170 3175 3180 Gln Phe Gly Ser Trp Ala Thr Ala Trp Pro Pro Pro Gly Ala Glu Pro 3185 3190 3195 3200 Leu Asp Val Thr Gly Val Tyr Ala Arg Phe Ala Asp Ala Glu Phe Thr 3205 3210 3215 Tyr Gly Glu Ala Phe Gln Gly Leu Val Ala Ala Trp Arg His Gly Asp 3220 3225 3230 Glu Thr Leu Ala Glu Val Arg Leu Pro Asp Gln Pro Ala Gly Asp Ala 3235 3240 3245 His Arg Phe Gly Leu His Pro Ala Leu Leu Asp Ala Ala Leu Gln Thr 3250 3255 3260 Met Trp Leu Val Glu Pro Asp Gly Thr Arg Pro Thr Gly Gly Leu Gly 3265 3270 3275 3280 Gly Pro Asp Arg Gly Leu Pro Phe Ala Trp Gln Gly Val Ser Leu Arg 3285 3290 3295 Thr Ala Gly Pro Ser Ala Leu Arg Val Arg Leu Arg Arg Pro Ala Pro 3300 3305 3310 Asp Thr Val Ala Val Ala Val Ala Asp Pro Ala Gly Arg Pro Val Ala 3315 3320 3325 Ser Val Glu Ser Leu Thr Leu Arg Pro Val Pro Arg Gly Ala Leu Arg 3330 3335 3340 Gly Ala Glu Ala Ala Val Arg Thr Ser Leu His Gly Leu Asp Trp Thr 3345 3350 3355 3360 Asp Val Pro Leu Pro Thr Pro Pro Pro Ala Arg Pro Arg Cys Ala Leu 3365 3370 3375 Ile Gly Ala Asp Thr Leu Gly Leu Gly Pro Ala Leu Glu Ala Ala Ala 3380 3385 3390 Pro Asp Arg Ile Thr Asp Gly Val Glu Arg Tyr Ala Asp Leu Glu Glu 3395 3400 3405 Leu Val Arg Ser Val Ala Ala Gly Ala Pro Ala Pro Asp Leu Val Ile 3410 3415 3420 Ala Thr Cys His Thr Ala Pro Glu Ala Asp Gly Ala Ser Glu Gln Pro 3425 3430 3435 3440 Gln Pro Glu Thr Val Arg Thr Arg Thr Gly Gln Val Leu Glu Leu Leu 3445 3450 3455 Gln Arg Trp Leu Gly Ala Asp Gly Leu Ala Asp Ala His Leu Val Leu 3460 3465 3470 Phe Thr Ser Gly Ala Val Ala Thr Arg Pro Gly Glu Leu Val Arg Asp 3475 3480 3485 Leu Ala Gly Ala Ala Val Trp Gly Leu Val Arg Ser Gly Gln Ser Glu 3490 3495 3500 His Pro Glu Cys Phe Thr Val Val Asp Met Asp Gly Ala Gln Glu Ser 3505 3510 3515 3520 Arg Ala Ala Leu Leu Gly Ala Leu Gly Leu Gly Glu Pro Gln Leu Ala 3525 3530 3535 Val Arg Gly Gly Arg Ala Leu Ala Pro Arg Leu Val Arg Pro Gly Ala 3540 3545 3550 Ala Ala Asp Asp Ser Gly Leu Ala Leu Pro Arg Gly Pro Glu Gly Trp 3555 3560 3565 Arg Leu Glu Cys Pro Gly Thr Gly Ser Leu Asp Gly Leu Thr Thr Thr 3570 3575 3580 Glu Ser Pro Ala Ala Ala Val Pro Leu Gly Pro Gly Glu Val Arg Val 3585 3590 3595 3600 Ala Val Arg Ala Ala Gly Leu Asn Phe Arg Asp Val Leu Ile Ala Leu 3605 3610 3615 Gly Val Val Pro Gly Arg Thr Ala Leu Gly Ser Glu Gly Ala Gly Ile 3620 3625 3630 Val Leu Glu Val Gly Ala Glu Val Arg Asp Leu Thr Pro Gly Asp Arg 3635 3640 3645 Val Val Gly Ile Phe Pro Glu Ala Phe Gly Pro Val Ala Val Ala Glu 3650 3655 3660 Arg Ala Thr Leu Ala Arg Ile Pro Asp Gly Trp Ser Phe Ala Gln Ala 3665 3670 3675 3680 Ala Ser Val Pro Ile Val Phe Ala Thr Ala Tyr His Gly Leu Val Asp 3685 3690 3695 Leu Ala Arg Leu Arg Pro Gly Glu Ser Val Leu Ile His Ala Ala Ala 3700 3705 3710 Gly Gly Val Gly Met Ala Ala Val Gln Leu Ala Arg His Leu Gly Ala 3715 3720 3725 Glu Val Tyr Ala Thr Ala Gly Pro Gly Lys Trp His Ile Leu Arg Ser 3730 3735 3740 Gln Gly Ile Asp Asp Asp His Leu Ala Ser Ser Arg Thr Leu Glu Phe 3745 3750 3755 3760 Glu Gln Arg Phe Ala Ala Thr His Gly Gly Arg Gly Ile Asp Val Val 3765 3770 3775 Leu Asp Cys Leu Ala His Glu Phe Val Asp Ala Ser Leu Arg Leu Val 3780 3785 3790 Ala Arg Asp Gly Gly Arg Phe Leu Glu Met Gly Lys Ser Asp Ile Arg 3795 3800 3805 Asp Pro Arg Gln Val Ala Leu Asp His Pro Gly Val Leu Tyr Arg Ala 3810 3815 3820 Phe Asp Leu Leu Glu Ala Gly Pro Glu Arg Val Gly Gln Ile Leu Arg 3825 3830 3835 3840 Thr Val Leu Asp Leu Phe Glu Arg Gly Val Leu Ala His Leu Pro Thr 3845 3850 3855 Thr Cys Trp Asp Ile Arg Gln Ala Glu Gln Ala Phe Arg His Leu Gln 3860 3865 3870 Gln Gly Arg His Ile Gly Lys Asn Val Leu Thr Val Pro Ala Gly Trp 3875 3880 3885 Asn Ala Glu Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Thr Leu Gly 3890 3895 3900 Ala Ala Leu Ala Arg His Leu Ala Gly Thr Gly Arg Ala Arg His Leu 3905 3910 3915 3920 Leu Leu Val Gly Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Glu Leu 3925 3930 3935 Arg Glu Glu Leu Thr Glu Leu Gly Ala Arg Val Thr Ile Ala Ala Cys 3940 3945 3950 Asp Leu Gly Asp Arg Ala Ala Val Ala Arg Leu Leu Gly Ala Ile Pro 3955 3960 3965 Ala Glu Arg Pro Leu Thr Ala Val Ile His Ala Ala Gly Val Val Asp 3970 3975 3980 Asp Ala Thr Leu Gly Ser Leu Thr Pro Arg His Leu Asp Ala Ala Leu 3985 3990 3995 4000 Ala Ala Lys Ala Asp Ala Ala Trp His Leu His Thr Leu Thr Arg His 4005 4010 4015 Ala Asp Val Ala Ala Phe Val Leu Phe Ser Ser Val Ala Gly Leu Leu 4020 4025 4030 Gly Ser Pro Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Phe Leu Asp 4035 4040 4045 Ala Leu Ala His His Arg Arg Cys Ser Gly Leu Pro Ala Val Ser Leu 4050 4055 4060 Ala Trp Gly Leu Trp Glu Gln Thr Ser Gly Met Thr Gly Asp Leu Asp 4065 4070 4075 4080 Gln Ala Asp Arg Ala Arg Leu Ala Arg Leu Gly Ile Ser Pro Leu Thr 4085 4090 4095 Thr Gly Gln Ala Leu Glu Leu Phe Asp Thr Ala Leu Gly His His Arg 4100 4105 4110 Pro Val Leu Val Pro Ala Arg Leu Asp Val Pro Asp Pro His Pro Gly 4115 4120 4125 Ser Ser Thr Val Pro Pro Leu Tyr Arg Gly Leu Val Gly Ser Arg Thr 4130 4135 4140 Arg Arg Thr Pro Pro Ala Ser Ala Ala Thr Gly Pro Phe Pro Leu His 4145 4150 4155 4160 Thr Arg Leu Asp Gly His Ala Pro Ala Glu Gln His Glu Met Leu Leu 4165 4170 4175 Ser Leu Val Arg Ser His Ala Ala Leu Val Leu Gly Arg Asp Asp Pro 4180 4185 4190 Asp Thr Val His Pro Gly Ala His Phe Arg Gly Leu Gly Phe Asp Ser 4195 4200 4205 Leu Thr Ala Val Glu Leu Arg Asn Arg Leu Asn Ala Ala Thr Gly Leu 4210 4215 4220 Arg Leu Ser Thr Thr Leu Val Phe Asp His Pro Thr Pro Asp Glu Leu 4225 4230 4235 4240 Ala Arg His Val Arg Glu Gln Val Leu Gly Asp Gly Glu Ala Ala Arg 4245 4250 4255 Val Ala Pro Val Leu Ala Glu Leu Asp Arg Leu Glu Ala Ala Leu Ser 4260 4265 4270 Arg Val Asn Gly Asp Asp Ala Leu Arg Ala Arg Val Thr Ala Arg Leu 4275 4280 4285 Gln Ala Leu Leu Leu Lys Trp Asn Glu Ser Asp Gly Pro Ala Thr Gly 4290 4295 4300 Ala Asp Gly Ala Gly Arg Leu Ala Ser Ala Thr Ala Ala Glu Val Leu 4305 4310 4315 4320 Asp Phe Ile Arg Asn Asp Leu Gly Leu Ser 4325 4330 <210> 9 <211> 16599 <212> DNA <213> Artificial Sequence <220> <223> aveA3 gene of Streptomyces avermitilis MA-4680 <400> 9 atggacacgt ccagcgaaaa gctcgtcgac gcgcttaggg cgtctctgaa ggcgaaccag 60 accctgcggg cacgtaatga gcaactggca gccgccatgg aggcgtccag cgagccgatt 120 gcgattgtgg ggatggcgtg tcgttttccg ggtggggtgt gttcgccgga ggagttgtgg 180 gagctggttg cgtcgggtgg ggatgcgatt ggtgaatttc cggccggtcg ggggtgggat 240 ctggaggggt tgtttgattc ggaccctgac cggtcgggga cgtcgtacgc gcggtatggc 300 gggtttttgt atgaggcggg ggagttcgat gcggacttct tcgggatcag tccgcgtgag 360 gcgttggcga tggatccgca gcagcggttg ttgctggaga cgtcgtggga ggcgttcgag 420 cgggcgggta tcgatccgct gtcgatgcgt ggctcccgta cgggtgtctt cgccggggtg 480 atgtaccacg actacggatc ccgcctgggt accatccccg agggattcga gggctacatc 540 ggcaacggta gcggcggcgc cgtcgcgtcg ggccgcgtcg cctacacgct cggtctcgag 600 ggccctgccg tctcggtgga cacggcatgt tcgtcgtcgt tggtggcgct gcatctggcg 660 tgccagtcgc tgcggtcggg tgagtgcacg ctcgcgctgg ccggcggtgt gacggtgatg 720 tcgaccccgc acctcttcgt cgagttctca cgccagcgcg gactgtcggt ggacggccgc 780 tgcaagtcct tcgcgggtgg agccgacggc accggcatgg gcgagggcgt cgggatgctg 840 ttggtggagc ggttgtcgga tgcggtgcgg ctggggcatc gggtgctggc ggtgctgcgc 900 ggcagtgcgg tcaatcagga cggtgcgtcg aatgggttga cggcgccgaa tggtccggct 960 caggagcggg tgatccggca ggcgttggcg aacgcggggt tgtccgtggc ggatgtggat 1020 gtggtggagg ggcatgggac gggcacgacg ctgggtgatc cgatcgaggc gcaggcgttg 1080 ctcgccacgt acgggcagcg ggccggtaac aggccgctgt ggctgggatc ggtgaagtcg 1140 aacatcggcc atgcgcaggc tgccgcgggt gtgggtgggg tcatcaagat ggtgatggcg 1200 ttgcgggagg gggtgttgcc gcggacgttg catgtggatg agccgtcgcc gcaggtggac 1260 tggtccgcgg gggcggtgcg gctgctgacg gaggcggtgc cgtggccggg ggacgcggca 1320 gggcggttgc ggcgggcggg agtgtcgtcg ttcggggtca gtggcacgaa tgcgcatgtg 1380 attttggagg aggcgccggc ggcggggggc tgtgttgccg ggggtggggt gttggagggt 1440 gctccgggtc ttgccatttc ggtggctgag tcggtggccg ctccagtggc tgtgtctgcg 1500 ccggtggctg agtcggtgcc ggtgccggtg ccggtgccgg ttcctgtgcc ggtgtcggct 1560 aggtctgagg ctgggttgcg ggcgcaggcg gaggcgttgc gtcagtacgt ggcagtccgg 1620 ccggacgttt cgcttgccga tgtgggtgcg ggtctggcct gtgggcgggc tgtgctggag 1680 catcgtgcgg tcgtcctggc cgcggaccgt gaggagctgg tgcaagggtt gggggcgctg 1740 gcggcgggtg agccggatcg gcgggtgacc acgggtcatg cgccgggtgg tgaccggggc 1800 ggtgtcgtct tcgtgtttcc cggacagggt gggcagtggg ccgggatggg tgtgcgtctg 1860 ctcgcctcct ctccggtgtt cgcccggcgg atgcaggcgt gcgaggaggc tctggcgccg 1920 tgggtggact ggtctgtggt ggacatcctg cgccgggacg cgggggatgc ggtgtgggag 1980 cgggccgatg tggtccagcc tgtgctgttc agcgtcatgg tgtctttggc tgctctgtgg 2040 cgttcctacg gtatcgaacc cgacgcggtc cttggccatt cccagggcga gatcgcggcc 2100 gcgcatgtgt gtggggcgct gagcctgaag gacgcggcga agactgttgc gctgcgcagc 2160 cgggcgctgg ccgctgtgcg gggccggggc ggcatggcct cagtgccgct gcctgcccag 2220 gaggtggagc agctcattgg tgagcggtgg gcggggcggt tgtgggtggc ggcggtcaac 2280 ggcccccgct ccaccgccgt ctcgggggat gccgaggcgg tggacgaggt gctggcgtac 2340 tgtgccggca ccggggtgcg ggcccggcgg atcccggtcg actatgcctc gcactgcccc 2400 catgtgcagc ccctgcggga ggagttgctg gagctgctgg gggacatcag cccgcagccg 2460 tccggcgtgc cgttcttctc cacggtggag ggcacctggc tggacaccac aaccctggac 2520 gccgcctact ggtaccgcaa cctgcaccag cctgtccgtt tcagcgatgc cgtccaggcc 2580 ctggcggatg acggacaccg cgtcttcgtc gaagtcagcc cccaccccac cctcgtcccc 2640 gccatcgaag acaccaccga agacaccgcc gaagacgtca ccgcgatcgg cagcctccgc 2700 cgcggcgaca acgacacccg ccgcttcctc accgccctcg cccacaccca caccaccggc 2760 atcggcacac ccaccacctg gcaccaccac tacacccacc accacaccca cccccacaac 2820 caccacctcg acctccccac ttatcccttc caacgccagc actactggct cgacgctccc 2880 acgggagcag gtgacgtcgc cgctgctggc ttggagccgg ccgaacaccc tctgctcgcg 2940 gcaacagtcc aactcgcaga cacggacggc tgcctactga cgggtcgcct gtccttgcgc 3000 tcgcatccgt ggctgggcga ttacgaggtg gggggtgcgg tcctgctgtc ggggtcggcg 3060 ttcgtggagc tggcggtcca ggttggcgaa cgcgtgggct gcacccgaat cgagcaactc 3120 actgtgcatg cgccgctggt ggttcctgtg ggtgggggtg tgagtgtgca ggttggggtt 3180 gcggctgcgg atggggaggg gcggcgtttg gtgagtgtgt atgcgcgggg tgggagtgct 3240 tgtggtgggg gtggtgcgtc gggtggggtg tggacgtgtc atgcctcggg ggtgctggtt 3300 gaggctgctg ctggtggtgg tgtggtggtg gatggtctgg cgggggtgtg gccgccgcgg 3360 ggtgcggtgg cggtggatgt cgatggtgtc cgtgaccgtt tggctggggc tggttgtgtt 3420 ttggggccgg tgttttcggg gctgcgtgcg gtgtggcgtg atggggggga tttgctggct 3480 gaggtgtgtc tgccggagga ggcgtggggt gatgcggctg gttttgggct gcatccggcg 3540 ttgctggatg gtgtggtcca gccgttgtcg gtgttgcttc cgggtgggac ggggtttggg 3600 gagggggcgg ggttcgggga gggtgttcgg gtgccggctg tgtggggtgg tgtgtcgctt 3660 caccgggcgg gtgtgaccgg tgtgcgggtg cgtgtgtggg ctgtagggcg gggcggcggg 3720 cgtgaggcgg tgtcggtcgt ggtcggggat gaggcgggtg tgccggtggc gtcggtcgat 3780 cgtcttgagt tgcggcctgt ggatatgggt cagttgcgtg ctgtctcggt ttcggcgggg 3840 cggcggggtt cgctgtatgc ggtgcagtgg gctgaggtgg gtcctgtgcc ggtgtgtggg 3900 caggcgtggg cgtggcacga ggacgtgggt gagagcggtg gtgggcctgt gccgggggtg 3960 gtggtgttgc ggtgcccgga tgccggtgcc ggtggcggcg gtggcggtgg tgtgggtgag 4020 gttgttggtg gggtgttggg tgtggtgcag gggtggctgg ggctggagcg gtttgcgggt 4080 tcgcggctgg tggtggtgac ccggggtgcg gtggtggccg gccaagaaga cggcccggtg 4140 gatgtggtgg gtgcggcggt gtgggggctg gtgcggtcgg cgcaggctga gcatccggac 4200 cggtttgtcc tcctcgacct cgacaccgac accgacaccg gcaccgacct cgacaccggt 4260 gctggtgctg gtgctggtgc tggttggggc gtggatggtg ggcatgtggc ggcggtggtg 4320 gcgtgtggtg agccgcagtt ggcggtgcgt ggtgagcggg tgctggccgc acgcctgacg 4380 cgacttgagt cgtccgttga tgtacctgct cagcggtccg gtgatgttgc tggtcgggag 4440 gtgttgccgt ggttgtcggg tgggtcggtg ttggtgacgg gtgggacggg tgtgctgggt 4500 gcggcggtgg cgcggcatct ggctggtgtg tgtggggtgc gggatctgct gttggtgagc 4560 cggcgtggtc cggatgctcc gggtgcggag ggtttgcggg cggagctggc cgcgttgggg 4620 gcggaggtgc ggattgttgc gtgtgatgtg ggggagcggc gggaggtggt ccggctgctg 4680 gagggtgttc ctgccgggtg tccgctgacg ggtgtcgtgc atgcggctgg tgtgctggac 4740 gatgcgacga tcgcctctct cacgcccgag cggctgggca cggtgttcgc ggccaaggtg 4800 gatgccgctc ttttgctgga tgagctgacg cggggtatgg agctgtcggc gttcgtgctg 4860 ttctcctcgg ccgcggggat cctggggtcg gccgggcagg gcaactacgc cgcggccaat 4920 gccgctctgg acgcgctggc gtaccggcgg cgggcggcgg gtctgccggg ggtgtcgctg 4980 gcgtgggggc tgtgggaaga ggccagcggg atgaccgggc acctggccgg caccgaccac 5040 cggcgcatca tccgttccgg tctgcatccc atgtcgaccc cggacgcact ggctctcttc 5100 gatgcggccc tggctctgga ccggccggtc ctgctgcccg ccgacctgcg tcccgccccg 5160 cccctgccgc ccctgctgca ggacctcctg cccgccaccc gccgccgcac cacccgcacc 5220 accactaccg gtggtgcgga caacggcgcc cagctgcatg cccggctggc cggccagaca 5280 cacgaacaac agcacaccac cctcctcgcc ctggtccgct cccacatcgc caccgtcctc 5340 ggccacacca cccccgacac catccccccc gaccgcgcgt tccgcgacct cggcttcgac 5400 tccctcaccg ccgtcgaact acgcaaccgg ctctcccgca ccaccggact ccgcctcccc 5460 accaccctcg ccttcgacca ccccaacccc accaccctca cccaccacct ccacacacaa 5520 cttctgggct cggacagcac tgcctccatc ccagctcccc gtgctgcggc tgtgcctgca 5580 gaccaggacg agcccgtcgc gatcattggc atggcgtgcc gctatcccgg aggcgtcacc 5640 tcagccgagg agctgtggga actgctcgca tcggggaggg acacggtcgg cgagtttccg 5700 acggaccgtg ggtgggacct ggaagcactg ttcgatccgg aaccgggtcg gccgggcacc 5760 tcgtacaccc gctgtgggag tttcctctac gacgcggggg agttcgacgc cggcttcttc 5820 gggatcagtc cgcgtgaggc actggcgatg gacccgcagc agcgattgct gctggaggcc 5880 tcatgggagg ccatggagca ggcaggtatt gaccctacga ccgtacgcgg gagccagaca 5940 ggcgtgttcg cgggcctcat tccgcaggcc tatggaccca ggctgcacga aaacgccgca 6000 gccgacaccg agggctatgt cctgaccggc acatccggga gtgtggcctc cggtcgtatc 6060 tcgtacacgt ttggttttga gggtcctgcg gtgtcggtgg acacggcttg ttcctcgtcg 6120 ttggtggctt tacatctggc ctgtcaggcg ttgcgtgcgg gtgagtgctc gatggcgctt 6180 gccgggggtg tgacggtgat gtcgtctccg ggtgccttcg tggagttttc gcggcagcgg 6240 ggtctggccg cggacgggca ttgcaaggcg ttctcggcgg cggcggacgg gaccggctgg 6300 ggtgagggtg tggggatgct gctggtggag cggctctccg acgcccgtcg caacggtcac 6360 cgtgtcctgg ccgtggtgcg tggcagtgcg gtcaaccagg acggtgcgag caacgggctg 6420 accgcgccca acgggccctc ccagcagcgt gtcatccgcc aggccctcgc caacgccggc 6480 ttgtcggccg gtgatgtcga tgcggtggag gcccacggca ccggcaccac tttgggcgac 6540 ccgatcgagg cccaggccct ccttgcgacc tacgggcagg accgtgccgg cgaggggccg 6600 ctgtggctgg gctcggtcaa gtccaatgtc ggtcacacac aggctgccgc gggcgtcgcc 6660 ggggtgatca agatggtgat ggcgctgcgg aatggtctgc tgccgcggac gttgcatgtg 6720 gatgagccgt cgccgcatgt ggactggtcc gcgggtgcgg tgcagctgct gacggagacg 6780 gtgccctggc ccggcgggga ggggcggcta cggcgggcag gagtgtcatc attcggcgtc 6840 agcggcacca acgcccacgt catcctcgaa gaagcacccg cccacaacat cccgtcagac 6900 acacccgccg acgacgttcc ggggggacca cccgccggcg aggatgccgg tagtggcgag 6960 gaggctgctg ccggcagtcc aggggtgtgg ccgtggctgg tgtcggccaa gtcgcagccg 7020 gccctgcgcg cccaggccca ggccctgcac gcccacctca ccgaccaccc cggcctcgac 7080 ctcgccgacg tcggatacac cctcgcccac gcccgcgccg tgttcgacca ccgcgccacc 7140 ctcatcgccg ccgaccgcga caccttcctg caagcactcc aggcactcgc cgcaggcgaa 7200 ccccaccccg ccgtcatcca cagcagcgcc ccaggcggga ccgggaccgg ggaggccgca 7260 ggaaagaccg cattcatctg ctccggacag ggcacccaac gccccggcat ggcccacggc 7320 ctctaccaca cccaccccgt cttcgccgcc gcactcaacg acatctgcac ccacctcgac 7380 ccccacctcg accaccccct cctccccctc ctcacccagg accccaacac ccaggacacc 7440 accaccctcg aagaagcggc cgcactgctc cagcagaccc cgtacgccca gcccgccctc 7500 ttcgccttcc aggtcgccct ccaccgcctc ctcaccgacg gctaccacat caccccccac 7560 tactacgccg gacactccct cggcgaaatc accgccgccc acctcgccgg catcctcacc 7620 ctcaccgacg ccaccaccct catcacccaa cgcgccaccc tcatgcaaac catgcccccc 7680 ggcaccatga ccaccctcca caccaccccc caccacatca cccaccacat caccgcccac 7740 gaaaacgacc tcgccatcgc cgccatcaac acccccacct ccctcgtcat cagcggcacc 7800 ccccacaccg tccaacacat caccaccctc tgccaacaac aaggcatcaa aaccaaaacc 7860 ctccccacca accacgcctt ccactccccc cacaccaacc ccatcctcaa ccaactccac 7920 cagcacaccc aaaccctcac ctaccaccca ccccacaccc ccctcatcac cgccaacacc 7980 ccacccgacc aactcctcac cccccactac tggacccaac aagcccgcaa caccgtcgac 8040 atagccacca ccacccaaac cctccaccaa cacggcgtca ccacctacat cgaactcgga 8100 cccgacaaca ccctcaccac cctcacccac cacaacctcc ccaacacccc caccaccacc 8160 ctcaccctca cccaccccca ccaccacccc caaacccacc tcctcaccaa cctcgccaaa 8220 accaccacca cctggcaccc ccaccactac acccaccacc acaaccaacc ccacacccac 8280 acccacctcg acctccccac ctaccccttc caacaccacc actactggct cgaaagcaca 8340 cagcccggtg ccggcaacgt gtcagcagcc ggactcgacc ccaccgaaca ccccctactc 8400 ggcgccacat tggaactggc cgaaggggac ggctgcctac tgacggggcg cctctcgttg 8460 cgcacgcatc cctggctcgc cggccatgcg gtaggcggtg tcgtgctgct gccgggtacg 8520 gccttcgcgg aactggccct tcatgccgga gaaagtgtgg gttgcgacca cgtggacgag 8580 ctgacgctcc acacaccgtt ggtcattcct gaggtcggag acgtgaccct tcaggttgcc 8640 attgcggcgc cggacgagtc gggtcgccgc atgatgacca tccactcacg cggtgagggc 8700 ggcagtggtg gagccgatgc gtcggccagt gcgtggacgc gtcatgccgc gggtgtgctg 8760 agccctgcca aggacgatga cactgcctcg tacgagctgc ttgcgggacc ctggcctccc 8820 gttggagcta cgcctgtcga cctgaacacg gcttacgatc aaatggccga cgccggcttt 8880 gcttatggcc tggcattcca agggttgcgc gcggcctggc gctacggcga cgacatcctc 8940 gtcgaggcac gtcttcccga agaagtgtcg ggagacgcgg cggcgtacgg tctgcacccg 9000 gccctgctcg acgctgccct tcagggcacc ggcctgcttt ctgtggcggg tccggggacg 9060 cccgtcgtgc cccatgtgtg gaacggtctg cggttccgta cgcatggtgc agtctccgtg 9120 cgcgcgtgcc tgtcgacgct tggagcgaca ggggcggccg tgtgcgtgcg catcaccgac 9180 gacaccgggg tgccggtggc gtcggtcgat cgtcttgagt tgcggcctgt ggatatgggt 9240 cagttgcgtg ctgtctcggt ttcggcgggg cggcggggtt cgctgtatgc ggtgcagtgg 9300 gctgaggtgg gtcctgtgcc ggtgtgtggg caggcgtggg cgtggcacga ggacgtgggt 9360 gagagcggtg gtgggcctgt gccgggggtg gtggtgttgc ggtgcccgga tgccggtgcc 9420 gatggcggcg gtggcggtgg tgtgggtgag gttgttggtg gggtgttggg tgtggtgcag 9480 gggtggctgg ggctggagcg gtttgcgggt tcgcggctgg tggtggtgac ccggggtgcg 9540 gtggtggccg gcccggagga cggcccggtg gatgtggtgg gtgcggcggt gtgggggctg 9600 gtgcggtcgg cgcaggctga gcatccggac cggtttgtcc tcctcgacct ggacaccgac 9660 ctcgacagcg gcgctgacgc cgatgccggc aacgaggccg gtatggggtc tggtctggat 9720 ggtgggcgtg tggctgcggt ggtggcgtgt ggtgagccgc agttggcggt gcgtggtgag 9780 cgggtgctgg ccgcacgcct gacacgactt gagtcgccgg ttgatgtatc gggtcgggag 9840 gtgttgccgt ggttgtcggg tgggtcggtg ttggtgacgg gtgggacggg tgtgctgggt 9900 gcggcggtgg cgcggcatct ggctggtgtg tgtggggtgc gggatctgtt gttggtgagc 9960 cggcgtggtc cggatgctcc gggtgcggag ggtttgcggg cggagctggc cgcgttgggg 10020 gcggaggtgc ggattgttgc gtgtgatgtg ggggagcggc gggaggtggt ccggctgctg 10080 gagggtgttc ctgccgggtg tccgctgacg ggtgtcgtgc atgcggctgg tgtgctggac 10140 gatgcgacga tcgcctctct cacgcccgag cggctgggca cggtgttcgc ggccaaggtg 10200 gatgccgctc ttttgctgga tgagctgacg cggggtatgg agctgtcggc gttcgtgctg 10260 ttctcctcgg ccgcggggat cctggggtcg gccgggcagg gcaactacgc cgcggccaat 10320 gccgctctgg acgcgctggc gtaccggcgg cgggcggcgg gtctgccggg ggtgtcgctg 10380 gcgtgggggc tgtgggaaga ggccagcggg atgaccgggc acctggccgg caccgaccac 10440 cggcgcatca tccgttccgg tctgcatccc atgtcgaccc cggacgcact ggctctcttc 10500 gatgcggccc tggctctgga ccggccggtc ctgctgcccg ccgacctgcg tcccgccccg 10560 cccctgccgc ccctgctgca ggacctcctg cccgccaccc gccgccgcac cacccgcacc 10620 accactaccg gtggtgcgga caacggcgcc cagctgcatg cccggctggc cggccagaca 10680 cacgaacaac agcacaccac cctcctcgcc ctggtccgct cccacatcgc caccgtcctc 10740 ggccacaacg cgccggagat gatccccgtt gactcggcgt tccgcgacct aggcttcgac 10800 tccttgacag cggtggaact ccgtaaccgc ctgggtgagg caacgggact gcgactgccg 10860 accagtctgg tcttcgacca gccgaatgca gcgaccctgg cgcgtcacct acgtcgtgag 10920 ctgatgggcg acgacgcgga aggcgagacg ccatcgcagg tcgcacttca tcaggttgcc 10980 gcggatgagc cgattgcgat tgtggggatg gcgtgtcgtt ttccgggtgg ggtgtgttcg 11040 ccggaggagt tgtgggagct ggttgcgtcg ggtggggatg cgattggtga atttccggcc 11100 ggtcgggggt gggatctgga ggggttgttt gattcggacc ctgaccggtc ggggacgtcg 11160 tacgcgcggt atggcgggtt tttgtatgag gcgggggagt tcgatgcgga cttcttcggg 11220 atcagtccgc gtgaggcgtt ggcgatggat ccgcagcagc ggttgttgct ggagacgtcg 11280 tgggaggcgt tcgagcgggc gggtatcgat ccgctgtcga tgcgtggctc ccgtacgggt 11340 gtcttcgccg gggtgatgta ccacgactac gccgcgcgtc tccaccatgt ccccgagggt 11400 ttcgaaggcc tcatcgccaa cggcagcgca ggcagcgtcg cgaccggccg ggtggcctac 11460 agctttggcc ttgagggtcc ggccgtgacc gtcgatacgg cgtgttcgtc gtcgttggtg 11520 gcgttgcatt gggcggcgca ggcgttgcgt gcgggtgagt gttcgatggc gcttgccggg 11580 ggtgtgacgg tgatgtcgtc tccgggtacg tttgtggagt tctcacgtca gcggggtctg 11640 gccgcggacg ggcggtgcaa ggcctattcg gcggctgctg acggtaccgg ctgggccgag 11700 ggtgtgggga tgctgctggt ggagcggctc tccgacgccc gtcgcaacgg tcaccgtgtc 11760 ctggccgtgg tgcgtggcag tgcggtcaac caggacggtg cgagcaacgg tctgaccgcg 11820 cccaacgggc cctcccagca gcgtgtcatc cgtcaggccc tggccaatgc gggactgacc 11880 ccggccgatg tcgacgcagt ggagggccac ggcaccggga ccactctggg ggacccgatc 11940 gaggcccagg cactcctggc cgcctacgga caacaccgcc cccaccaccg ccccttgtgg 12000 ctgggatccc tcaaatccaa catcgggcac gcacaggccg ccgcgggcgt gggcggagtc 12060 atcaagatgg tgatggccct gcgcaacggg ctgctgccac agaccctcca cgtggacgag 12120 cccacccccc aggtcgactg gtccacaggc gcagtacaac tcctgacaca accggtgccc 12180 tggcccgccg acccggccgg ccggccacgc cacgccggcg tgtcatcatt cggcgtcagc 12240 ggcaccaacg cccatgtgat tttggaggag gcgcctgcgg cggcgggcgg tgctgccggt 12300 ggtggggtgt cggtgggtgc tccgaatcca gcccttccgg tggctgagtc tgagccggtg 12360 ccggtgccgg tgccggtgtc ggcgaggtct gaggccgggt tgcgggcgca ggcacaggcg 12420 ttgcgccagt acgtggcagc ccgcccggac atgtcacctg ccgacatcgg tgcgggtctg 12480 gcccgcggcc gggccgtact ggaacaccgc gccgtcatcc tggccgcgga ccgcgaggaa 12540 ctggcgcagg cactgacagc cctggcagcc ggcgaacccc acccccacat caccacaggc 12600 cacacccggg gcagtgaccg cggcggcgtc gtcttcgtct tccccggaca gggcggccag 12660 tgggccggga tgggcctgac cctgctcacc tcctcacccg tgttcgccga acacatcgac 12720 gcatgcgaga aagccctcac cccctgggtg ccctggtccc tgaccgacat cctgcaccgc 12780 gaccccgacg accccgcatg gcaacaagcc gacgtggtcc agcccgtgct cttcagcatc 12840 atggtctccc tcgccgccct gtggcgctcc tacggcatcg aacccgacgc ggtcctcggc 12900 cactcccagg gagaaatcgc cgccgcccac atctgcggcg cactcagcct gaaagacgcc 12960 gccaaaaccg ttgcactgcg cagccaggca ctggccgccg tacgaggccg gggcgccatg 13020 gtctcactgc ccctgcccgc ccaggacgtg cagcagctca tttccgaacg gtgggaaggg 13080 cagttgtggg tggcagccct caacggcccc cactccacca ccgtctccgg cgacaccacc 13140 gcagtagaag aactcctcac ccactgtgcc gacaccggcc tacgggccaa acgcatcccc 13200 gtcgactacg cctcccactg cccccacgtc caacccctcc acgacgaact cctgcacctg 13260 ctgggagaca tcacccccca gccgtccacc atgccgttct tctccaccgt cgtagggcac 13320 ctggtctggt acaccacaac cctggacgcc gcctactggt accgcaacct ccaccagccc 13380 gtccgcttca gccacgccat ccagaccctg accgacgacg gacaccgccc cttcatcgaa 13440 atcagtcccc accccaccct cgtccccgcc atcgaagaca ccaccgaaaa caccaccgaa 13500 aacatcaccg cgaccggcag cctccgccgc ggcgacaacg acacccaccg cttcctcacc 13560 gccctcgccc acacccacac caccggcatt cggacaccca ccacctggca ccaccactac 13620 acccaaaccc acccccaccc ccacaaccac cacctcgacc tgcccaccta ccccttccaa 13680 caccagcact actggctcca accacccacc acgacaaccg acctcaccac caccggcctc 13740 acccccaccc accaccccct cctcaccgca acactcaccc tcgccaacaa caacacacaa 13800 ctactcaccg gccgcctctc cctacgcacc cacccctggc tcaccgacca caccgtcgtc 13860 ggtaccactc ttgtgccagg aaccgccctc ctcgaactcg ccctccaagc aaccacgacc 13920 gaccacctcg aagaactcgc cctccacacg cctctcgtca tcccccgtga gggtgccgtc 13980 gacgttcagg tgcacatcaa tccaccggac gacaccgaca ctcgttcact gacgatctac 14040 tcgcgaagcg agaacgcccc cgcagcggct ccctggcgtc atcacgccac ggccgttctg 14100 ggaaccaaga cctcgcgcat tgagacaggc cgtagccacg atgatctgtc gatgtggccg 14160 ccagcgggcg cagttcgctg tgctgatgag gaattggcag ccttgtatgg cgactacgag 14220 gcaaatggct ttgtctatgg ccccgcattc cgggggctga ctgctgcctg gcgtctggga 14280 gacgaggtgt ttgccgaggt tcgccttcca gaacaggtgc acggcgaggc atccgcgtac 14340 aacctgcacc cggcactgct ggatgctgcc ttgcacgcag cggcctttgc gccgtcgggc 14400 agtctgccgc agggatccgt accgttctcc ttcaccggtg tgacgctgca cgccgccaat 14460 gcgtcgtcgt tgcgcgtgcg actctcgccg gccgatccga acagcggcca cgccgcagtt 14520 tccgtgctgg tcacggatga caccggtacg cccgtggcgt ccgtcgaggc gttggcggtg 14580 cgcccgttgg cggcggacga attgcgagct gccgagcgcg ccgtacagcg cgctgagctc 14640 ttcgacatga agtgggttga ggtgccctca gatgtactgg tgtcgggcgg ggcatcggtg 14700 gtggtgctgg atggtgccga cgacctcgtt ggtctggcgg ctgaggagga tggtgtgccg 14760 ggggtggtgg tgttgcggtg cccggatgcc ggtgccgatg gcggcggtgg tggcggtggt 14820 gtgggtgagg ttgttggtgg ggtgttgggt gtggtgcagg ggtggctggg gctggagcgg 14880 tttgcgggtt cgcggctggt ggtggtgacc cggggtgcgg tggtggccgg cccggaggac 14940 ggcccggtgg atggcccggt ggatgtggtg ggtgcggcgg tgtgggggct ggtgcggtcg 15000 gcgcaggctg agcatccgga ccggtttgtc ctcctcgacc tggacaccga cctcgacagc 15060 ggcgctgacc gcgatgccgg caacgaggcc ggtatggggt ctggtctgga tggtgggcgt 15120 gtggctgcgg tggtggcgtg tggtgagccg cagttggcgg tgcgtggtga gcgggtgctg 15180 gccgcacgcc tgacacgact tgagtcgccg gttgatgtat cgggtcggga ggtgttgccg 15240 tggttgtcgg gtgggtcggt gttggtgacg ggtgggacgg gtgtgctggg tgcggcggtg 15300 gcgcggcatc tggctggtgt gtgtggggtg cgggatctgt tgttggtgag ccggcgtggt 15360 ccggatgctc cgggtgcgga gggtttgcgg gcggagctgg ccgcgttggg ggcggaggtg 15420 cggattgttg cgtgtgatgt gggggagcgg cgggaggtgg tccggctgct ggagggtgtt 15480 cctgccgggt gtccgctgac gggtgtcgtg catgcggctg gtgtgctgga cgatgcgacg 15540 atcgcctctc tcacgcccga gcggctgggc acggtgttcg cggccaaggt ggatgccgct 15600 cttttgctgg atgagctgac gcggggtatg gagctgtcgg cgttcgtgct gttctcctcg 15660 gccgcgggga tcctggggtc ggccgggcag ggcaactacg ccgcggccaa tgccgctctg 15720 gacgcgctgg cgtaccggcg gcgggcggcg ggtctgccgg gggtgtcgct ggcgtggggg 15780 ctgtgggaag aggccagcgg gatgaccggg catctggccg gcaccgacca ccggcgcatc 15840 atccgttccg gtctgcatcc catgtcgacc ccggacgcac tggccctctt cgatgcggcc 15900 ctggctctgg accggccggt cctgctgccc gccgacctgc gtcccgcccc gcccctgccg 15960 cccctgctgc aggacctcct gcccgccacc cgccgccgca ccacccgcac caccactacc 16020 ggtggtgcgg acaacggcgc ccagctgcac ggccggctgg ccggccagac acacgaacaa 16080 cagcacacca ccctcctcgc cctggtccgc tcccacatcg ccaccgtcct gggccacacc 16140 acccccgaca ccatcccccc cgaccgcgcg ttccgcgacc tcggcttcga ctccctcacc 16200 gccgtcgaac tacgcaaccg gctctcccac accaccggac tccgcctccc caccaccctc 16260 gccttcgacc accccaaccc caccaccctc acccaccacc tccacacaca actcgtcagc 16320 aagggactca ccgccgcggc cgagccggac gccgcaacga cacccccggg gctgccctcg 16380 ctgctctcgg agctcgagcg gctggaggcg gtagtgctct cctccaccac atcctccgct 16440 gccccgctgg acgacggcgc gcgcacgcgg ctggcctccc gactgcattc cctcgcccag 16500 aagttgaacg gcgacgacac cgcccccgac ctcgcagaga catcggacga ggagatgttc 16560 gctctcatcg acagggaagt cggattcgaa tctcaatga 16599 <210> 10 <211> 5532 <212> PRT <213> Artificial Sequence <220> <223> type I polyketide synthase AVES 3 (BAA84478.1) <400> 10 Met Asp Thr Ser Ser Glu Lys Leu Val Asp Ala Leu Arg Ala Ser Leu 1 5 10 15 Lys Ala Asn Gln Thr Leu Arg Ala Arg Asn Glu Gln Leu Ala Ala Ala 20 25 30 Met Glu Ala Ser Ser Glu Pro Ile Ala Ile Val Gly Met Ala Cys Arg 35 40 45 Phe Pro Gly Gly Val Cys Ser Pro Glu Glu Leu Trp Glu Leu Val Ala 50 55 60 Ser Gly Gly Asp Ala Ile Gly Glu Phe Pro Ala Gly Arg Gly Trp Asp 65 70 75 80 Leu Glu Gly Leu Phe Asp Ser Asp Pro Asp Arg Ser Gly Thr Ser Tyr 85 90 95 Ala Arg Tyr Gly Gly Phe Leu Tyr Glu Ala Gly Glu Phe Asp Ala Asp 100 105 110 Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln 115 120 125 Arg Leu Leu Leu Glu Thr Ser Trp Glu Ala Phe Glu Arg Ala Gly Ile 130 135 140 Asp Pro Leu Ser Met Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Val 145 150 155 160 Met Tyr His Asp Tyr Gly Ser Arg Leu Gly Thr Ile Pro Glu Gly Phe 165 170 175 Glu Gly Tyr Ile Gly Asn Gly Ser Gly Gly Ala Val Ala Ser Gly Arg 180 185 190 Val Ala Tyr Thr Leu Gly Leu Glu Gly Pro Ala Val Ser Val Asp Thr 195 200 205 Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ser Leu 210 215 220 Arg Ser Gly Glu Cys Thr Leu Ala Leu Ala Gly Gly Val Thr Val Met 225 230 235 240 Ser Thr Pro His Leu Phe Val Glu Phe Ser Arg Gln Arg Gly Leu Ser 245 250 255 Val Asp Gly Arg Cys Lys Ser Phe Ala Gly Gly Ala Asp Gly Thr Gly 260 265 270 Met Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala 275 280 285 Val Arg Leu Gly His Arg Val Leu Ala Val Leu Arg Gly Ser Ala Val 290 295 300 Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ala 305 310 315 320 Gln Glu Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu Ser Val 325 330 335 Ala Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly 340 345 350 Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Arg Ala 355 360 365 Gly Asn Arg Pro Leu Trp Leu Gly Ser Val Lys Ser Asn Ile Gly His 370 375 380 Ala Gln Ala Ala Ala Gly Val Gly Gly Val Ile Lys Met Val Met Ala 385 390 395 400 Leu Arg Glu Gly Val Leu Pro Arg Thr Leu His Val Asp Glu Pro Ser 405 410 415 Pro Gln Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr Glu Ala 420 425 430 Val Pro Trp Pro Gly Asp Ala Ala Gly Arg Leu Arg Arg Ala Gly Val 435 440 445 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Glu 450 455 460 Ala Pro Ala Ala Gly Gly Cys Val Ala Gly Gly Gly Val Leu Glu Gly 465 470 475 480 Ala Pro Gly Leu Ala Ile Ser Val Ala Glu Ser Val Ala Ala Pro Val 485 490 495 Ala Val Ser Ala Pro Val Ala Glu Ser Val Pro Val Pro Val Pro Val 500 505 510 Pro Val Pro Val Pro Val Ser Ala Arg Ser Glu Ala Gly Leu Arg Ala 515 520 525 Gln Ala Glu Ala Leu Arg Gln Tyr Val Ala Val Arg Pro Asp Val Ser 530 535 540 Leu Ala Asp Val Gly Ala Gly Leu Ala Cys Gly Arg Ala Val Leu Glu 545 550 555 560 His Arg Ala Val Val Leu Ala Ala Asp Arg Glu Glu Leu Val Gln Gly 565 570 575 Leu Gly Ala Leu Ala Ala Gly Glu Pro Asp Arg Arg Val Thr Thr Gly 580 585 590 His Ala Pro Gly Gly Asp Arg Gly Gly Val Val Phe Val Phe Pro Gly 595 600 605 Gln Gly Gly Gln Trp Ala Gly Met Gly Val Arg Leu Leu Ala Ser Ser 610 615 620 Pro Val Phe Ala Arg Arg Met Gln Ala Cys Glu Glu Ala Leu Ala Pro 625 630 635 640 Trp Val Asp Trp Ser Val Val Asp Ile Leu Arg Arg Asp Ala Gly Asp 645 650 655 Ala Val Trp Glu Arg Ala Asp Val Val Gln Pro Val Leu Phe Ser Val 660 665 670 Met Val Ser Leu Ala Ala Leu Trp Arg Ser Tyr Gly Ile Glu Pro Asp 675 680 685 Ala Val Leu Gly His Ser Gln Gly Glu Ile Ala Ala Ala His Val Cys 690 695 700 Gly Ala Leu Ser Leu Lys Asp Ala Ala Lys Thr Val Ala Leu Arg Ser 705 710 715 720 Arg Ala Leu Ala Ala Val Arg Gly Arg Gly Gly Met Ala Ser Val Pro 725 730 735 Leu Pro Ala Gln Glu Val Glu Gln Leu Ile Gly Glu Arg Trp Ala Gly 740 745 750 Arg Leu Trp Val Ala Ala Val Asn Gly Pro Arg Ser Thr Ala Val Ser 755 760 765 Gly Asp Ala Glu Ala Val Asp Glu Val Leu Ala Tyr Cys Ala Gly Thr 770 775 780 Gly Val Arg Ala Arg Arg Ile Pro Val Asp Tyr Ala Ser His Cys Pro 785 790 795 800 His Val Gln Pro Leu Arg Glu Glu Leu Leu Glu Leu Leu Gly Asp Ile 805 810 815 Ser Pro Gln Pro Ser Gly Val Pro Phe Phe Ser Thr Val Glu Gly Thr 820 825 830 Trp Leu Asp Thr Thr Thr Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu 835 840 845 His Gln Pro Val Arg Phe Ser Asp Ala Val Gln Ala Leu Ala Asp Asp 850 855 860 Gly His Arg Val Phe Val Glu Val Ser Pro His Pro Thr Leu Val Pro 865 870 875 880 Ala Ile Glu Asp Thr Thr Glu Asp Thr Ala Glu Asp Val Thr Ala Ile 885 890 895 Gly Ser Leu Arg Arg Gly Asp Asn Asp Thr Arg Arg Phe Leu Thr Ala 900 905 910 Leu Ala His Thr His Thr Thr Gly Ile Gly Thr Pro Thr Thr Trp His 915 920 925 His His Tyr Thr His His His Thr His Pro His Asn His His Leu Asp 930 935 940 Leu Pro Thr Tyr Pro Phe Gln Arg Gln His Tyr Trp Leu Asp Ala Pro 945 950 955 960 Thr Gly Ala Gly Asp Val Ala Ala Ala Gly Leu Glu Pro Ala Glu His 965 970 975 Pro Leu Leu Ala Ala Thr Val Gln Leu Ala Asp Thr Asp Gly Cys Leu 980 985 990 Leu Thr Gly Arg Leu Ser Leu Arg Ser His Pro Trp Leu Gly Asp Tyr 995 1000 1005 Glu Val Gly Gly Ala Val Leu Leu Ser Gly Ser Ala Phe Val Glu Leu 1010 1015 1020 Ala Val Gln Val Gly Glu Arg Val Gly Cys Thr Arg Ile Glu Gln Leu 1025 1030 1035 1040 Thr Val His Ala Pro Leu Val Val Pro Val Gly Gly Gly Val Ser Val 1045 1050 1055 Gln Val Gly Val Ala Ala Ala Asp Gly Glu Gly Arg Arg Leu Val Ser 1060 1065 1070 Val Tyr Ala Arg Gly Gly Ser Ala Cys Gly Gly Gly Gly Ala Ser Gly 1075 1080 1085 Gly Val Trp Thr Cys His Ala Ser Gly Val Leu Val Glu Ala Ala Ala 1090 1095 1100 Gly Gly Gly Val Val Val Asp Gly Leu Ala Gly Val Trp Pro Pro Arg 1105 1110 1115 1120 Gly Ala Val Ala Val Asp Val Asp Gly Val Arg Asp Arg Leu Ala Gly 1125 1130 1135 Ala Gly Cys Val Leu Gly Pro Val Phe Ser Gly Leu Arg Ala Val Trp 1140 1145 1150 Arg Asp Gly Gly Asp Leu Leu Ala Glu Val Cys Leu Pro Glu Glu Ala 1155 1160 1165 Trp Gly Asp Ala Ala Gly Phe Gly Leu His Pro Ala Leu Leu Asp Gly 1170 1175 1180 Val Val Gln Pro Leu Ser Val Leu Leu Pro Gly Gly Thr Gly Phe Gly 1185 1190 1195 1200 Glu Gly Ala Gly Phe Gly Glu Gly Val Arg Val Pro Ala Val Trp Gly 1205 1210 1215 Gly Val Ser Leu His Arg Ala Gly Val Thr Gly Val Arg Val Arg Val 1220 1225 1230 Trp Ala Val Gly Arg Gly Gly Gly Arg Glu Ala Val Ser Val Val Val 1235 1240 1245 Gly Asp Glu Ala Gly Val Pro Val Ala Ser Val Asp Arg Leu Glu Leu 1250 1255 1260 Arg Pro Val Asp Met Gly Gln Leu Arg Ala Val Ser Val Ser Ala Gly 1265 1270 1275 1280 Arg Arg Gly Ser Leu Tyr Ala Val Gln Trp Ala Glu Val Gly Pro Val 1285 1290 1295 Pro Val Cys Gly Gln Ala Trp Ala Trp His Glu Asp Val Gly Glu Ser 1300 1305 1310 Gly Gly Gly Pro Val Pro Gly Val Val Val Leu Arg Cys Pro Asp Ala 1315 1320 1325 Gly Ala Gly Gly Gly Gly Gly Gly Gly Val Gly Glu Val Val Gly Gly 1330 1335 1340 Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu Glu Arg Phe Ala Gly 1345 1350 1355 1360 Ser Arg Leu Val Val Val Thr Arg Gly Ala Val Val Ala Gly Gln Glu 1365 1370 1375 Asp Gly Pro Val Asp Val Val Gly Ala Ala Val Trp Gly Leu Val Arg 1380 1385 1390 Ser Ala Gln Ala Glu His Pro Asp Arg Phe Val Leu Leu Asp Leu Asp 1395 1400 1405 Thr Asp Thr Asp Thr Gly Thr Asp Leu Asp Thr Gly Ala Gly Ala Gly 1410 1415 1420 Ala Gly Ala Gly Trp Gly Val Asp Gly Gly His Val Ala Ala Val Val 1425 1430 1435 1440 Ala Cys Gly Glu Pro Gln Leu Ala Val Arg Gly Glu Arg Val Leu Ala 1445 1450 1455 Ala Arg Leu Thr Arg Leu Glu Ser Ser Val Asp Val Pro Ala Gln Arg 1460 1465 1470 Ser Gly Asp Val Ala Gly Arg Glu Val Leu Pro Trp Leu Ser Gly Gly 1475 1480 1485 Ser Val Leu Val Thr Gly Gly Thr Gly Val Leu Gly Ala Ala Val Ala 1490 1495 1500 Arg His Leu Ala Gly Val Cys Gly Val Arg Asp Leu Leu Leu Val Ser 1505 1510 1515 1520 Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu Leu 1525 1530 1535 Ala Ala Leu Gly Ala Glu Val Arg Ile Val Ala Cys Asp Val Gly Glu 1540 1545 1550 Arg Arg Glu Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly Cys Pro 1555 1560 1565 Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp Asp Ala Thr Ile 1570 1575 1580 Ala Ser Leu Thr Pro Glu Arg Leu Gly Thr Val Phe Ala Ala Lys Val 1585 1590 1595 1600 Asp Ala Ala Leu Leu Leu Asp Glu Leu Thr Arg Gly Met Glu Leu Ser 1605 1610 1615 Ala Phe Val Leu Phe Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala Gly 1620 1625 1630 Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala Tyr 1635 1640 1645 Arg Arg Arg Ala Ala Gly Leu Pro Gly Val Ser Leu Ala Trp Gly Leu 1650 1655 1660 Trp Glu Glu Ala Ser Gly Met Thr Gly His Leu Ala Gly Thr Asp His 1665 1670 1675 1680 Arg Arg Ile Ile Arg Ser Gly Leu His Pro Met Ser Thr Pro Asp Ala 1685 1690 1695 Leu Ala Leu Phe Asp Ala Ala Leu Ala Leu Asp Arg Pro Val Leu Leu 1700 1705 1710 Pro Ala Asp Leu Arg Pro Ala Pro Pro Leu Pro Pro Leu Leu Gln Asp 1715 1720 1725 Leu Leu Pro Ala Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr Thr Gly 1730 1735 1740 Gly Ala Asp Asn Gly Ala Gln Leu His Ala Arg Leu Ala Gly Gln Thr 1745 1750 1755 1760 His Glu Gln Gln His Thr Thr Leu Leu Ala Leu Val Arg Ser His Ile 1765 1770 1775 Ala Thr Val Leu Gly His Thr Thr Pro Asp Thr Ile Pro Pro Asp Arg 1780 1785 1790 Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg 1795 1800 1805 Asn Arg Leu Ser Arg Thr Thr Gly Leu Arg Leu Pro Thr Thr Leu Ala 1810 1815 1820 Phe Asp His Pro Asn Pro Thr Thr Leu Thr His His Leu His Thr Gln 1825 1830 1835 1840 Leu Leu Gly Ser Asp Ser Thr Ala Ser Ile Pro Ala Pro Arg Ala Ala 1845 1850 1855 Ala Val Pro Ala Asp Gln Asp Glu Pro Val Ala Ile Ile Gly Met Ala 1860 1865 1870 Cys Arg Tyr Pro Gly Gly Val Thr Ser Ala Glu Glu Leu Trp Glu Leu 1875 1880 1885 Leu Ala Ser Gly Arg Asp Thr Val Gly Glu Phe Pro Thr Asp Arg Gly 1890 1895 1900 Trp Asp Leu Glu Ala Leu Phe Asp Pro Glu Pro Gly Arg Pro Gly Thr 1905 1910 1915 1920 Ser Tyr Thr Arg Cys Gly Ser Phe Leu Tyr Asp Ala Gly Glu Phe Asp 1925 1930 1935 Ala Gly Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro 1940 1945 1950 Gln Gln Arg Leu Leu Leu Glu Ala Ser Trp Glu Ala Met Glu Gln Ala 1955 1960 1965 Gly Ile Asp Pro Thr Thr Val Arg Gly Ser Gln Thr Gly Val Phe Ala 1970 1975 1980 Gly Leu Ile Pro Gln Ala Tyr Gly Pro Arg Leu His Glu Asn Ala Ala 1985 1990 1995 2000 Ala Asp Thr Glu Gly Tyr Val Leu Thr Gly Thr Ser Gly Ser Val Ala 2005 2010 2015 Ser Gly Arg Ile Ser Tyr Thr Phe Gly Phe Glu Gly Pro Ala Val Ser 2020 2025 2030 Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys 2035 2040 2045 Gln Ala Leu Arg Ala Gly Glu Cys Ser Met Ala Leu Ala Gly Gly Val 2050 2055 2060 Thr Val Met Ser Ser Pro Gly Ala Phe Val Glu Phe Ser Arg Gln Arg 2065 2070 2075 2080 Gly Leu Ala Ala Asp Gly His Cys Lys Ala Phe Ser Ala Ala Ala Asp 2085 2090 2095 Gly Thr Gly Trp Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu 2100 2105 2110 Ser Asp Ala Arg Arg Asn Gly His Arg Val Leu Ala Val Val Arg Gly 2115 2120 2125 Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn 2130 2135 2140 Gly Pro Ser Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly 2145 2150 2155 2160 Leu Ser Ala Gly Asp Val Asp Ala Val Glu Ala His Gly Thr Gly Thr 2165 2170 2175 Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly 2180 2185 2190 Gln Asp Arg Ala Gly Glu Gly Pro Leu Trp Leu Gly Ser Val Lys Ser 2195 2200 2205 Asn Val Gly His Thr Gln Ala Ala Ala Gly Val Ala Gly Val Ile Lys 2210 2215 2220 Met Val Met Ala Leu Arg Asn Gly Leu Leu Pro Arg Thr Leu His Val 2225 2230 2235 2240 Asp Glu Pro Ser Pro His Val Asp Trp Ser Ala Gly Ala Val Gln Leu 2245 2250 2255 Leu Thr Glu Thr Val Pro Trp Pro Gly Gly Glu Gly Arg Leu Arg Arg 2260 2265 2270 Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile 2275 2280 2285 Leu Glu Glu Ala Pro Ala His Asn Ile Pro Ser Asp Thr Pro Ala Asp 2290 2295 2300 Asp Val Pro Gly Gly Pro Pro Ala Gly Glu Asp Ala Gly Ser Gly Glu 2305 2310 2315 2320 Glu Ala Ala Ala Gly Ser Pro Gly Val Trp Pro Trp Leu Val Ser Ala 2325 2330 2335 Lys Ser Gln Pro Ala Leu Arg Ala Gln Ala Gln Ala Leu His Ala His 2340 2345 2350 Leu Thr Asp His Pro Gly Leu Asp Leu Ala Asp Val Gly Tyr Thr Leu 2355 2360 2365 Ala His Ala Arg Ala Val Phe Asp His Arg Ala Thr Leu Ile Ala Ala 2370 2375 2380 Asp Arg Asp Thr Phe Leu Gln Ala Leu Gln Ala Leu Ala Ala Gly Glu 2385 2390 2395 2400 Pro His Pro Ala Val Ile His Ser Ser Ala Pro Gly Gly Thr Gly Thr 2405 2410 2415 Gly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys Ser Gly Gln Gly Thr 2420 2425 2430 Gln Arg Pro Gly Met Ala His Gly Leu Tyr His Thr His Pro Val Phe 2435 2440 2445 Ala Ala Ala Leu Asn Asp Ile Cys Thr His Leu Asp Pro His Leu Asp 2450 2455 2460 His Pro Leu Leu Pro Leu Leu Thr Gln Asp Pro Asn Thr Gln Asp Thr 2465 2470 2475 2480 Thr Thr Leu Glu Glu Ala Ala Ala Leu Leu Gln Gln Thr Pro Tyr Ala 2485 2490 2495 Gln Pro Ala Leu Phe Ala Phe Gln Val Ala Leu His Arg Leu Leu Thr 2500 2505 2510 Asp Gly Tyr His Ile Thr Pro His Tyr Tyr Ala Gly His Ser Leu Gly 2515 2520 2525 Glu Ile Thr Ala Ala His Leu Ala Gly Ile Leu Thr Leu Thr Asp Ala 2530 2535 2540 Thr Thr Leu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr Met Pro Pro 2545 2550 2555 2560 Gly Thr Met Thr Thr Leu His Thr Thr Pro His His Ile Thr His His 2565 2570 2575 Ile Thr Ala His Glu Asn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro 2580 2585 2590 Thr Ser Leu Val Ile Ser Gly Thr Pro His Thr Val Gln His Ile Thr 2595 2600 2605 Thr Leu Cys Gln Gln Gln Gly Ile Lys Thr Lys Thr Leu Pro Thr Asn 2610 2615 2620 His Ala Phe His Ser Pro His Thr Asn Pro Ile Leu Asn Gln Leu His 2625 2630 2635 2640 Gln His Thr Gln Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu Ile 2645 2650 2655 Thr Ala Asn Thr Pro Pro Asp Gln Leu Leu Thr Pro His Tyr Trp Thr 2660 2665 2670 Gln Gln Ala Arg Asn Thr Val Asp Ile Ala Thr Thr Thr Gln Thr Leu 2675 2680 2685 His Gln His Gly Val Thr Thr Tyr Ile Glu Leu Gly Pro Asp Asn Thr 2690 2695 2700 Leu Thr Thr Leu Thr His His Asn Leu Pro Asn Thr Pro Thr Thr Thr 2705 2710 2715 2720 Leu Thr Leu Thr His Pro His His His Pro Gln Thr His Leu Leu Thr 2725 2730 2735 Asn Leu Ala Lys Thr Thr Thr Thr Trp His Pro His His Tyr Thr His 2740 2745 2750 His His Asn Gln Pro His Thr His Thr His Leu Asp Leu Pro Thr Tyr 2755 2760 2765 Pro Phe Gln His His His Tyr Trp Leu Glu Ser Thr Gln Pro Gly Ala 2770 2775 2780 Gly Asn Val Ser Ala Ala Gly Leu Asp Pro Thr Glu His Pro Leu Leu 2785 2790 2795 2800 Gly Ala Thr Leu Glu Leu Ala Glu Gly Asp Gly Cys Leu Leu Thr Gly 2805 2810 2815 Arg Leu Ser Leu Arg Thr His Pro Trp Leu Ala Gly His Ala Val Gly 2820 2825 2830 Gly Val Val Leu Leu Pro Gly Thr Ala Phe Ala Glu Leu Ala Leu His 2835 2840 2845 Ala Gly Glu Ser Val Gly Cys Asp His Val Asp Glu Leu Thr Leu His 2850 2855 2860 Thr Pro Leu Val Ile Pro Glu Val Gly Asp Val Thr Leu Gln Val Ala 2865 2870 2875 2880 Ile Ala Ala Pro Asp Glu Ser Gly Arg Arg Met Met Thr Ile His Ser 2885 2890 2895 Arg Gly Glu Gly Gly Ser Gly Gly Ala Asp Ala Ser Ala Ser Ala Trp 2900 2905 2910 Thr Arg His Ala Ala Gly Val Leu Ser Pro Ala Lys Asp Asp Asp Thr 2915 2920 2925 Ala Ser Tyr Glu Leu Leu Ala Gly Pro Trp Pro Pro Val Gly Ala Thr 2930 2935 2940 Pro Val Asp Leu Asn Thr Ala Tyr Asp Gln Met Ala Asp Ala Gly Phe 2945 2950 2955 2960 Ala Tyr Gly Leu Ala Phe Gln Gly Leu Arg Ala Ala Trp Arg Tyr Gly 2965 2970 2975 Asp Asp Ile Leu Val Glu Ala Arg Leu Pro Glu Glu Val Ser Gly Asp 2980 2985 2990 Ala Ala Ala Tyr Gly Leu His Pro Ala Leu Leu Asp Ala Ala Leu Gln 2995 3000 3005 Gly Thr Gly Leu Leu Ser Val Ala Gly Pro Gly Thr Pro Val Val Pro 3010 3015 3020 His Val Trp Asn Gly Leu Arg Phe Arg Thr His Gly Ala Val Ser Val 3025 3030 3035 3040 Arg Ala Cys Leu Ser Thr Leu Gly Ala Thr Gly Ala Ala Val Cys Val 3045 3050 3055 Arg Ile Thr Asp Asp Thr Gly Val Pro Val Ala Ser Val Asp Arg Leu 3060 3065 3070 Glu Leu Arg Pro Val Asp Met Gly Gln Leu Arg Ala Val Ser Val Ser 3075 3080 3085 Ala Gly Arg Arg Gly Ser Leu Tyr Ala Val Gln Trp Ala Glu Val Gly 3090 3095 3100 Pro Val Pro Val Cys Gly Gln Ala Trp Ala Trp His Glu Asp Val Gly 3105 3110 3115 3120 Glu Ser Gly Gly Gly Pro Val Pro Gly Val Val Val Leu Arg Cys Pro 3125 3130 3135 Asp Ala Gly Ala Asp Gly Gly Gly Gly Gly Gly Val Gly Glu Val Val 3140 3145 3150 Gly Gly Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu Glu Arg Phe 3155 3160 3165 Ala Gly Ser Arg Leu Val Val Val Thr Arg Gly Ala Val Val Ala Gly 3170 3175 3180 Pro Glu Asp Gly Pro Val Asp Val Val Gly Ala Ala Val Trp Gly Leu 3185 3190 3195 3200 Val Arg Ser Ala Gln Ala Glu His Pro Asp Arg Phe Val Leu Leu Asp 3205 3210 3215 Leu Asp Thr Asp Leu Asp Ser Gly Ala Asp Ala Asp Ala Gly Asn Glu 3220 3225 3230 Ala Gly Met Gly Ser Gly Leu Asp Gly Gly Arg Val Ala Ala Val Val 3235 3240 3245 Ala Cys Gly Glu Pro Gln Leu Ala Val Arg Gly Glu Arg Val Leu Ala 3250 3255 3260 Ala Arg Leu Thr Arg Leu Glu Ser Pro Val Asp Val Ser Gly Arg Glu 3265 3270 3275 3280 Val Leu Pro Trp Leu Ser Gly Gly Ser Val Leu Val Thr Gly Gly Thr 3285 3290 3295 Gly Val Leu Gly Ala Ala Val Ala Arg His Leu Ala Gly Val Cys Gly 3300 3305 3310 Val Arg Asp Leu Leu Leu Val Ser Arg Arg Gly Pro Asp Ala Pro Gly 3315 3320 3325 Ala Glu Gly Leu Arg Ala Glu Leu Ala Ala Leu Gly Ala Glu Val Arg 3330 3335 3340 Ile Val Ala Cys Asp Val Gly Glu Arg Arg Glu Val Val Arg Leu Leu 3345 3350 3355 3360 Glu Gly Val Pro Ala Gly Cys Pro Leu Thr Gly Val Val His Ala Ala 3365 3370 3375 Gly Val Leu Asp Asp Ala Thr Ile Ala Ser Leu Thr Pro Glu Arg Leu 3380 3385 3390 Gly Thr Val Phe Ala Ala Lys Val Asp Ala Ala Leu Leu Leu Asp Glu 3395 3400 3405 Leu Thr Arg Gly Met Glu Leu Ser Ala Phe Val Leu Phe Ser Ser Ala 3410 3415 3420 Ala Gly Ile Leu Gly Ser Ala Gly Gln Gly Asn Tyr Ala Ala Ala Asn 3425 3430 3435 3440 Ala Ala Leu Asp Ala Leu Ala Tyr Arg Arg Arg Ala Ala Gly Leu Pro 3445 3450 3455 Gly Val Ser Leu Ala Trp Gly Leu Trp Glu Glu Ala Ser Gly Met Thr 3460 3465 3470 Gly His Leu Ala Gly Thr Asp His Arg Arg Ile Ile Arg Ser Gly Leu 3475 3480 3485 His Pro Met Ser Thr Pro Asp Ala Leu Ala Leu Phe Asp Ala Ala Leu 3490 3495 3500 Ala Leu Asp Arg Pro Val Leu Leu Pro Ala Asp Leu Arg Pro Ala Pro 3505 3510 3515 3520 Pro Leu Pro Pro Leu Leu Gln Asp Leu Leu Pro Ala Thr Arg Arg Arg 3525 3530 3535 Thr Thr Arg Thr Thr Thr Thr Gly Gly Ala Asp Asn Gly Ala Gln Leu 3540 3545 3550 His Ala Arg Leu Ala Gly Gln Thr His Glu Gln Gln His Thr Thr Leu 3555 3560 3565 Leu Ala Leu Val Arg Ser His Ile Ala Thr Val Leu Gly His Asn Ala 3570 3575 3580 Pro Glu Met Ile Pro Val Asp Ser Ala Phe Arg Asp Leu Gly Phe Asp 3585 3590 3595 3600 Ser Leu Thr Ala Val Glu Leu Arg Asn Arg Leu Gly Glu Ala Thr Gly 3605 3610 3615 Leu Arg Leu Pro Thr Ser Leu Val Phe Asp Gln Pro Asn Ala Ala Thr 3620 3625 3630 Leu Ala Arg His Leu Arg Arg Glu Leu Met Gly Asp Asp Ala Glu Gly 3635 3640 3645 Glu Thr Pro Ser Gln Val Ala Leu His Gln Val Ala Ala Asp Glu Pro 3650 3655 3660 Ile Ala Ile Val Gly Met Ala Cys Arg Phe Pro Gly Gly Val Cys Ser 3665 3670 3675 3680 Pro Glu Glu Leu Trp Glu Leu Val Ala Ser Gly Gly Asp Ala Ile Gly 3685 3690 3695 Glu Phe Pro Ala Gly Arg Gly Trp Asp Leu Glu Gly Leu Phe Asp Ser 3700 3705 3710 Asp Pro Asp Arg Ser Gly Thr Ser Tyr Ala Arg Tyr Gly Gly Phe Leu 3715 3720 3725 Tyr Glu Ala Gly Glu Phe Asp Ala Asp Phe Phe Gly Ile Ser Pro Arg 3730 3735 3740 Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser 3745 3750 3755 3760 Trp Glu Ala Phe Glu Arg Ala Gly Ile Asp Pro Leu Ser Met Arg Gly 3765 3770 3775 Ser Arg Thr Gly Val Phe Ala Gly Val Met Tyr His Asp Tyr Ala Ala 3780 3785 3790 Arg Leu His His Val Pro Glu Gly Phe Glu Gly Leu Ile Ala Asn Gly 3795 3800 3805 Ser Ala Gly Ser Val Ala Thr Gly Arg Val Ala Tyr Ser Phe Gly Leu 3810 3815 3820 Glu Gly Pro Ala Val Thr Val Asp Thr Ala Cys Ser Ser Ser Leu Val 3825 3830 3835 3840 Ala Leu His Trp Ala Ala Gln Ala Leu Arg Ala Gly Glu Cys Ser Met 3845 3850 3855 Ala Leu Ala Gly Gly Val Thr Val Met Ser Ser Pro Gly Thr Phe Val 3860 3865 3870 Glu Phe Ser Arg Gln Arg Gly Leu Ala Ala Asp Gly Arg Cys Lys Ala 3875 3880 3885 Tyr Ser Ala Ala Ala Asp Gly Thr Gly Trp Ala Glu Gly Val Gly Met 3890 3895 3900 Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Asn Gly His Arg Val 3905 3910 3915 3920 Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn 3925 3930 3935 Gly Leu Thr Ala Pro Asn Gly Pro Ser Gln Gln Arg Val Ile Arg Gln 3940 3945 3950 Ala Leu Ala Asn Ala Gly Leu Thr Pro Ala Asp Val Asp Ala Val Glu 3955 3960 3965 Gly His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala 3970 3975 3980 Leu Leu Ala Ala Tyr Gly Gln His Arg Pro His His Arg Pro Leu Trp 3985 3990 3995 4000 Leu Gly Ser Leu Lys Ser Asn Ile Gly His Ala Gln Ala Ala Ala Gly 4005 4010 4015 Val Gly Gly Val Ile Lys Met Val Met Ala Leu Arg Asn Gly Leu Leu 4020 4025 4030 Pro Gln Thr Leu His Val Asp Glu Pro Thr Pro Gln Val Asp Trp Ser 4035 4040 4045 Thr Gly Ala Val Gln Leu Leu Thr Gln Pro Val Pro Trp Pro Ala Asp 4050 4055 4060 Pro Ala Gly Arg Pro Arg His Ala Gly Val Ser Ser Phe Gly Val Ser 4065 4070 4075 4080 Gly Thr Asn Ala His Val Ile Leu Glu Glu Ala Pro Ala Ala Ala Gly 4085 4090 4095 Gly Ala Ala Gly Gly Gly Val Ser Val Gly Ala Pro Asn Pro Ala Leu 4100 4105 4110 Pro Val Ala Glu Ser Glu Pro Val Pro Val Pro Val Pro Val Ser Ala 4115 4120 4125 Arg Ser Glu Ala Gly Leu Arg Ala Gln Ala Gln Ala Leu Arg Gln Tyr 4130 4135 4140 Val Ala Ala Arg Pro Asp Met Ser Pro Ala Asp Ile Gly Ala Gly Leu 4145 4150 4155 4160 Ala Arg Gly Arg Ala Val Leu Glu His Arg Ala Val Ile Leu Ala Ala 4165 4170 4175 Asp Arg Glu Glu Leu Ala Gln Ala Leu Thr Ala Leu Ala Ala Gly Glu 4180 4185 4190 Pro His Pro His Ile Thr Thr Gly His Thr Arg Gly Ser Asp Arg Gly 4195 4200 4205 Gly Val Val Phe Val Phe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met 4210 4215 4220 Gly Leu Thr Leu Leu Thr Ser Ser Pro Val Phe Ala Glu His Ile Asp 4225 4230 4235 4240 Ala Cys Glu Lys Ala Leu Thr Pro Trp Val Pro Trp Ser Leu Thr Asp 4245 4250 4255 Ile Leu His Arg Asp Pro Asp Asp Pro Ala Trp Gln Gln Ala Asp Val 4260 4265 4270 Val Gln Pro Val Leu Phe Ser Ile Met Val Ser Leu Ala Ala Leu Trp 4275 4280 4285 Arg Ser Tyr Gly Ile Glu Pro Asp Ala Val Leu Gly His Ser Gln Gly 4290 4295 4300 Glu Ile Ala Ala Ala His Ile Cys Gly Ala Leu Ser Leu Lys Asp Ala 4305 4310 4315 4320 Ala Lys Thr Val Ala Leu Arg Ser Gln Ala Leu Ala Ala Val Arg Gly 4325 4330 4335 Arg Gly Ala Met Val Ser Leu Pro Leu Pro Ala Gln Asp Val Gln Gln 4340 4345 4350 Leu Ile Ser Glu Arg Trp Glu Gly Gln Leu Trp Val Ala Ala Leu Asn 4355 4360 4365 Gly Pro His Ser Thr Thr Val Ser Gly Asp Thr Thr Ala Val Glu Glu 4370 4375 4380 Leu Leu Thr His Cys Ala Asp Thr Gly Leu Arg Ala Lys Arg Ile Pro 4385 4390 4395 4400 Val Asp Tyr Ala Ser His Cys Pro His Val Gln Pro Leu His Asp Glu 4405 4410 4415 Leu Leu His Leu Leu Gly Asp Ile Thr Pro Gln Pro Ser Thr Met Pro 4420 4425 4430 Phe Phe Ser Thr Val Val Gly His Leu Val Trp Tyr Thr Thr Thr Leu 4435 4440 4445 Asp Ala Ala Tyr Trp Tyr Arg Asn Leu His Gln Pro Val Arg Phe Ser 4450 4455 4460 His Ala Ile Gln Thr Leu Thr Asp Asp Gly His Arg Pro Phe Ile Glu 4465 4470 4475 4480 Ile Ser Pro His Pro Thr Leu Val Pro Ala Ile Glu Asp Thr Thr Glu 4485 4490 4495 Asn Thr Thr Glu Asn Ile Thr Ala Thr Gly Ser Leu Arg Arg Gly Asp 4500 4505 4510 Asn Asp Thr His Arg Phe Leu Thr Ala Leu Ala His Thr His Thr Thr 4515 4520 4525 Gly Ile Arg Thr Pro Thr Thr Trp His His His Tyr Thr Gln Thr His 4530 4535 4540 Pro His Pro His Asn His His Leu Asp Leu Pro Thr Tyr Pro Phe Gln 4545 4550 4555 4560 His Gln His Tyr Trp Leu Gln Pro Pro Thr Thr Thr Thr Asp Leu Thr 4565 4570 4575 Thr Thr Gly Leu Thr Pro Thr His His Pro Leu Leu Thr Ala Thr Leu 4580 4585 4590 Thr Leu Ala Asn Asn Asn Thr Gln Leu Leu Thr Gly Arg Leu Ser Leu 4595 4600 4605 Arg Thr His Pro Trp Leu Thr Asp His Thr Val Val Gly Thr Thr Leu 4610 4615 4620 Val Pro Gly Thr Ala Leu Leu Glu Leu Ala Leu Gln Ala Thr Thr Thr 4625 4630 4635 4640 Asp His Leu Glu Glu Leu Ala Leu His Thr Pro Leu Val Ile Pro Arg 4645 4650 4655 Glu Gly Ala Val Asp Val Gln Val His Ile Asn Pro Pro Asp Asp Thr 4660 4665 4670 Asp Thr Arg Ser Leu Thr Ile Tyr Ser Arg Ser Glu Asn Ala Pro Ala 4675 4680 4685 Ala Ala Pro Trp Arg His His Ala Thr Ala Val Leu Gly Thr Lys Thr 4690 4695 4700 Ser Arg Ile Glu Thr Gly Arg Ser His Asp Asp Leu Ser Met Trp Pro 4705 4710 4715 4720 Pro Ala Gly Ala Val Arg Cys Ala Asp Glu Glu Leu Ala Ala Leu Tyr 4725 4730 4735 Gly Asp Tyr Glu Ala Asn Gly Phe Val Tyr Gly Pro Ala Phe Arg Gly 4740 4745 4750 Leu Thr Ala Ala Trp Arg Leu Gly Asp Glu Val Phe Ala Glu Val Arg 4755 4760 4765 Leu Pro Glu Gln Val His Gly Glu Ala Ser Ala Tyr Asn Leu His Pro 4770 4775 4780 Ala Leu Leu Asp Ala Ala Leu His Ala Ala Ala Phe Ala Pro Ser Gly 4785 4790 4795 4800 Ser Leu Pro Gln Gly Ser Val Pro Phe Ser Phe Thr Gly Val Thr Leu 4805 4810 4815 His Ala Ala Asn Ala Ser Ser Leu Arg Val Arg Leu Ser Pro Ala Asp 4820 4825 4830 Pro Asn Ser Gly His Ala Ala Val Ser Val Leu Val Thr Asp Asp Thr 4835 4840 4845 Gly Thr Pro Val Ala Ser Val Glu Ala Leu Ala Val Arg Pro Leu Ala 4850 4855 4860 Ala Asp Glu Leu Arg Ala Ala Glu Arg Ala Val Gln Arg Ala Glu Leu 4865 4870 4875 4880 Phe Asp Met Lys Trp Val Glu Val Pro Ser Asp Val Leu Val Ser Gly 4885 4890 4895 Gly Ala Ser Val Val Val Leu Asp Gly Ala Asp Asp Leu Val Gly Leu 4900 4905 4910 Ala Ala Glu Glu Asp Gly Val Pro Gly Val Val Val Leu Arg Cys Pro 4915 4920 4925 Asp Ala Gly Ala Asp Gly Gly Gly Gly Gly Gly Gly Val Gly Glu Val 4930 4935 4940 Val Gly Gly Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu Glu Arg 4945 4950 4955 4960 Phe Ala Gly Ser Arg Leu Val Val Val Thr Arg Gly Ala Val Val Ala 4965 4970 4975 Gly Pro Glu Asp Gly Pro Val Asp Gly Pro Val Asp Val Val Gly Ala 4980 4985 4990 Ala Val Trp Gly Leu Val Arg Ser Ala Gln Ala Glu His Pro Asp Arg 4995 5000 5005 Phe Val Leu Leu Asp Leu Asp Thr Asp Leu Asp Ser Gly Ala Asp Arg 5010 5015 5020 Asp Ala Gly Asn Glu Ala Gly Met Gly Ser Gly Leu Asp Gly Gly Arg 5025 5030 5035 5040 Val Ala Ala Val Val Ala Cys Gly Glu Pro Gln Leu Ala Val Arg Gly 5045 5050 5055 Glu Arg Val Leu Ala Ala Arg Leu Thr Arg Leu Glu Ser Pro Val Asp 5060 5065 5070 Val Ser Gly Arg Glu Val Leu Pro Trp Leu Ser Gly Gly Ser Val Leu 5075 5080 5085 Val Thr Gly Gly Thr Gly Val Leu Gly Ala Ala Val Ala Arg His Leu 5090 5095 5100 Ala Gly Val Cys Gly Val Arg Asp Leu Leu Leu Val Ser Arg Arg Gly 5105 5110 5115 5120 Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu Leu Ala Ala Leu 5125 5130 5135 Gly Ala Glu Val Arg Ile Val Ala Cys Asp Val Gly Glu Arg Arg Glu 5140 5145 5150 Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly Cys Pro Leu Thr Gly 5155 5160 5165 Val Val His Ala Ala Gly Val Leu Asp Asp Ala Thr Ile Ala Ser Leu 5170 5175 5180 Thr Pro Glu Arg Leu Gly Thr Val Phe Ala Ala Lys Val Asp Ala Ala 5185 5190 5195 5200 Leu Leu Leu Asp Glu Leu Thr Arg Gly Met Glu Leu Ser Ala Phe Val 5205 5210 5215 Leu Phe Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala Gly Gln Gly Asn 5220 5225 5230 Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala Tyr Arg Arg Arg 5235 5240 5245 Ala Ala Gly Leu Pro Gly Val Ser Leu Ala Trp Gly Leu Trp Glu Glu 5250 5255 5260 Ala Ser Gly Met Thr Gly His Leu Ala Gly Thr Asp His Arg Arg Ile 5265 5270 5275 5280 Ile Arg Ser Gly Leu His Pro Met Ser Thr Pro Asp Ala Leu Ala Leu 5285 5290 5295 Phe Asp Ala Ala Leu Ala Leu Asp Arg Pro Val Leu Leu Pro Ala Asp 5300 5305 5310 Leu Arg Pro Ala Pro Pro Leu Pro Pro Leu Leu Gln Asp Leu Leu Pro 5315 5320 5325 Ala Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr Thr Gly Gly Ala Asp 5330 5335 5340 Asn Gly Ala Gln Leu His Gly Arg Leu Ala Gly Gln Thr His Glu Gln 5345 5350 5355 5360 Gln His Thr Thr Leu Leu Ala Leu Val Arg Ser His Ile Ala Thr Val 5365 5370 5375 Leu Gly His Thr Thr Pro Asp Thr Ile Pro Pro Asp Arg Ala Phe Arg 5380 5385 5390 Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg Asn Arg Leu 5395 5400 5405 Ser His Thr Thr Gly Leu Arg Leu Pro Thr Thr Leu Ala Phe Asp His 5410 5415 5420 Pro Asn Pro Thr Thr Leu Thr His His Leu His Thr Gln Leu Val Ser 5425 5430 5435 5440 Lys Gly Leu Thr Ala Ala Ala Glu Pro Asp Ala Ala Thr Thr Pro Pro 5445 5450 5455 Gly Leu Pro Ser Leu Leu Ser Glu Leu Glu Arg Leu Glu Ala Val Val 5460 5465 5470 Leu Ser Ser Thr Thr Ser Ser Ala Ala Pro Leu Asp Asp Gly Ala Arg 5475 5480 5485 Thr Arg Leu Ala Ser Arg Leu His Ser Leu Ala Gln Lys Leu Asn Gly 5490 5495 5500 Asp Asp Thr Ala Pro Asp Leu Ala Glu Thr Ser Asp Glu Glu Met Phe 5505 5510 5515 5520 Ala Leu Ile Asp Arg Glu Val Gly Phe Glu Ser Gln 5525 5530 <210> 11 <211> 17460 <212> DNA <213> Artificial Sequence <220> <223> milA3 gene of Streptomyces milbemycinicus <400> 11 atggccgctg gccacgacaa ggtgatcgag gcgctgcggg cgtccctcaa gaccaacgag 60 cggcagaggg aacagatcca ccggctcact acggcggcgc gggaacccat cgccatcatc 120 ggcatggcct gccgctatcc gggcggagtg ggatcgccgg aggacctgtg ggagctggtg 180 gccgccggtc gtgacgccat cggcaccttc cccgaggacc ggggctggga cgtggagcgg 240 ctgtacgacc ccgatccgga gcgggccggc acctcgtgta cccagcatgg cggattcctg 300 taccaggcag gggagttcga ccccggtttc ttcgggatca gcccgcgcga ggcgctggcg 360 atggacccgc agcagcggct gctgctggag atctcctggg aggtgttcga gcgggccggg 420 atcgacccgg cctcggtgcg cggcagccgc accggggtgt tcgcgggcgt catgtaccac 480 gactacggct cccggctgca caccgtcccc gaaggcttcg agggctatgt cggcaacggc 540 agcggcggcg gcgtggcgtc cggccgggtc gcctacaccc tcggcctcga aggcccggcc 600 gtgaccgtgg acaccgcctg ctcctcctcg ttggtcgccc tgcacctggc ctgccaggcg 660 ctgcgggccg gcgagtgctc actcgccctg gcgggcgggg tgacggtgat gtccaccccc 720 agcctgttcg tcgagtactc ccggcagcgc gcgctcgcgg cagacggccg gtgcaaggcg 780 tacggggcgg gggcggacgg caccggctgg gcagaaggcg ccgggatgct gctggtggaa 840 cggctcacgg acgcacagcg cctcggccac cgggtgctgg cggtggtccg gggcagcgcg 900 gtcaaccagg acggcgcgag caacggcctc accgccccca acggccccgc gcaacaacgg 960 gccatccggc aggcactggc gagcgccggg gtgtcggcgt ccgaggtcga cgccgtggag 1020 gggcatggga cggggacgcg gctgggcgat ccgatcgagg cgcaggcgtt gctggcgacc 1080 tacggtcagc agcggcccgc ggaccggccg ctgtggctcg ggtcgatgaa gtccaacgtc 1140 ggccatgcgc aggcggccgc cggcgtgggc gggatcatca agatggtgat ggccatgcgg 1200 agcgggacgc tgccgcgcac cctgcacgcg gacgagccgt cgccacacat cgactgggac 1260 tcgggcgcgg tacggctgct gaccgagccg gtcgcctggc cggagcgcga ccggccccgc 1320 cgcgccgcgg tgtcctcctt cggggtcagc ggcaccaacg cccatgtgat cctcgaggcc 1380 gcatcgcaga cggcgccgca gacggattcc gcgtcgcagg cggaaaccga cgacgctccc 1440 gcaccgcacg gcgcgccggg ccatgccgtg gcggggccgc tgctctggcc cttgtcgggc 1500 gcgacggccg aggcgctgcg ggcccaggcc ggggagctgc gtcgcttcgt ggcggccgat 1560 gagctgctgc gccccgccga cgtcgggcac accctggtct tcggccgctc ggacctcgca 1620 caccgcgcag tcgtcctcgg ctccgaccgg gaaaccctgc tgcgcgctct ggacactctg 1680 gcaggggagg ggccggacga cggctcggtc gtacggggca tggcggccgc cggggccggt 1740 gcgggcgtgg tgttcgtctt cccgggacag ggcggccagt gggccggcat ggggctgcgg 1800 ctgctggaga cctcgtcgtt cttcgccgag cggatggcgg agtgcgaggc ggcgttggca 1860 ccgtatgccg actggtcgct gctcgacgtt ctgcgccggg accccgggga cccggtctgg 1920 gagcgggccg atgtcgtcca gccgatgctg ttctcggtga tggtgtcgct ggcgcagctg 1980 tggcgctcgt acggcgtcga accggacgcc gtactcggcc actcccaggg cgagatcgcc 2040 gccgcccaca tctgcggcgc gctgaccctg gacgacgccg cgaaggttgt cgcgctgcgc 2100 agccgggccc tgcagaccct gcgcggttcg ggcggcatgg cctccgtacc actgccggcg 2160 gacgaggtca ccgggctgct gcggaccgca tggccggacc ggctgtgggt ggccgccgtc 2220 aacgccccca cggccacggt gatctccggc gacgcggact ctctggcgga ggcgctggaa 2280 cactaccggg accagggcgt cgaagcgaag cgggtcccgg tcgactacgc ctcccactgc 2340 ccgcatatcg aagccgtgga gcaggagctg ctgggcctgt tgcgggggat cgctccaagg 2400 gccgccgaca tccccttcta ctccaccgtg gacaaccagt gggccgacac catgggactc 2460 gacgcccggt actggtaccg caatctgcgc cggcccgtac gcttcgccga agcgctccgc 2520 gccctcggcg ccgccgagta ccggacgtat gtcgaggtcg gcccgcaccc caccctcacc 2580 cccgccatcg aggacaccac tgaggccgcc ggcgtcgcgg ccacggttgt cggatccctg 2640 cgccgcggcg aggacgacgc ccaccgcatc ctgacctcgc tggcccgggc tcatattcat 2700 ggcctgcccg tggcgtggga ccgccactac cgggcgctcg cccccgaggc gaaccatgtc 2760 gacctgccca cctacgcctt ccagcgccgc cgctactggc tggacgcccc ggcgaccacc 2820 ggggacgtga cggccgcggg gctggccccg gtcggacacc cactgctcgg cgcggcggtc 2880 ggactcgccg agggcgacgg atatctgctc accggccggc tcgccccgca cacccacccc 2940 tggctcaccg accacgcggt cgccggcacc gtcctgctgc cgggcaccgc atacgtggaa 3000 ctggccgtgc acgtcggcgg acacctcggc tgcccccggc tggaggagct caccctgcac 3060 gccccgctcg tcctccccga caccggcggc gtggcgctcc aggtggccgt cggggcaccg 3120 gacgagaccg gccgccgcgc actgagcgtc tacgcacagc gcgacgacga ccccgcgtgg 3180 gagggggcgg cccggggcgc gtggacacgg catgcgaccg gcacactggc ggccgaggcc 3240 ccgactgatg gcatcagcgg tgccgacggt gccgggaccc tggcgggggc gtggcctccg 3300 ccgggcgcgg agcccctgga catcagcggc ctctacgaca cgctggccgc cgcagacttc 3360 ggctacggcc cggccttcca ggggctgcgc gccgtctggc ggcaaggcga ggagacctac 3420 gccgaggtgc ggctccccga ccaggtggcc gccgacgccc cacgcttctg cctccacccc 3480 gcgctgctcg acgccgcgct ccacccgctg gcactcgaca gcggccgaag cgaggagaat 3540 ccagcgggac atggcctgct gccgttcgcc tggcgcggcg tcagcctgcg ctccccgggc 3600 acaccgacgc tgcgcgtacg gctgcggccg cagggcccgg actcgattgc cgtcgacgtg 3660 gccgacgaga cgggcgcgcc ggtggcctcg gccgaatcgc tcacgctgcg gccggtggcc 3720 ctggaggacc tgcgggccct cggcggccag gcgggcgaca ccctctacgc cctggagtgg 3780 accgccgcgc ccgagccccc ggcgacggcc ctcgggcggt gcgctgtgat tggccaagcc 3840 attcctggat gggctgccgc gctggagacg gcggcagcgg ggcccgtacg gcggtacccg 3900 gaccttgccg gactggtgac ggccctggac gcgggcgatc cgcctccgga cctggtgttc 3960 gtgggctgcc ctccggctgc cgccgggccc gacgacacga cggtcgccga cgtccacacc 4020 gcccgtaccc gtgtccgtac ccgacaagcg ctggacctgc ttcagggctg gctcggcgaa 4080 gcgcggctgg ccggcgcgag gctggtgctg gtcacctgcg gcgcggtggc caccgggccg 4140 gcggagggag tgatggacct ggcgggcgcg gcgatctgcg gactggtgcg atccgcgcag 4200 gccgaggagc ccgaccgtat cctcctggtg gacctggacg cggccgagga gtcgtgggcg 4260 gcgctaccac gggcggtcgc gctgggcgaa ccgcagatgg ccatccgggc cggccagccg 4320 cacatggccc ggctggttcg agccgacacc gaggggggcg ccctgctcac gccgccacag 4380 gggagcggcg gctggcggct cgactgcgcc gacgcgggca cggtccaggg gctggcgcct 4440 gtggcgtcct cggccgaccg cgacccgctg ggcccgcacc aggtacggat cgaggtgcgt 4500 gcggccgggc tgaacttccg cgatgtcctg gtggccctgg ggatggtccc tgggcagcgg 4560 gggctgggca gcgagggcgc cggggtggtg ctcgaagccg ggcctgaagt ggccgacctg 4620 gcgcccgggg accgggtgat gggcgtgttc gcggatgcgt tcggcccgtt cgcgatcgcc 4680 gaccgggcca ccgtgatccg cgtccccgac cactggacct tcggccaggc cgccgccgtc 4740 cccgtcgtgt tcgccaccgc ctattacggg ctggtggacc tggcaggact gcgcccgggt 4800 gagtcggtgc tggtgcacgc tgcggccggc ggagtgggac tggccgctgt ccaactggcc 4860 cgccacctgg gcgctgaggt ctacgccacg gcgagccccg gcaaatggga caccctacgc 4920 gcccacggca tccccccgga gcgcatcgcc tcgtcccgca ccctcgactt cgagagccgg 4980 ttcaccggcc ggaacatcga cgtcgtcctc aactccctgg cccatgagta cgtcgacgcc 5040 tcgctgcgcc tggtgtccgg cgacagcggc cggttcctgg agatgggcaa gaccgacctc 5100 cgcgacccgg aggaggtggc gcaggcgtac cccggtgtcg cctaccgggc gtacgacctg 5160 atggaggccg gacccgagcg catcggggag atcctgcgca ccgtgttgcg gctgttcgac 5220 gagggcgtgc tcaccccgct gccgctcacc tgctgggaca tccggcaggc cagggatgcc 5280 ttccgccaac tccagcaggg ccgcaccgtc ggaaagaatg tgctcacgct ggaccgcacc 5340 cccgaccccg acggcaccgt cctcatcacc ggtggcaccg gtaccctcgg cgccgcgctc 5400 gcccgccatc tcgccgccac cggccgagca cggcatctgc tactgatcag ccgccgtggc 5460 ctcgatgcgc caggcgctcc cgaactcatc gctgagattg acgagttggg cgccacggcg 5520 accgtcgcca cctgcgacgt cggcgaccgt gccgcgctcg ccgaactgct cgggcggatc 5580 cccgccgagc acccgctgac cgccgtcgtc cacgccgcgg gcaccctcga cgacgccacg 5640 ctcggctccc tcaccgcgcg ccacctcgac accgttctgc ccgcgaaggc cgatgccgcc 5700 tggcatctgc acgacctgac ctgccggctg gatctggccg cgttcgtgct gttctcgtcc 5760 gccgcgggtg tcctgggctc gccggggcag ggcaactacg ccgccgccaa cgcctttctc 5820 gacgcgctcg ccttccagcg acgggcgatg ggactccccg ccgtgtccct ggcatgggga 5880 ctgtgggagg aggccagcgg aatgaccggc cacctcgacc agaccgaccg cacccgcatg 5940 gcccgcgtcg gcctccggcc actggccacg gacgaggccc tggcgctgtt cgacaacgct 6000 ctcgtcgacg gcccaccgct gctgctcccg gcccgtatcg acaccaaggc gctacggggc 6060 accaccgcac cgcccctgtt ccagagcctc gtacgcccca ccaccggcca ccggccacgc 6120 cccgcgacac ccgacggccg ctcctccctc cgagcccggc tcgccgggct cgaccccgcc 6180 gcacagcacg aggtcctgct caccctcgtc cgcggccacg ccgccacggt cctcggccac 6240 ccgagccccg acgccatcgc ccgcgaggcg gccttccgtg acctcggctt cgactccctc 6300 accgccgtgg agctccgcaa ccgcctcaag gaggcaaccg gcctgcggct ccccgccacc 6360 atcgtcttcg accatcccac tcctgccgct ctcgcccagc acctgcggga cggcctcatc 6420 ggcggcgccg atacggtcac cctggctgcg gctcctgctc cgagcaaggt ggcgatggtg 6480 gcggatgagg ccatcgcgat catcggcatg gcctgccggt atccgggggg cgtgcggtcg 6540 gccgaggggc tgtgggatct ggtcgcctcc ggcaccgacg ccatgagcgg attccccagc 6600 gaccgcggct gggacctcga ccgcctctac gccccccagg accaggacgt gccgggcacc 6660 acatacaccc gccacggggg cttcctccac gacgcgggca agttcgacgc gggattcttc 6720 ggcatcggcc cacgtgaggc gctggcgatg gatccgcagc agcggctgct gctggagacc 6780 tcctgggagg ttttcgaaca cgcgggaatc gacccctcgt cggtacggcg gagccggacc 6840 ggagtcttcg ccggtgtgat gccgacggac tacggccccc ggctgcaaga caccgtggcc 6900 gaggtcgagg gctatgtcct caccggaaac tccggcagcg tcgcctcggg ccgtatcgcc 6960 tacaccttcg gcctggaagg ccccgcggtg tcggtggaca cggcgtgttc gtcgtctctg 7020 gtggcgttgc atctggcgtg tcaggcgctg cgtgcggggg agtgctccat ggcgctggcc 7080 ggcggggtga cggtgatggc gacgcctggt gccttcgtgg agtttgcgcg gcagcggggg 7140 ttgtcggtgg atgggcggtg caaggcgttt ggggtgggtg cggatggtac ggggtgggcg 7200 gagggggtgg ggatgctgtt ggtggagcgg ttgtctgatg cgcggcggtt ggggcatcgg 7260 gtgttggcgg tggtgcgggg ttctgcggtg aatcaggatg gtgcgtcgaa tggtttgacg 7320 gcgccgaatg gtccgtcgca gcagcgggtg atccggcagg cgttggccag tgcgcgggtt 7380 ggcggggcgg atgtggatgt ggtggagggg cacggtacgg ggacgcggct gggtgatccg 7440 atcgaggcgc aggcgttgct ggcgacctac ggtcaggagc gggtggggga cggctcgttg 7500 tggttggggt cggtgaagtc gaatatcggg catgcgcagg ccgcggcggg ggttgcgggt 7560 gtcatcaaga tggtgatggc gatgcggtat ggggtgttgc cgcggacgtt gcatgtgcag 7620 gagccgtcgc cgcatgtgga ctggtcctcg ggcggggtgc ggctgctgac ggaggcggtg 7680 ccgtggccgg agacggggcg tgcgcggcgt gcgggggtgt cgtcgttcgg ggtcagtggc 7740 accaacgcgc acatcatcct cgaacaggcg ccgcctgagg agcacgacga tccggcggac 7800 gtctcgtccg ggtcgtttcc gtggatggtg tcggccaagt ccgaacaggc actacaggcg 7860 caggcagcac agttgcgcgc gtatctggcg gcacatcctg agctggggct ggctgatgtc 7920 gggtatgcgc tggcctccgg ccgcacggcc ttcggccacc gtgccgtgct cctgggcccg 7980 gaccgcgaag ccttcgtcga agagctggga gctctggagg ccggtgagga acacgccggg 8040 ctggtacggg gcgtggcgac gggtgcgggg aagctggcgt ttgtgtgttc cgggcaggga 8100 acgcaacgtc cccgtatggg acacgggctg tactacgcct tcccgctgtt cgccgcagcc 8160 atggacgaag cctgcgcaca cctggaccca cacctcgacc atcccctgcg ggatgtcatg 8220 ttcgccgagc cgggcaccga caccgcccag ctgctccacc agacccgcta cgcccagccc 8280 gccctgttcg ccctccagat cgccctgcac cgcctggtca ccgaacacca cggccttacc 8340 ccccactact acgccggcca ttccctcgga gagatcaccg cggcccacct cgccgggatc 8400 ctcaccctcc ccgacgcggc ccgcctggtc accacccgcg cccgcctcat gcaatctctc 8460 cccgccaccg gcgccatgac caccctccaa gcagaccccg acgaactcca cgaacacctc 8520 acacgatgcg aaggacgggt ctcactcgcg gccgtgaacg cgcccgggtc cgtggtcatc 8580 agcggtgatc gccacgacgt agacgctacg gccgaaaacc tccgcgccat gggacgcaag 8640 accactgcgc tgaaggtcag cggcgctttc cactcacacc acatcgaccc actcctcaac 8700 gaactccgca acacggcaga aaccctcacc taccacccac cccacacccc cctcatcacc 8760 accaacccca ccgaccacga ccccaccaca ccccactact gggtccggca agcgcgcgag 8820 acggtccact acgcccacac cacccaacaa ctccacaccc acggcgtcac cgcctacctc 8880 gaactcggcc ccgaccacac cctcaccgcc ctcacccacc acaacctccc cgaccacacc 8940 ccgctagccg tcccgcttct ccaccccgac caatccgaga cccacaccac ccacaccgcc 9000 ctcgcccacc tccacaccca cggccacccc accacctggc accaccatca cacccccacc 9060 cactaccacc caaacctccc cacctacccc ttccaacacc accactactg gctcaacacc 9120 accactgcca ccggtgatat gtcggctgca ggccttgagc cggcgcggca tcccctgttg 9180 ggcgcggcgg tcgggttggc cgatggtgag gggttgctgt tcactgggcg gatttctctc 9240 cgtacgcatc cctggctggc cgaccacgcc gtcggcggcg ccgtgttgct ccccggtacg 9300 gcctttctcg aactcgccct ccaagccgcc gcccatgccg actgccgtcg ggtcgaggag 9360 cttacgctcc acaccccgct cgtcgtaccg gatagcgccg gcgtagtgct gcaggtcact 9420 gtggccgcgc cgaacgaagc aggaaaccgg gcggtggata tctactcgcg aatcgatgtc 9480 ggcggcctca ccgccgattc ggctggcgag ccgtggacgc gccatgccgc cgggtacctt 9540 gccgacaagc ctgacccaga ctgcggtgac tcggcggatg gtgtcatgcc cgcgggcgca 9600 tggccgccgc cgggtgcggt cgccgtggat ctggagggac tgtacgagca actggccgag 9660 gggggtttcc actacggtgc ggccttccgt tgcctggacg ccgcctggca acgcggggac 9720 gaggtcttcg cgaccgcgta tatgtcagag gatcagctgg gcgacacggc tgcggctcgg 9780 ttcgcgctgc accccgcgct gctggattcc gcactgcaca ccattccact tttgccctcc 9840 ctacggggac aacaggacag cgggctgccg ttcacgtgga caggagtcac cctgcgtgca 9900 tccggggcga cggctctgcg cgtccggctg aggccggacg gccatggccc gggggcggtg 9960 tcggtcgacg tgtccgacga ggcgggtgag cccgtagcat cggtccggtc gttggccctg 10020 cggccggtga ccagggccga gttgcatacg gccgagttgc gcacagccgc cccggttgcc 10080 ccccatggct cgctcttcga ggtgcgatgg gaacccgtcc cccagccttc agcggccgaa 10140 gaagccgccc catgggtgat gatcgggacc gggccgacgc tgcgcccggt cgaggacttc 10200 gtcactccgc cggagcggac gtacgccgac ctggccgcgc tgtgcgtggc aatcgccgat 10260 gacgcgcccg ttccccggac ggtcgtggcc tggtccccag ccgggagcga agacgagtcg 10320 agtgaggcgc tgcgccaggc cacacaccac atgctgggcc tactgcagca gtggttggcg 10380 gacagccggt tcgccgacag tcgcctggtg atcctcaccc gagccgcggt ggccactgcg 10440 ccggacgagg aggtagaaga cctggcggga gcggcggcgc ggggtctgat ccgctccgcc 10500 cagtcggagc accctgaccg attcgtcctg ctcgacctgg acgaccgtcc cgctgacgcg 10560 aaagaccacg accgaatgct gtcgatggcc ctggcctgcg gggaaccgga agtggccgta 10620 cgcgatggag ccctgcgcac accccggctg agcccgctgg ccggcaccgc caccgaggcc 10680 atggacgagc atccctggga tcaggacggc accgtactca tcaccggcgg caccggcagc 10740 ctcggcgcca tgcttgcccg ccacttggtg gccacccatg gcgtacggca tctgatgctg 10800 atcagccgac gtggcctcga cgccccgggg gccaggcgac tgggggtcga acttgcggag 10860 ctcggggcgc aggtgacgat caccgcgtgc gatgccgcag accaaaggca acttgcgaac 10920 gtattgtcgg agatctccgt cgaccatccg ctgaccgctg tggtgcatgc ggcaggcgta 10980 ctggacgacg gggtgatcac atccctcaca ccggagggcc tgacccatgt cctgcgggcc 11040 aaggtcgatt cggcgctcaa tctccaccag ctcacacgcg acctgccgct gtccgcgttt 11100 gtgctcttct cctcgctggc cggggtgatg ggttcggcag ggcagggcaa ctacgccgcc 11160 gccaacgcag ccctggacgc gctggcgagt caccggaggg ccgctcggct gccggcggtg 11220 tccttggcct ggggagtttg ggagcagacc gagggcatga ccgggcagtt ggaggccacg 11280 gaccacgcgc ggctccgccg ctcgggcctg aggccgctgg ccatcagcga gggcctggag 11340 ctcttcgaca aggccctgag ctgtggacac gccctggtgg tgcccgccgc actcagcacg 11400 agggagcttc agacatccgg atccgtcccg ccattcctgc gccacctgac gggtgtcgct 11460 ccggcccggc cgtcccggac ccgcgacgcc tcggccggtg agccgacctc cctgcggcgg 11520 cggttgaccg gcctcgggcc ggaagaacgg ctacgcgagg tgctgcggct ggtgcgctcc 11580 cgggcggctg cggtgctggg gcacggcacg gccgaatcgg tcccggcgga ctcggcgttc 11640 cgcgacctgg ggttcgactc cctcgccgcg gtggacctgc ggaaccggtt gcagcaggcc 11700 accgggctgc gcctgccggc cggcttgatc ttcgaccggc cgcgtccgga cgtgctcgcc 11760 cgtttcctgt gtgacgagtt ggccggcgcc ggcggtacgt cggcggccac ggccgcccca 11820 cccgttgcgg ccgtcggcgg ggcagccggc gagccggtgg ccatcgtcgg catggcatgc 11880 cggtttccgg gaggtgtgcg gtcggccgag ggcctgtggg atctggtcgc ctccggtatg 11940 gacgcggtgg gtgacttccc cgcagaccga ggctgggagg tggaacggct ctacgacccc 12000 gacccggacc gaaccggcac ctcctacacc cggcaaggcg ggttccttta cgacgcgggt 12060 gagttcgacg cggcattctt cgggatcggc ccgcgtgagg cggtagccat ggatccacag 12120 cagcggctgc tgctggagat ctcctgggag gcgctggaac gtgcggggat cgacccggcg 12180 tcgctgcggg ggagttcgac cggggtgttc gctggggtga tgtaccacga ctacggcacc 12240 cgcctgcgcg agatcccaga gggctacgag ggctatatcg gcaatggaaa cgcgggcagc 12300 gtcgcgtcgg gacgtgtcgc ctacaccttc ggcctggagg ggccggcggt caccgtggac 12360 acggcgtgtt cgtcgtccct ggtcgccctg catctggcct gccaggcgct gcggtcaggg 12420 gagtgctcca tggcgctggc cggcggggtc accgtcatgt ccacccccac cacttttgtc 12480 gagttctcgc gccagcgggg actggccccg gacgggcggt gcaagtcctt cggggccggc 12540 gcggacggaa caggctgggc ggagggggcg gggatgctcc tggtggaacg gctttcggac 12600 gcccggcgca acggccaccg ggtcctggcg gtggtacggg ggagtgcggt caaccaggac 12660 ggggcgagca atgggctgac ggcgccgaac ggcccgtcgc aagagcgggt gatccgccag 12720 gcgtgggcaa acgcgggtgt ggccgcgatg gacatcgacg cggtggaggg acacggcacg 12780 gggacgacgc tcggtgaccc catcgaggcc caggcgctgc tggggacgta cggacaggga 12840 cggtcggccg atcggccgtt gtggttggga tcgatcaagt ccaacgtcgg acacacccag 12900 gccgccgcgg gggtgggcgg cgtcatcaag atggtgatgg ccatgcgcca cgggctgctc 12960 ccgcagaccc tgcacgccga ggagccctca cctcatgtgg actggtcggg cgggacggtg 13020 cggttgctga ccgagtcggt ggcctggccc gagcaggggc ggatgcgccg tgcgggcgtc 13080 tcctctttcg gtgtcagcgg taccaacgcc cacgtcatcc tggaacaagc accgcctgcc 13140 gcggagaccc acgaaccggc agagcccaac accgcgccag gcccactgcc ctgggcgatc 13200 tccgcgaaga gcccgcaagc gctacgtgcc caggcgcgcc aactgcacac gtacctgacc 13260 aacgcccccg aggcgaaccc cgccgacgtc ggccacaccc tcgcgacggg ccgcgcctct 13320 ttcgagcatc gtgctgtggt catcggctcc gaccgagcgg agttcctggg tggcctggat 13380 gctctggcgg ccgacgaggc ccacaccgcc gtcgtcacgg ggatcgcgag gaaggccggt 13440 gaccagggca aggtggtgtt cgtgttcccc gggcagggcg gtcagtgggc cgggatggga 13500 ctgcggctgc ttaagacctc acccgtcttc gcccaatcga tccaggcctg cgaacaagcc 13560 ctcgcccccc acaccgactg gaccctgacc gacatcctgc accggcccca caccgacccc 13620 ctgtggcagc gcgccgacgt catccagccc gtcctcttcg ccctcatgac ctccctcgcc 13680 gccctctggc aatcccacgg ccttaacccc gacgccgtca tcggccactc ccaaggcgaa 13740 atcaccgccg cccacatcag cggagcgctg agcctggagg acgccgcgaa aaccgtcgcg 13800 ctgcgcagcc gggccctgca gaccctgcgc ggttcgggcg gcatggcctc cgtaccactg 13860 ccggcggacc aggtcaccgg gctgctgcag accatgtggc cggaccggct gtgggtggcc 13920 gccgtcaacg cccctaccgc cacggtgatc tccggcaacg cggaagctct cacacaggcg 13980 ctggaacact accgggacca aggcgtcgac gcgaaacgga tcccggtcga ctacgcctcc 14040 cactgccccc acatccaggc cgtggaacag gaactgtcac ggctgttgcg gggcatcacc 14100 ccacgggccg ccaccacccc cttctactcc accaccgaca accaatggac cgacaccacc 14160 accctcaacg cccactactg gtaccgaaac ctccgccaac ccgtccacct cgccgacgcc 14220 atcaccaacc tcacccacca aggccaccac accttcatcg aaatcagccc ccaccccacc 14280 ctcacccccg ccatccaaga aaccaccgac accacccaca cccccaccac cgtcatcagc 14340 acactccgcc gcaaccacaa cgacacccac caaatcctcc acgccctcgc ccacgcccac 14400 accaccggcc accccatcaa ctggcacacc acccaccaac accacacccc aaccccccaa 14460 cacatcgacc tacccaccta ccccttccaa caccaccact actggctcaa cacccccacc 14520 cagacagggg atgcggcggc cgtcggcctg gacccggcac atcacccgtt gctgggcgcg 14580 gcggtcgcgg tggccgaggg ggagggctat ctgctcaccg gtcggctcgc cctgtccacc 14640 cacccctggc tcgccgatca caccatcgcc ggcgcggttg tcctccctgg aactgccctt 14700 ctcgagatcg cccttcaggc gggccatcgt gtggactgct ggcgcatcga agaactcacc 14760 ctccaatcac cgctgttcat cccggaagag ggagcagtac aggtgcaggc atgggtggcg 14820 gcaccggatg agaacgggtg ccgaagcctg acggtgtcct cccgacgcga gggtacgtac 14880 gaggacgcca cgtgggtgcg ccatgccacg ggccgggtcg gccccgcacc ggccgaccag 14940 gatgaagcca tcgcacggct caccgaccca caaggcgacg gagcggcggc ggcggtctgg 15000 ccaccgcagg gcgctgtcgc gttcaccgca gacgatctgg agggcctgta cgacgggtac 15060 gcggcgcggg gattcgagta cggcccggtg ttccgaggcc tgcgggcggc ctggcgacgt 15120 ggcgaggaca tcttcgccga ggtgcgcctt cccgacacgg cggacggcga cgcctcccag 15180 ttctccgtac accccgccct gctggacgcc gcactgcacg ccgcggcctt ccgcccggcc 15240 gacaaactcc cgcacggcgc cctgccgttc tccttcagcg gggtgaggct gcacgggccc 15300 ggagcgtcga ccctgcgggt gcgcctcacc ccggacggcc aggcgcggga cacgcacgca 15360 tggtcggtcg cggtggtcga cggcgagggg cggccggtgg cctcgatcgc atcgctcgcg 15420 gtccgcccgg tgtcgacgca ggagttgctg gcggcctccg gtacggcgcg gcgggactcg 15480 ctcttcgcgg tcgagtgggt gaccgccctg gcgccgacct cgtcgtccgt tccgcaacgc 15540 ctggccacgg tggggcccag cgaccgcctc ccctcggcag acgcgtacgc gaacctcgcc 15600 gacctggccg ccgcagtgct ggaggcgggg gccccggcgc ccgatgcggt cgtggtcgac 15660 tgcggccgcc gcgatgcgcg cgccaccgcc gtgccggagg acgtaaggac cctcacccgg 15720 cgcatcctgg gtctgctgca ggagtggctg gcggacgaga ggccggcctc gagccggatg 15780 gtcgtactga cccgtggtgc ggtggccacc actccggggg aggacgtggc ggacctggcg 15840 ggcgcggcgg tgtgcggcat ggtgcgctcc gcgcagtcgg aacatcccgg ccggttcgtc 15900 ctgctggacc tcgaccccga cccggacctc gacggcgggg aagtgccacc gaccgtcgtt 15960 ccggcggctc tcgcctgtgg tgagccgcag atcgcggtgc gtgcgaaccg gcacctggtg 16020 ccccggctga cccgcgttcc ggcgtccgtc cccgtccccg ggcgtgttcc cgttcccgcc 16080 gccgaggcag ccgacccgga caccacgccc acggcgttcg accccgacgg caccgtagtg 16140 atcaccggcg gcaccggcac ccttggcgcg atgctcgcgc gccatctggt cagccgtcac 16200 ggtgtacgac acctcctgct ggcatcgcga cgcggacccg acgcacccgg cgccaccgag 16260 ctgcgggcgg aactggccga gctcggcgcc gaggtgacgg tgcgcgcttg tgacaccggt 16320 gaccgaggcg cgctggcgga tctcatcgcg gggattccca ccggccaccc tttgaccggt 16380 gtggtccacg ctgcgggcgt cctggacgac gccaccgtcg cctcgctcac cccccgacac 16440 ctggacaccg cgctgacacc caaggccgac gccgccttcc atctgcacga gctcacccgc 16500 cacgcccggc cgcgcgcctt cgtcctgttc tcctcggccg ccggtgtcct cggcgcagcc 16560 gggcagggca actatgcggc cgccaacgct ttcctcgacg ccctcgccga acaccgcagg 16620 gcgcagggcc tgccggcctt gtcgctcgcg tggggcctgt gggagcaggg cagcggcatg 16680 accgggcatc tcgaccgcac cgaccgggcc cgcatcaacc gctccggact cgcccccctc 16740 gccacggagg acgctctcgc gctcttcgac gccgccctcg ccggcgatcg gccgttcctg 16800 gtgcccgccc ggctggacct gcggggttca agcgccgccg agaccccggc gccgctgttc 16860 tccaggatcg ccccggctcg tacgacccgg ggccggtccc ccggcgccga gggcgccgct 16920 gaccttcgta cccgtctcgc ggcccaggac gccgccgagc agcgcgacac gcttctcacg 16980 atcgtccgca cccacaccgc cgccgtcctg gggcatgaca cggctgccgc cgtgcggccg 17040 gacggggcct tccgtgaact gggtttcgac tccctcgccg ccgtggaact ccgtaaccgc 17100 cttcaaacga ccaccgccct caccctgccc gcgaccaccg tcttcgacca ccccaccccc 17160 gctgccctcg ccgatcatct gcgtactcag ctctgccagg acgctcagtc ctcggcggcg 17220 gccacggcca tggcggcgat ggcggagctg gccaggctgg agtccgccgt ctccgattcg 17280 gtggcgctcg acgacgacac gcgcagcggc ctcgcggagc gcctgcggtc cctcgcccgc 17340 aagatgagca gtggccgtgt cgtcgaccac gacggcggcg gcgctgcgga cctggatctt 17400 cagtcggtca cggacgatga gatgttcgag ctgatcgaca aggaggtcag ccgagactga 17460 17460 <210> 12 <211> 5819 <212> PRT <213> Artificial Sequence <220> <223> milA3 protein of Streptomyces milbemycinicus <400> 12 Met Ala Ala Gly His Asp Lys Val Ile Glu Ala Leu Arg Ala Ser Leu 1 5 10 15 Lys Thr Asn Glu Arg Gln Arg Glu Gln Ile His Arg Leu Thr Thr Ala 20 25 30 Ala Arg Glu Pro Ile Ala Ile Ile Gly Met Ala Cys Arg Tyr Pro Gly 35 40 45 Gly Val Gly Ser Pro Glu Asp Leu Trp Glu Leu Val Ala Ala Gly Arg 50 55 60 Asp Ala Ile Gly Thr Phe Pro Glu Asp Arg Gly Trp Asp Val Glu Arg 65 70 75 80 Leu Tyr Asp Pro Asp Pro Glu Arg Ala Gly Thr Ser Cys Thr Gln His 85 90 95 Gly Gly Phe Leu Tyr Gln Ala Gly Glu Phe Asp Pro Gly Phe Phe Gly 100 105 110 Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu 115 120 125 Leu Glu Ile Ser Trp Glu Val Phe Glu Arg Ala Gly Ile Asp Pro Ala 130 135 140 Ser Val Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Val Met Tyr His 145 150 155 160 Asp Tyr Gly Ser Arg Leu His Thr Val Pro Glu Gly Phe Glu Gly Tyr 165 170 175 Val Gly Asn Gly Ser Gly Gly Gly Val Ala Ser Gly Arg Val Ala Tyr 180 185 190 Thr Leu Gly Leu Glu Gly Pro Ala Val Thr Val Asp Thr Ala Cys Ser 195 200 205 Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ala Gly 210 215 220 Glu Cys Ser Leu Ala Leu Ala Gly Gly Val Thr Val Met Ser Thr Pro 225 230 235 240 Ser Leu Phe Val Glu Tyr Ser Arg Gln Arg Ala Leu Ala Ala Asp Gly 245 250 255 Arg Cys Lys Ala Tyr Gly Ala Gly Ala Asp Gly Thr Gly Trp Ala Glu 260 265 270 Gly Ala Gly Met Leu Leu Val Glu Arg Leu Thr Asp Ala Gln Arg Leu 275 280 285 Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp 290 295 300 Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ala Gln Gln Arg 305 310 315 320 Ala Ile Arg Gln Ala Leu Ala Ser Ala Gly Val Ser Ala Ser Glu Val 325 330 335 Asp Ala Val Glu Gly His Gly Thr Gly Thr Arg Leu Gly Asp Pro Ile 340 345 350 Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gln Arg Pro Ala Asp 355 360 365 Arg Pro Leu Trp Leu Gly Ser Met Lys Ser Asn Val Gly His Ala Gln 370 375 380 Ala Ala Ala Gly Val Gly Gly Ile Ile Lys Met Val Met Ala Met Arg 385 390 395 400 Ser Gly Thr Leu Pro Arg Thr Leu His Ala Asp Glu Pro Ser Pro His 405 410 415 Ile Asp Trp Asp Ser Gly Ala Val Arg Leu Leu Thr Glu Pro Val Ala 420 425 430 Trp Pro Glu Arg Asp Arg Pro Arg Arg Ala Ala Val Ser Ser Phe Gly 435 440 445 Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Ala Ala Ser Gln Thr 450 455 460 Ala Pro Gln Thr Asp Ser Ala Ser Gln Ala Glu Thr Asp Asp Ala Pro 465 470 475 480 Ala Pro His Gly Ala Pro Gly His Ala Val Ala Gly Pro Leu Leu Trp 485 490 495 Pro Leu Ser Gly Ala Thr Ala Glu Ala Leu Arg Ala Gln Ala Gly Glu 500 505 510 Leu Arg Arg Phe Val Ala Ala Asp Glu Leu Leu Arg Pro Ala Asp Val 515 520 525 Gly His Thr Leu Val Phe Gly Arg Ser Asp Leu Ala His Arg Ala Val 530 535 540 Val Leu Gly Ser Asp Arg Glu Thr Leu Leu Arg Ala Leu Asp Thr Leu 545 550 555 560 Ala Gly Glu Gly Pro Asp Asp Gly Ser Val Val Arg Gly Met Ala Ala 565 570 575 Ala Gly Ala Gly Ala Gly Val Val Phe Val Phe Pro Gly Gln Gly Gly 580 585 590 Gln Trp Ala Gly Met Gly Leu Arg Leu Leu Glu Thr Ser Ser Phe Phe 595 600 605 Ala Glu Arg Met Ala Glu Cys Glu Ala Ala Leu Ala Pro Tyr Ala Asp 610 615 620 Trp Ser Leu Leu Asp Val Leu Arg Arg Asp Pro Gly Asp Pro Val Trp 625 630 635 640 Glu Arg Ala Asp Val Val Gln Pro Met Leu Phe Ser Val Met Val Ser 645 650 655 Leu Ala Gln Leu Trp Arg Ser Tyr Gly Val Glu Pro Asp Ala Val Leu 660 665 670 Gly His Ser Gln Gly Glu Ile Ala Ala Ala His Ile Cys Gly Ala Leu 675 680 685 Thr Leu Asp Asp Ala Ala Lys Val Val Ala Leu Arg Ser Arg Ala Leu 690 695 700 Gln Thr Leu Arg Gly Ser Gly Gly Met Ala Ser Val Pro Leu Pro Ala 705 710 715 720 Asp Glu Val Thr Gly Leu Leu Arg Thr Ala Trp Pro Asp Arg Leu Trp 725 730 735 Val Ala Ala Val Asn Ala Pro Thr Ala Thr Val Ile Ser Gly Asp Ala 740 745 750 Asp Ser Leu Ala Glu Ala Leu Glu His Tyr Arg Asp Gln Gly Val Glu 755 760 765 Ala Lys Arg Val Pro Val Asp Tyr Ala Ser His Cys Pro His Ile Glu 770 775 780 Ala Val Glu Gln Glu Leu Leu Gly Leu Leu Arg Gly Ile Ala Pro Arg 785 790 795 800 Ala Ala Asp Ile Pro Phe Tyr Ser Thr Val Asp Asn Gln Trp Ala Asp 805 810 815 Thr Met Gly Leu Asp Ala Arg Tyr Trp Tyr Arg Asn Leu Arg Arg Pro 820 825 830 Val Arg Phe Ala Glu Ala Leu Arg Ala Leu Gly Ala Ala Glu Tyr Arg 835 840 845 Thr Tyr Val Glu Val Gly Pro His Pro Thr Leu Thr Pro Ala Ile Glu 850 855 860 Asp Thr Thr Glu Ala Ala Gly Val Ala Ala Thr Val Val Gly Ser Leu 865 870 875 880 Arg Arg Gly Glu Asp Asp Ala His Arg Ile Leu Thr Ser Leu Ala Arg 885 890 895 Ala His Ile His Gly Leu Pro Val Ala Trp Asp Arg His Tyr Arg Ala 900 905 910 Leu Ala Pro Glu Ala Asn His Val Asp Leu Pro Thr Tyr Ala Phe Gln 915 920 925 Arg Arg Arg Tyr Trp Leu Asp Ala Pro Ala Thr Thr Gly Asp Val Thr 930 935 940 Ala Ala Gly Leu Ala Pro Val Gly His Pro Leu Leu Gly Ala Ala Val 945 950 955 960 Gly Leu Ala Glu Gly Asp Gly Tyr Leu Leu Thr Gly Arg Leu Ala Pro 965 970 975 His Thr His Pro Trp Leu Thr Asp His Ala Val Ala Gly Thr Val Leu 980 985 990 Leu Pro Gly Thr Ala Tyr Val Glu Leu Ala Val His Val Gly Gly His 995 1000 1005 Leu Gly Cys Pro Arg Leu Glu Glu Leu Thr Leu His Ala Pro Leu Val 1010 1015 1020 Leu Pro Asp Thr Gly Gly Val Ala Leu Gln Val Ala Val Gly Ala Pro 1025 1030 1035 1040 Asp Glu Thr Gly Arg Arg Ala Leu Ser Val Tyr Ala Gln Arg Asp Asp 1045 1050 1055 Asp Pro Ala Trp Glu Gly Ala Ala Arg Gly Ala Trp Thr Arg His Ala 1060 1065 1070 Thr Gly Thr Leu Ala Ala Glu Ala Pro Thr Asp Gly Ile Ser Gly Ala 1075 1080 1085 Asp Gly Ala Gly Thr Leu Ala Gly Ala Trp Pro Pro Pro Gly Ala Glu 1090 1095 1100 Pro Leu Asp Ile Ser Gly Leu Tyr Asp Thr Leu Ala Ala Ala Asp Phe 1105 1110 1115 1120 Gly Tyr Gly Pro Ala Phe Gln Gly Leu Arg Ala Val Trp Arg Gln Gly 1125 1130 1135 Glu Glu Thr Tyr Ala Glu Val Arg Leu Pro Asp Gln Val Ala Ala Asp 1140 1145 1150 Ala Pro Arg Phe Cys Leu His Pro Ala Leu Leu Asp Ala Ala Leu His 1155 1160 1165 Pro Leu Ala Leu Asp Ser Gly Arg Ser Glu Glu Asn Pro Ala Gly His 1170 1175 1180 Gly Leu Leu Pro Phe Ala Trp Arg Gly Val Ser Leu Arg Ser Pro Gly 1185 1190 1195 1200 Thr Pro Thr Leu Arg Val Arg Leu Arg Pro Gln Gly Pro Asp Ser Ile 1205 1210 1215 Ala Val Asp Val Ala Asp Glu Thr Gly Ala Pro Val Ala Ser Ala Glu 1220 1225 1230 Ser Leu Thr Leu Arg Pro Val Ala Leu Glu Asp Leu Arg Ala Leu Gly 1235 1240 1245 Gly Gln Ala Gly Asp Thr Leu Tyr Ala Leu Glu Trp Thr Ala Ala Pro 1250 1255 1260 Glu Pro Pro Ala Thr Ala Leu Gly Arg Cys Ala Val Ile Gly Gln Ala 1265 1270 1275 1280 Ile Pro Gly Trp Ala Ala Ala Leu Glu Thr Ala Ala Ala Gly Pro Val 1285 1290 1295 Arg Arg Tyr Pro Asp Leu Ala Gly Leu Val Thr Ala Leu Asp Ala Gly 1300 1305 1310 Asp Pro Pro Pro Asp Leu Val Phe Val Gly Cys Pro Pro Ala Ala Ala 1315 1320 1325 Gly Pro Asp Asp Thr Thr Val Ala Asp Val His Thr Ala Arg Thr Arg 1330 1335 1340 Val Arg Thr Arg Gln Ala Leu Asp Leu Leu Gln Gly Trp Leu Gly Glu 1345 1350 1355 1360 Ala Arg Leu Ala Gly Ala Arg Leu Val Leu Val Thr Cys Gly Ala Val 1365 1370 1375 Ala Thr Gly Pro Ala Glu Gly Val Met Asp Leu Ala Gly Ala Ala Ile 1380 1385 1390 Cys Gly Leu Val Arg Ser Ala Gln Ala Glu Glu Pro Asp Arg Ile Leu 1395 1400 1405 Leu Val Asp Leu Asp Ala Ala Glu Glu Ser Trp Ala Ala Leu Pro Arg 1410 1415 1420 Ala Val Ala Leu Gly Glu Pro Gln Met Ala Ile Arg Ala Gly Gln Pro 1425 1430 1435 1440 His Met Ala Arg Leu Val Arg Ala Asp Thr Glu Gly Gly Ala Leu Leu 1445 1450 1455 Thr Pro Pro Gln Gly Ser Gly Gly Trp Arg Leu Asp Cys Ala Asp Ala 1460 1465 1470 Gly Thr Val Gln Gly Leu Ala Pro Val Ala Ser Ser Ala Asp Arg Asp 1475 1480 1485 Pro Leu Gly Pro His Gln Val Arg Ile Glu Val Arg Ala Ala Gly Leu 1490 1495 1500 Asn Phe Arg Asp Val Leu Val Ala Leu Gly Met Val Pro Gly Gln Arg 1505 1510 1515 1520 Gly Leu Gly Ser Glu Gly Ala Gly Val Val Leu Glu Ala Gly Pro Glu 1525 1530 1535 Val Ala Asp Leu Ala Pro Gly Asp Arg Val Met Gly Val Phe Ala Asp 1540 1545 1550 Ala Phe Gly Pro Phe Ala Ile Ala Asp Arg Ala Thr Val Ile Arg Val 1555 1560 1565 Pro Asp His Trp Thr Phe Gly Gln Ala Ala Ala Val Pro Val Val Phe 1570 1575 1580 Ala Thr Ala Tyr Tyr Gly Leu Val Asp Leu Ala Gly Leu Arg Pro Gly 1585 1590 1595 1600 Glu Ser Val Leu Val His Ala Ala Ala Gly Gly Val Gly Leu Ala Ala 1605 1610 1615 Val Gln Leu Ala Arg His Leu Gly Ala Glu Val Tyr Ala Thr Ala Ser 1620 1625 1630 Pro Gly Lys Trp Asp Thr Leu Arg Ala His Gly Ile Pro Pro Glu Arg 1635 1640 1645 Ile Ala Ser Ser Arg Thr Leu Asp Phe Glu Ser Arg Phe Thr Gly Arg 1650 1655 1660 Asn Ile Asp Val Val Leu Asn Ser Leu Ala His Glu Tyr Val Asp Ala 1665 1670 1675 1680 Ser Leu Arg Leu Val Ser Gly Asp Ser Gly Arg Phe Leu Glu Met Gly 1685 1690 1695 Lys Thr Asp Leu Arg Asp Pro Glu Glu Val Ala Gln Ala Tyr Pro Gly 1700 1705 1710 Val Ala Tyr Arg Ala Tyr Asp Leu Met Glu Ala Gly Pro Glu Arg Ile 1715 1720 1725 Gly Glu Ile Leu Arg Thr Val Leu Arg Leu Phe Asp Glu Gly Val Leu 1730 1735 1740 Thr Pro Leu Pro Leu Thr Cys Trp Asp Ile Arg Gln Ala Arg Asp Ala 1745 1750 1755 1760 Phe Arg Gln Leu Gln Gln Gly Arg Thr Val Gly Lys Asn Val Leu Thr 1765 1770 1775 Leu Asp Arg Thr Pro Asp Pro Asp Gly Thr Val Leu Ile Thr Gly Gly 1780 1785 1790 Thr Gly Thr Leu Gly Ala Ala Leu Ala Arg His Leu Ala Ala Thr Gly 1795 1800 1805 Arg Ala Arg His Leu Leu Leu Ile Ser Arg Arg Gly Leu Asp Ala Pro 1810 1815 1820 Gly Ala Pro Glu Leu Ile Ala Glu Ile Asp Glu Leu Gly Ala Thr Ala 1825 1830 1835 1840 Thr Val Ala Thr Cys Asp Val Gly Asp Arg Ala Ala Leu Ala Glu Leu 1845 1850 1855 Leu Gly Arg Ile Pro Ala Glu His Pro Leu Thr Ala Val Val His Ala 1860 1865 1870 Ala Gly Thr Leu Asp Asp Ala Thr Leu Gly Ser Leu Thr Ala Arg His 1875 1880 1885 Leu Asp Thr Val Leu Pro Ala Lys Ala Asp Ala Ala Trp His Leu His 1890 1895 1900 Asp Leu Thr Cys Arg Leu Asp Leu Ala Ala Phe Val Leu Phe Ser Ser 1905 1910 1915 1920 Ala Ala Gly Val Leu Gly Ser Pro Gly Gln Gly Asn Tyr Ala Ala Ala 1925 1930 1935 Asn Ala Phe Leu Asp Ala Leu Ala Phe Gln Arg Arg Ala Met Gly Leu 1940 1945 1950 Pro Ala Val Ser Leu Ala Trp Gly Leu Trp Glu Glu Ala Ser Gly Met 1955 1960 1965 Thr Gly His Leu Asp Gln Thr Asp Arg Thr Arg Met Ala Arg Val Gly 1970 1975 1980 Leu Arg Pro Leu Ala Thr Asp Glu Ala Leu Ala Leu Phe Asp Asn Ala 1985 1990 1995 2000 Leu Val Asp Gly Pro Pro Leu Leu Leu Pro Ala Arg Ile Asp Thr Lys 2005 2010 2015 Ala Leu Arg Gly Thr Thr Ala Pro Pro Leu Phe Gln Ser Leu Val Arg 2020 2025 2030 Pro Thr Thr Gly His Arg Pro Arg Pro Ala Thr Pro Asp Gly Arg Ser 2035 2040 2045 Ser Leu Arg Ala Arg Leu Ala Gly Leu Asp Pro Ala Ala Gln His Glu 2050 2055 2060 Val Leu Leu Thr Leu Val Arg Gly His Ala Ala Thr Val Leu Gly His 2065 2070 2075 2080 Pro Ser Pro Asp Ala Ile Ala Arg Glu Ala Ala Phe Arg Asp Leu Gly 2085 2090 2095 Phe Asp Ser Leu Thr Ala Val Glu Leu Arg Asn Arg Leu Lys Glu Ala 2100 2105 2110 Thr Gly Leu Arg Leu Pro Ala Thr Ile Val Phe Asp His Pro Thr Pro 2115 2120 2125 Ala Ala Leu Ala Gln His Leu Arg Asp Gly Leu Ile Gly Gly Ala Asp 2130 2135 2140 Thr Val Thr Leu Ala Ala Ala Pro Ala Pro Ser Lys Val Ala Met Val 2145 2150 2155 2160 Ala Asp Glu Ala Ile Ala Ile Ile Gly Met Ala Cys Arg Tyr Pro Gly 2165 2170 2175 Gly Val Arg Ser Ala Glu Gly Leu Trp Asp Leu Val Ala Ser Gly Thr 2180 2185 2190 Asp Ala Met Ser Gly Phe Pro Ser Asp Arg Gly Trp Asp Leu Asp Arg 2195 2200 2205 Leu Tyr Ala Pro Gln Asp Gln Asp Val Pro Gly Thr Thr Tyr Thr Arg 2210 2215 2220 His Gly Gly Phe Leu His Asp Ala Gly Lys Phe Asp Ala Gly Phe Phe 2225 2230 2235 2240 Gly Ile Gly Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu 2245 2250 2255 Leu Leu Glu Thr Ser Trp Glu Val Phe Glu His Ala Gly Ile Asp Pro 2260 2265 2270 Ser Ser Val Arg Arg Ser Arg Thr Gly Val Phe Ala Gly Val Met Pro 2275 2280 2285 Thr Asp Tyr Gly Pro Arg Leu Gln Asp Thr Val Ala Glu Val Glu Gly 2290 2295 2300 Tyr Val Leu Thr Gly Asn Ser Gly Ser Val Ala Ser Gly Arg Ile Ala 2305 2310 2315 2320 Tyr Thr Phe Gly Leu Glu Gly Pro Ala Val Ser Val Asp Thr Ala Cys 2325 2330 2335 Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ala 2340 2345 2350 Gly Glu Cys Ser Met Ala Leu Ala Gly Gly Val Thr Val Met Ala Thr 2355 2360 2365 Pro Gly Ala Phe Val Glu Phe Ala Arg Gln Arg Gly Leu Ser Val Asp 2370 2375 2380 Gly Arg Cys Lys Ala Phe Gly Val Gly Ala Asp Gly Thr Gly Trp Ala 2385 2390 2395 2400 Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg 2405 2410 2415 Leu Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln 2420 2425 2430 Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ser Gln Gln 2435 2440 2445 Arg Val Ile Arg Gln Ala Leu Ala Ser Ala Arg Val Gly Gly Ala Asp 2450 2455 2460 Val Asp Val Val Glu Gly His Gly Thr Gly Thr Arg Leu Gly Asp Pro 2465 2470 2475 2480 Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Glu Arg Val Gly 2485 2490 2495 Asp Gly Ser Leu Trp Leu Gly Ser Val Lys Ser Asn Ile Gly His Ala 2500 2505 2510 Gln Ala Ala Ala Gly Val Ala Gly Val Ile Lys Met Val Met Ala Met 2515 2520 2525 Arg Tyr Gly Val Leu Pro Arg Thr Leu His Val Gln Glu Pro Ser Pro 2530 2535 2540 His Val Asp Trp Ser Ser Gly Gly Val Arg Leu Leu Thr Glu Ala Val 2545 2550 2555 2560 Pro Trp Pro Glu Thr Gly Arg Ala Arg Arg Ala Gly Val Ser Ser Phe 2565 2570 2575 Gly Val Ser Gly Thr Asn Ala His Ile Ile Leu Glu Gln Ala Pro Pro 2580 2585 2590 Glu Glu His Asp Asp Pro Ala Asp Val Ser Ser Gly Ser Phe Pro Trp 2595 2600 2605 Met Val Ser Ala Lys Ser Glu Gln Ala Leu Gln Ala Gln Ala Ala Gln 2610 2615 2620 Leu Arg Ala Tyr Leu Ala Ala His Pro Glu Leu Gly Leu Ala Asp Val 2625 2630 2635 2640 Gly Tyr Ala Leu Ala Ser Gly Arg Thr Ala Phe Gly His Arg Ala Val 2645 2650 2655 Leu Leu Gly Pro Asp Arg Glu Ala Phe Val Glu Glu Leu Gly Ala Leu 2660 2665 2670 Glu Ala Gly Glu Glu His Ala Gly Leu Val Arg Gly Val Ala Thr Gly 2675 2680 2685 Ala Gly Lys Leu Ala Phe Val Cys Ser Gly Gln Gly Thr Gln Arg Pro 2690 2695 2700 Arg Met Gly His Gly Leu Tyr Tyr Ala Phe Pro Leu Phe Ala Ala Ala 2705 2710 2715 2720 Met Asp Glu Ala Cys Ala His Leu Asp Pro His Leu Asp His Pro Leu 2725 2730 2735 Arg Asp Val Met Phe Ala Glu Pro Gly Thr Asp Thr Ala Gln Leu Leu 2740 2745 2750 His Gln Thr Arg Tyr Ala Gln Pro Ala Leu Phe Ala Leu Gln Ile Ala 2755 2760 2765 Leu His Arg Leu Val Thr Glu His His Gly Leu Thr Pro His Tyr Tyr 2770 2775 2780 Ala Gly His Ser Leu Gly Glu Ile Thr Ala Ala His Leu Ala Gly Ile 2785 2790 2795 2800 Leu Thr Leu Pro Asp Ala Ala Arg Leu Val Thr Thr Arg Ala Arg Leu 2805 2810 2815 Met Gln Ser Leu Pro Ala Thr Gly Ala Met Thr Thr Leu Gln Ala Asp 2820 2825 2830 Pro Asp Glu Leu His Glu His Leu Thr Arg Cys Glu Gly Arg Val Ser 2835 2840 2845 Leu Ala Ala Val Asn Ala Pro Gly Ser Val Val Ile Ser Gly Asp Arg 2850 2855 2860 His Asp Val Asp Ala Thr Ala Glu Asn Leu Arg Ala Met Gly Arg Lys 2865 2870 2875 2880 Thr Thr Ala Leu Lys Val Ser Gly Ala Phe His Ser His His Ile Asp 2885 2890 2895 Pro Leu Leu Asn Glu Leu Arg Asn Thr Ala Glu Thr Leu Thr Tyr His 2900 2905 2910 Pro Pro His Thr Pro Leu Ile Thr Thr Asn Pro Thr Asp His Asp Pro 2915 2920 2925 Thr Thr Pro His Tyr Trp Val Arg Gln Ala Arg Glu Thr Val His Tyr 2930 2935 2940 Ala His Thr Thr Gln Gln Leu His Thr His Gly Val Thr Ala Tyr Leu 2945 2950 2955 2960 Glu Leu Gly Pro Asp His Thr Leu Thr Ala Leu Thr His His Asn Leu 2965 2970 2975 Pro Asp His Thr Pro Leu Ala Val Pro Leu Leu His Pro Asp Gln Ser 2980 2985 2990 Glu Thr His Thr Thr His Thr Ala Leu Ala His Leu His Thr His Gly 2995 3000 3005 His Pro Thr Thr Trp His His His His Thr Pro Thr His Tyr His Pro 3010 3015 3020 Asn Leu Pro Thr Tyr Pro Phe Gln His His His Tyr Trp Leu Asn Thr 3025 3030 3035 3040 Thr Thr Ala Thr Gly Asp Met Ser Ala Ala Gly Leu Glu Pro Ala Arg 3045 3050 3055 His Pro Leu Leu Gly Ala Ala Val Gly Leu Ala Asp Gly Glu Gly Leu 3060 3065 3070 Leu Phe Thr Gly Arg Ile Ser Leu Arg Thr His Pro Trp Leu Ala Asp 3075 3080 3085 His Ala Val Gly Gly Ala Val Leu Leu Pro Gly Thr Ala Phe Leu Glu 3090 3095 3100 Leu Ala Leu Gln Ala Ala Ala His Ala Asp Cys Arg Arg Val Glu Glu 3105 3110 3115 3120 Leu Thr Leu His Thr Pro Leu Val Val Pro Asp Ser Ala Gly Val Val 3125 3130 3135 Leu Gln Val Thr Val Ala Ala Pro Asn Glu Ala Gly Asn Arg Ala Val 3140 3145 3150 Asp Ile Tyr Ser Arg Ile Asp Val Gly Gly Leu Thr Ala Asp Ser Ala 3155 3160 3165 Gly Glu Pro Trp Thr Arg His Ala Ala Gly Tyr Leu Ala Asp Lys Pro 3170 3175 3180 Asp Pro Asp Cys Gly Asp Ser Ala Asp Gly Val Met Pro Ala Gly Ala 3185 3190 3195 3200 Trp Pro Pro Pro Gly Ala Val Ala Val Asp Leu Glu Gly Leu Tyr Glu 3205 3210 3215 Gln Leu Ala Glu Gly Gly Phe His Tyr Gly Ala Ala Phe Arg Cys Leu 3220 3225 3230 Asp Ala Ala Trp Gln Arg Gly Asp Glu Val Phe Ala Thr Ala Tyr Met 3235 3240 3245 Ser Glu Asp Gln Leu Gly Asp Thr Ala Ala Ala Arg Phe Ala Leu His 3250 3255 3260 Pro Ala Leu Leu Asp Ser Ala Leu His Thr Ile Pro Leu Leu Pro Ser 3265 3270 3275 3280 Leu Arg Gly Gln Gln Asp Ser Gly Leu Pro Phe Thr Trp Thr Gly Val 3285 3290 3295 Thr Leu Arg Ala Ser Gly Ala Thr Ala Leu Arg Val Arg Leu Arg Pro 3300 3305 3310 Asp Gly His Gly Pro Gly Ala Val Ser Val Asp Val Ser Asp Glu Ala 3315 3320 3325 Gly Glu Pro Val Ala Ser Val Arg Ser Leu Ala Leu Arg Pro Val Thr 3330 3335 3340 Arg Ala Glu Leu His Thr Ala Glu Leu Arg Thr Ala Ala Pro Val Ala 3345 3350 3355 3360 Pro His Gly Ser Leu Phe Glu Val Arg Trp Glu Pro Val Pro Gln Pro 3365 3370 3375 Ser Ala Ala Glu Glu Ala Ala Pro Trp Val Met Ile Gly Thr Gly Pro 3380 3385 3390 Thr Leu Arg Pro Val Glu Asp Phe Val Thr Pro Pro Glu Arg Thr Tyr 3395 3400 3405 Ala Asp Leu Ala Ala Leu Cys Val Ala Ile Ala Asp Asp Ala Pro Val 3410 3415 3420 Pro Arg Thr Val Val Ala Trp Ser Pro Ala Gly Ser Glu Asp Glu Ser 3425 3430 3435 3440 Ser Glu Ala Leu Arg Gln Ala Thr His His Met Leu Gly Leu Leu Gln 3445 3450 3455 Gln Trp Leu Ala Asp Ser Arg Phe Ala Asp Ser Arg Leu Val Ile Leu 3460 3465 3470 Thr Arg Ala Ala Val Ala Thr Ala Pro Asp Glu Glu Val Glu Asp Leu 3475 3480 3485 Ala Gly Ala Ala Ala Arg Gly Leu Ile Arg Ser Ala Gln Ser Glu His 3490 3495 3500 Pro Asp Arg Phe Val Leu Leu Asp Leu Asp Asp Arg Pro Ala Asp Ala 3505 3510 3515 3520 Lys Asp His Asp Arg Met Leu Ser Met Ala Leu Ala Cys Gly Glu Pro 3525 3530 3535 Glu Val Ala Val Arg Asp Gly Ala Leu Arg Thr Pro Arg Leu Ser Pro 3540 3545 3550 Leu Ala Gly Thr Ala Thr Glu Ala Met Asp Glu His Pro Trp Asp Gln 3555 3560 3565 Asp Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Ser Leu Gly Ala Met 3570 3575 3580 Leu Ala Arg His Leu Val Ala Thr His Gly Val Arg His Leu Met Leu 3585 3590 3595 3600 Ile Ser Arg Arg Gly Leu Asp Ala Pro Gly Ala Arg Arg Leu Gly Val 3605 3610 3615 Glu Leu Ala Glu Leu Gly Ala Gln Val Thr Ile Thr Ala Cys Asp Ala 3620 3625 3630 Ala Asp Gln Arg Gln Leu Ala Asn Val Leu Ser Glu Ile Ser Val Asp 3635 3640 3645 His Pro Leu Thr Ala Val Val His Ala Ala Gly Val Leu Asp Asp Gly 3650 3655 3660 Val Ile Thr Ser Leu Thr Pro Glu Gly Leu Thr His Val Leu Arg Ala 3665 3670 3675 3680 Lys Val Asp Ser Ala Leu Asn Leu His Gln Leu Thr Arg Asp Leu Pro 3685 3690 3695 Leu Ser Ala Phe Val Leu Phe Ser Ser Leu Ala Gly Val Met Gly Ser 3700 3705 3710 Ala Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu 3715 3720 3725 Ala Ser His Arg Arg Ala Ala Arg Leu Pro Ala Val Ser Leu Ala Trp 3730 3735 3740 Gly Val Trp Glu Gln Thr Glu Gly Met Thr Gly Gln Leu Glu Ala Thr 3745 3750 3755 3760 Asp His Ala Arg Leu Arg Arg Ser Gly Leu Arg Pro Leu Ala Ile Ser 3765 3770 3775 Glu Gly Leu Glu Leu Phe Asp Lys Ala Leu Ser Cys Gly His Ala Leu 3780 3785 3790 Val Val Pro Ala Ala Leu Ser Thr Arg Glu Leu Gln Thr Ser Gly Ser 3795 3800 3805 Val Pro Pro Phe Leu Arg His Leu Thr Gly Val Ala Pro Ala Arg Pro 3810 3815 3820 Ser Arg Thr Arg Asp Ala Ser Ala Gly Glu Pro Thr Ser Leu Arg Arg 3825 3830 3835 3840 Arg Leu Thr Gly Leu Gly Pro Glu Glu Arg Leu Arg Glu Val Leu Arg 3845 3850 3855 Leu Val Arg Ser Arg Ala Ala Ala Val Leu Gly His Gly Thr Ala Glu 3860 3865 3870 Ser Val Pro Ala Asp Ser Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu 3875 3880 3885 Ala Ala Val Asp Leu Arg Asn Arg Leu Gln Gln Ala Thr Gly Leu Arg 3890 3895 3900 Leu Pro Ala Gly Leu Ile Phe Asp Arg Pro Arg Pro Asp Val Leu Ala 3905 3910 3915 3920 Arg Phe Leu Cys Asp Glu Leu Ala Gly Ala Gly Gly Thr Ser Ala Ala 3925 3930 3935 Thr Ala Ala Pro Pro Val Ala Ala Val Gly Gly Ala Ala Gly Glu Pro 3940 3945 3950 Val Ala Ile Val Gly Met Ala Cys Arg Phe Pro Gly Gly Val Arg Ser 3955 3960 3965 Ala Glu Gly Leu Trp Asp Leu Val Ala Ser Gly Met Asp Ala Val Gly 3970 3975 3980 Asp Phe Pro Ala Asp Arg Gly Trp Glu Val Glu Arg Leu Tyr Asp Pro 3985 3990 3995 4000 Asp Pro Asp Arg Thr Gly Thr Ser Tyr Thr Arg Gln Gly Gly Phe Leu 4005 4010 4015 Tyr Asp Ala Gly Glu Phe Asp Ala Ala Phe Phe Gly Ile Gly Pro Arg 4020 4025 4030 Glu Ala Val Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Ile Ser 4035 4040 4045 Trp Glu Ala Leu Glu Arg Ala Gly Ile Asp Pro Ala Ser Leu Arg Gly 4050 4055 4060 Ser Ser Thr Gly Val Phe Ala Gly Val Met Tyr His Asp Tyr Gly Thr 4065 4070 4075 4080 Arg Leu Arg Glu Ile Pro Glu Gly Tyr Glu Gly Tyr Ile Gly Asn Gly 4085 4090 4095 Asn Ala Gly Ser Val Ala Ser Gly Arg Val Ala Tyr Thr Phe Gly Leu 4100 4105 4110 Glu Gly Pro Ala Val Thr Val Asp Thr Ala Cys Ser Ser Ser Leu Val 4115 4120 4125 Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ser Gly Glu Cys Ser Met 4130 4135 4140 Ala Leu Ala Gly Gly Val Thr Val Met Ser Thr Pro Thr Thr Phe Val 4145 4150 4155 4160 Glu Phe Ser Arg Gln Arg Gly Leu Ala Pro Asp Gly Arg Cys Lys Ser 4165 4170 4175 Phe Gly Ala Gly Ala Asp Gly Thr Gly Trp Ala Glu Gly Ala Gly Met 4180 4185 4190 Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Asn Gly His Arg Val 4195 4200 4205 Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn 4210 4215 4220 Gly Leu Thr Ala Pro Asn Gly Pro Ser Gln Glu Arg Val Ile Arg Gln 4225 4230 4235 4240 Ala Trp Ala Asn Ala Gly Val Ala Ala Met Asp Ile Asp Ala Val Glu 4245 4250 4255 Gly His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala 4260 4265 4270 Leu Leu Gly Thr Tyr Gly Gln Gly Arg Ser Ala Asp Arg Pro Leu Trp 4275 4280 4285 Leu Gly Ser Ile Lys Ser Asn Val Gly His Thr Gln Ala Ala Ala Gly 4290 4295 4300 Val Gly Gly Val Ile Lys Met Val Met Ala Met Arg His Gly Leu Leu 4305 4310 4315 4320 Pro Gln Thr Leu His Ala Glu Glu Pro Ser Pro His Val Asp Trp Ser 4325 4330 4335 Gly Gly Thr Val Arg Leu Leu Thr Glu Ser Val Ala Trp Pro Glu Gln 4340 4345 4350 Gly Arg Met Arg Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr 4355 4360 4365 Asn Ala His Val Ile Leu Glu Gln Ala Pro Pro Ala Ala Glu Thr His 4370 4375 4380 Glu Pro Ala Glu Pro Asn Thr Ala Pro Gly Pro Leu Pro Trp Ala Ile 4385 4390 4395 4400 Ser Ala Lys Ser Pro Gln Ala Leu Arg Ala Gln Ala Arg Gln Leu His 4405 4410 4415 Thr Tyr Leu Thr Asn Ala Pro Glu Ala Asn Pro Ala Asp Val Gly His 4420 4425 4430 Thr Leu Ala Thr Gly Arg Ala Ser Phe Glu His Arg Ala Val Val Ile 4435 4440 4445 Gly Ser Asp Arg Ala Glu Phe Leu Gly Gly Leu Asp Ala Leu Ala Ala 4450 4455 4460 Asp Glu Ala His Thr Ala Val Val Thr Gly Ile Ala Arg Lys Ala Gly 4465 4470 4475 4480 Asp Gln Gly Lys Val Val Phe Val Phe Pro Gly Gln Gly Gly Gln Trp 4485 4490 4495 Ala Gly Met Gly Leu Arg Leu Leu Lys Thr Ser Pro Val Phe Ala Gln 4500 4505 4510 Ser Ile Gln Ala Cys Glu Gln Ala Leu Ala Pro His Thr Asp Trp Thr 4515 4520 4525 Leu Thr Asp Ile Leu His Arg Pro His Thr Asp Pro Leu Trp Gln Arg 4530 4535 4540 Ala Asp Val Ile Gln Pro Val Leu Phe Ala Leu Met Thr Ser Leu Ala 4545 4550 4555 4560 Ala Leu Trp Gln Ser His Gly Leu Asn Pro Asp Ala Val Ile Gly His 4565 4570 4575 Ser Gln Gly Glu Ile Thr Ala Ala His Ile Ser Gly Ala Leu Ser Leu 4580 4585 4590 Glu Asp Ala Ala Lys Thr Val Ala Leu Arg Ser Arg Ala Leu Gln Thr 4595 4600 4605 Leu Arg Gly Ser Gly Gly Met Ala Ser Val Pro Leu Pro Ala Asp Gln 4610 4615 4620 Val Thr Gly Leu Leu Gln Thr Met Trp Pro Asp Arg Leu Trp Val Ala 4625 4630 4635 4640 Ala Val Asn Ala Pro Thr Ala Thr Val Ile Ser Gly Asn Ala Glu Ala 4645 4650 4655 Leu Thr Gln Ala Leu Glu His Tyr Arg Asp Gln Gly Val Asp Ala Lys 4660 4665 4670 Arg Ile Pro Val Asp Tyr Ala Ser His Cys Pro His Ile Gln Ala Val 4675 4680 4685 Glu Gln Glu Leu Ser Arg Leu Leu Arg Gly Ile Thr Pro Arg Ala Ala 4690 4695 4700 Thr Thr Pro Phe Tyr Ser Thr Thr Asp Asn Gln Trp Thr Asp Thr Thr 4705 4710 4715 4720 Thr Leu Asn Ala His Tyr Trp Tyr Arg Asn Leu Arg Gln Pro Val His 4725 4730 4735 Leu Ala Asp Ala Ile Thr Asn Leu Thr His Gln Gly His His Thr Phe 4740 4745 4750 Ile Glu Ile Ser Pro His Pro Thr Leu Thr Pro Ala Ile Gln Glu Thr 4755 4760 4765 Thr Asp Thr Thr His Thr Pro Thr Thr Val Ile Ser Thr Leu Arg Arg 4770 4775 4780 Asn His Asn Asp Thr His Gln Ile Leu His Ala Leu Ala His Ala His 4785 4790 4795 4800 Thr Thr Gly His Pro Ile Asn Trp His Thr Thr His Gln His His Thr 4805 4810 4815 Pro Thr Pro Gln His Ile Asp Leu Pro Thr Tyr Pro Phe Gln His His 4820 4825 4830 His Tyr Trp Leu Asn Thr Pro Thr Gln Thr Gly Asp Ala Ala Ala Val 4835 4840 4845 Gly Leu Asp Pro Ala His His Pro Leu Leu Gly Ala Ala Val Ala Val 4850 4855 4860 Ala Glu Gly Glu Gly Tyr Leu Leu Thr Gly Arg Leu Ala Leu Ser Thr 4865 4870 4875 4880 His Pro Trp Leu Ala Asp His Thr Ile Ala Gly Ala Val Val Leu Pro 4885 4890 4895 Gly Thr Ala Leu Leu Glu Ile Ala Leu Gln Ala Gly His Arg Val Asp 4900 4905 4910 Cys Trp Arg Ile Glu Glu Leu Thr Leu Gln Ser Pro Leu Phe Ile Pro 4915 4920 4925 Glu Glu Gly Ala Val Gln Val Gln Ala Trp Val Ala Ala Pro Asp Glu 4930 4935 4940 Asn Gly Cys Arg Ser Leu Thr Val Ser Ser Arg Arg Glu Gly Thr Tyr 4945 4950 4955 4960 Glu Asp Ala Thr Trp Val Arg His Ala Thr Gly Arg Val Gly Pro Ala 4965 4970 4975 Pro Ala Asp Gln Asp Glu Ala Ile Ala Arg Leu Thr Asp Pro Gln Gly 4980 4985 4990 Asp Gly Ala Ala Ala Ala Val Trp Pro Pro Gln Gly Ala Val Ala Phe 4995 5000 5005 Thr Ala Asp Asp Leu Glu Gly Leu Tyr Asp Gly Tyr Ala Ala Arg Gly 5010 5015 5020 Phe Glu Tyr Gly Pro Val Phe Arg Gly Leu Arg Ala Ala Trp Arg Arg 5025 5030 5035 5040 Gly Glu Asp Ile Phe Ala Glu Val Arg Leu Pro Asp Thr Ala Asp Gly 5045 5050 5055 Asp Ala Ser Gln Phe Ser Val His Pro Ala Leu Leu Asp Ala Ala Leu 5060 5065 5070 His Ala Ala Ala Phe Arg Pro Ala Asp Lys Leu Pro His Gly Ala Leu 5075 5080 5085 Pro Phe Ser Phe Ser Gly Val Arg Leu His Gly Pro Gly Ala Ser Thr 5090 5095 5100 Leu Arg Val Arg Leu Thr Pro Asp Gly Gln Ala Arg Asp Thr His Ala 5105 5110 5115 5120 Trp Ser Val Ala Val Val Asp Gly Glu Gly Arg Pro Val Ala Ser Ile 5125 5130 5135 Ala Ser Leu Ala Val Arg Pro Val Ser Thr Gln Glu Leu Leu Ala Ala 5140 5145 5150 Ser Gly Thr Ala Arg Arg Asp Ser Leu Phe Ala Val Glu Trp Val Thr 5155 5160 5165 Ala Leu Ala Pro Thr Ser Ser Ser Val Pro Gln Arg Leu Ala Thr Val 5170 5175 5180 Gly Pro Ser Asp Arg Leu Pro Ser Ala Asp Ala Tyr Ala Asn Leu Ala 5185 5190 5195 5200 Asp Leu Ala Ala Ala Val Leu Glu Ala Gly Ala Pro Ala Pro Asp Ala 5205 5210 5215 Val Val Val Asp Cys Gly Arg Arg Asp Ala Arg Ala Thr Ala Val Pro 5220 5225 5230 Glu Asp Val Arg Thr Leu Thr Arg Arg Ile Leu Gly Leu Leu Gln Glu 5235 5240 5245 Trp Leu Ala Asp Glu Arg Pro Ala Ser Ser Arg Met Val Val Leu Thr 5250 5255 5260 Arg Gly Ala Val Ala Thr Thr Pro Gly Glu Asp Val Ala Asp Leu Ala 5265 5270 5275 5280 Gly Ala Ala Val Cys Gly Met Val Arg Ser Ala Gln Ser Glu His Pro 5285 5290 5295 Gly Arg Phe Val Leu Leu Asp Leu Asp Pro Asp Pro Asp Leu Asp Gly 5300 5305 5310 Gly Glu Val Pro Pro Thr Val Val Pro Ala Ala Leu Ala Cys Gly Glu 5315 5320 5325 Pro Gln Ile Ala Val Arg Ala Asn Arg His Leu Val Pro Arg Leu Thr 5330 5335 5340 Arg Val Pro Ala Ser Val Pro Val Pro Gly Arg Val Pro Val Pro Ala 5345 5350 5355 5360 Ala Glu Ala Ala Asp Pro Asp Thr Thr Pro Thr Ala Phe Asp Pro Asp 5365 5370 5375 Gly Thr Val Val Ile Thr Gly Gly Thr Gly Thr Leu Gly Ala Met Leu 5380 5385 5390 Ala Arg His Leu Val Ser Arg His Gly Val Arg His Leu Leu Leu Ala 5395 5400 5405 Ser Arg Arg Gly Pro Asp Ala Pro Gly Ala Thr Glu Leu Arg Ala Glu 5410 5415 5420 Leu Ala Glu Leu Gly Ala Glu Val Thr Val Arg Ala Cys Asp Thr Gly 5425 5430 5435 5440 Asp Arg Gly Ala Leu Ala Asp Leu Ile Ala Gly Ile Pro Thr Gly His 5445 5450 5455 Pro Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp Asp Ala Thr 5460 5465 5470 Val Ala Ser Leu Thr Pro Arg His Leu Asp Thr Ala Leu Thr Pro Lys 5475 5480 5485 Ala Asp Ala Ala Phe His Leu His Glu Leu Thr Arg His Ala Arg Pro 5490 5495 5500 Arg Ala Phe Val Leu Phe Ser Ser Ala Ala Gly Val Leu Gly Ala Ala 5505 5510 5515 5520 Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Phe Leu Asp Ala Leu Ala 5525 5530 5535 Glu His Arg Arg Ala Gln Gly Leu Pro Ala Leu Ser Leu Ala Trp Gly 5540 5545 5550 Leu Trp Glu Gln Gly Ser Gly Met Thr Gly His Leu Asp Arg Thr Asp 5555 5560 5565 Arg Ala Arg Ile Asn Arg Ser Gly Leu Ala Pro Leu Ala Thr Glu Asp 5570 5575 5580 Ala Leu Ala Leu Phe Asp Ala Ala Leu Ala Gly Asp Arg Pro Phe Leu 5585 5590 5595 5600 Val Pro Ala Arg Leu Asp Leu Arg Gly Ser Ser Ala Ala Glu Thr Pro 5605 5610 5615 Ala Pro Leu Phe Ser Arg Ile Ala Pro Ala Arg Thr Thr Arg Gly Arg 5620 5625 5630 Ser Pro Gly Ala Glu Gly Ala Ala Asp Leu Arg Thr Arg Leu Ala Ala 5635 5640 5645 Gln Asp Ala Ala Glu Gln Arg Asp Thr Leu Leu Thr Ile Val Arg Thr 5650 5655 5660 His Thr Ala Ala Val Leu Gly His Asp Thr Ala Ala Ala Val Arg Pro 5665 5670 5675 5680 Asp Gly Ala Phe Arg Glu Leu Gly Phe Asp Ser Leu Ala Ala Val Glu 5685 5690 5695 Leu Arg Asn Arg Leu Gln Thr Thr Thr Ala Leu Thr Leu Pro Ala Thr 5700 5705 5710 Thr Val Phe Asp His Pro Thr Pro Ala Ala Leu Ala Asp His Leu Arg 5715 5720 5725 Thr Gln Leu Cys Gln Asp Ala Gln Ser Ser Ala Ala Ala Thr Ala Met 5730 5735 5740 Ala Ala Met Ala Glu Leu Ala Arg Leu Glu Ser Ala Val Ser Asp Ser 5745 5750 5755 5760 Val Ala Leu Asp Asp Asp Thr Arg Ser Gly Leu Ala Glu Arg Leu Arg 5765 5770 5775 Ser Leu Ala Arg Lys Met Ser Ser Gly Arg Val Val Asp His Asp Gly 5780 5785 5790 Gly Gly Ala Ala Asp Leu Asp Leu Gln Ser Val Thr Asp Asp Glu Met 5795 5800 5805 Phe Glu Leu Ile Asp Lys Glu Val Ser Arg Asp 5810 5815 <210> 13 <211> 17469 <212> DNA <213> Artificial Sequence <220> <223> meiA3 gene of Streptomyces nanchangensis <400> 13 ttggagatac cgatggccgc tggccacgac aaggtgatcg aggcgctgcg ggcgtccctc 60 aagaccaacg agcggcagag ggaacagatc caccggctca ctacggcggc gcgggaaccc 120 atcgccatca tcggcatggc ctgccgctat cccggcggag tgggatcgcc ggaggacctg 180 tgggagctgg tggccgccgg ccgtgacgcc atcggcacct tccccgagga ccggggctgg 240 gacgcggcgc ggctgtacga ccccgatccg gagcgggccg gcacctcgta cacccagcat 300 ggcggattcc tttaccaggc aggggagttc gaccccggtt tcttcgggat cagcccgcgc 360 gaggcgctgg cgatggaccc gcagcagcgg ctgctgctgg agatctcctg ggaggcgttc 420 gagcgggccg ggatcgaccc ggcctcggtg cgcggcagcc gcaccggggt cttcgcgggc 480 gtcatgtacc acgactacgg ctcccggctg cacaccgtcc ccgaaggctt cgagggctac 540 gtcggcaacg gcagcggcgg cggcgtggcg tccggccggg tcgcctacac cctcggcctc 600 gaaggcccgg ccgtgaccgt ggacaccgcc tgctcctcct cactggtcgc cctgcacctg 660 gcctgccagg cgctgcgggc cggcgagtgc tcactcgccc tcgcgggcgg ggtgacggtg 720 atgtccaccc ccagcctgtt cgtcgagtac tcccggcagc gcgcgctcgc ggcggatggc 780 cggtgcaagg cgtacggggc gggggcggac ggcaccggct gggcagaagg cgccgggatg 840 ttgctggtgg aacggctcac ggacgcacag cggctcggcc accgggtgct ggcagtggtc 900 cggggcagcg cggtcaacca ggacggcgcg agcaacggcc tcaccgcccc caacggcccc 960 gcgcagcaac gggtcatccg gcaggcactg gcgagcgccg gggtgtcggc gtccgaggtc 1020 gacgccgtgg aggggcatgg gacggggacg cggctgggcg atccgatcga ggcgcaggcg 1080 ttgctggcga cctacggtca gcagcggccc gcggaccggc cgctgtggct cgggtcgatg 1140 aagtccaacg tcggccatgc gcaggcggcc gccggcgtgg gcgggatcat caagatggtg 1200 atggccatgc ggagcgggac gctgccgcgc accctgcacg cggacgagcc gtcgccgcac 1260 atcgactggg actcgggcgc ggtgcggctg ctgaccgagc cggtcgcctg gccggagcgc 1320 gaccggccgc gccgcgccgc ggtgtcctcc ttcggggtca gcggcaccaa cgcccatgtg 1380 atcctcgagg ccgcgtcgca gacggcgccg cacacggaat ccgcgtcgca gacggaaacc 1440 gacgacgctc ccgcgccgca cggcgcgccg ggccatgccg tggcggggcc gctgccctgg 1500 cccctgtcgg gcgcgacggc cgaggcgctg cgggcccagg ccagggagct gcgtcgcttc 1560 gtggcggccg atgagctgct gcgccccgcc gacgtcgggc acaccctggt cttgggccgc 1620 tcggacctcg cacaccgcgc agtcgtcctc ggctccgacc gggaaaccct gctgcgcggt 1680 ctggacactc tgacagggga ggggccggac ggcggctcgg tcgtacgggg cgtggcggcg 1740 gcaggggccg gtgcgggcgt ggtgttcgtc ttcccgggac agggcggcca gtgggccggc 1800 atggggctgc ggctgctgga gacctcgtcg ttcttcgccg agcggatggc ggagtgcgag 1860 gcggccttgg caccgtatgt cgactggtcg ctgctcgacg tgctgcgccg ggaccccggg 1920 gacccggtgt gggagcgggc cgatgtcgtc cagccgatgc tgttctcggt gatggtgtcg 1980 ctggcgcagc tgtggcgctc gtatggcgtc gaaccggacg ccgtactcgg ccactcccag 2040 ggcgagatcg ccgccgccca catctgcggc gcgctgaccc tggacgacgc cgcgaaggtt 2100 gtcgccctgc gcagccgggc cctgcagacc ctgcgcggtt cgggcggcat ggcctccgta 2160 ccactgacgg cggacgaggt cgccgggctg ctgcggaccg catggccgga ccggctgtgg 2220 gtggccgccg tcaacgcccc cacggccacg gtgatctccg gcgacgcgga ctctctggcg 2280 gaggcgctgg aacactaccg ggaccagggc gtcgacgcga agcgggtccc ggtcgactac 2340 gcctcccact gcccgcatat cgaggccgtg gagcaggagc tgctgagcct gttgcggggg 2400 atcgctccaa gggccgccga cattcccttc tactccactg tggacaacca gtgggccgac 2460 accatgggac tcgacgcccg gtactggtac cgcaatctgc gccggcccgt acgcttcgcc 2520 gaagcgctcc gcgctctcgg tgccgccgag taccggtcgt atgtcgaggt cggcccgcac 2580 cccaccctca cccccgccat cgaggacacc actgaggccg ccggcgccgc ggccacggtt 2640 gtcggctccc tgcgccgcgg cgaggacgac gcccaccgca tcctcacctc gctggcccgg 2700 gctcatattc atggcctgcc cgtggcgtgg gaccgccact accgggcgct cgcccccgag 2760 gcgaaccatg tcgacctgcc cacctacgcc ttccagcgcc gccgctactg gctggacgcc 2820 ccggcgacca ccggggacgt gacggccgcg gggctggccc cggtcggaca cccactgctc 2880 ggcgcggcgg tcggactcgc cgagggcgac ggatatctgc tcaccggccg gctcgccccg 2940 cacacccacc cctggctcac cgaccacgcg gtcgccggca ccgtcctgct gccgggcacc 3000 gcatacgtgg aactggccgt gcacgtcggc gaacacctcg gctgcccccg gctggaggag 3060 ctcaccctgc acgccccgct cgtcctcccc gacacgggcg gtgtggcgct ccaggtggcc 3120 gtcggcgcac cggacgagac cggccgccgc gcactgagcg tctacgcaca gcgcgacgac 3180 gaccccacgt gggaaggggc ggcccggggc gcgtggacac ggcatgcgac cggcacactg 3240 gcggccgagg ccgcgaccga tggcatcaac ggtgccgacg gtgccgggcc cctggcgggg 3300 gcgtggcctc cgccgggcgc ggagcccctg gacatcagcg gcctctacga cacgctggcc 3360 gccgcggact tcggctacgg cccggccttc caggggctgc gcgccgtctg gcggcacggc 3420 gaggagacct acgccgaggt gcggctcccc gaccaggtgg ccgccgacgc cccacgcttc 3480 tgcctccacc ccgcgttgct cgacgccgcg ctccacccgc tggcactcga cagcggccga 3540 agcgaggaga atccagcggg acatggcctg ctgccattcg cctggcgcgg cgtcagcctg 3600 cgctccccgg gcacaccgac gctgcgcgta cggctgcggc cgcagggccc ggactcgatt 3660 gccgtcgacg tggccgacga gacgggcgcg tcggtggtct cggccgaatc gctcacgctg 3720 cgaccggtgg ccctggagga cctgcgggtc ctcggcggcc aggcgaacga ccccctctat 3780 gccctggagt ggaccgccgc gcccgagccc ctgacaacag ccctcgggcg gtgcgccgtg 3840 cttggccacg ccacccccgg atgggccgcc gcgttggaga cggcggcagc ggagcccgta 3900 cggcggtacc cggaccttgc cggactggta gcggccctgg acgccggcga tccgcctccg 3960 gacctggtgt tcgtgggctg ccctccggct gccgccgggc ccgacgacac gacggtcgcc 4020 gacgttcaca ccacccgtac ccgtgtccgt acccgacaag cgctggagct gcttcaaggc 4080 tggctcggcg aagcgcggct ggccggcgcg cggctggtgc tggtcacccg cggcgcggtg 4140 gccaccgggc cggcgggggg agggatggac ctggcgggcg cggcgatctg cggactggtg 4200 cgatccgcac aggccgagga gcccgatcgc atcctcctgg tggacttgga cacggccgag 4260 gagtcgtggg cggcgctgcc acgggcggtc gcgctgggcg aaccgcagat ggccatccgg 4320 gccggccagc cgcacatggc ccggctggtg cgagccgaca ccgagaggga cgccctgctc 4380 acgccgccac gggggagcgg cggctggcgg ctcgactgcg ccgatgcggg cacgctccag 4440 gggttggcgc cggtggcgtc ctcggccgac cacgacccgc tgggcccgca gcaggtacgg 4500 atcgaggtgc gtgcggccgg gctgaacttc cgcgatgtcc tggtggccct ggggatggtc 4560 cctgggcagc aggggctggg cagcgagggc gccggggtgg tgctcgaagc cgggcctgaa 4620 gtggccgacc tggcgcccgg agaccgggtg atgggcgtgt tcgcggacgc gttcggcccg 4680 ttcgcgatcg ccgaccgggc cacagtgatc cgcgtccccg agcactggac cttcgcccag 4740 gccgccgccg tccccgtcgt gttcgccacc gcctactacg ggctggtgga cctggcagga 4800 ctgcgcccgg gcgagtcggt gctggtgcac gccgcggccg gcggagtggg actggccgcc 4860 gtccaactgg cccgccacct gggcgctgag gtctacgcca cggcgagccc cggcaaatgg 4920 gacaccctac gcgcccacgg catccccccg gagcgcatcg cctcgtcccg caccctcgac 4980 ttcgagagcc ggttcaccgg ccggaacatc gacgtcgtcc tcaactccct ggcccatgag 5040 tacgtcgacg cctcgctgcg cctggtgtcc ggcgacagcg gccggttcct cgagatgggc 5100 aagaccgacc tccgtgaccc ggaggaggtg gcggaggcgt accccggtgt cgcctaccgg 5160 gcgtacgacc tgatggaggc cggacccgag cgcatcgggg agatcctgcg caccgtgctg 5220 cggctgttcg acgagggcgt gctcaccccg ctgccgctca cctgctggga catccggcag 5280 gccagggatg ccttccgcca actccagcag ggccgcaccg tcggaaagaa tgtgctcacg 5340 ctggaccgca cccccgaccc cgacggcacc gtcctcatca ccggtggcac cggcaccctc 5400 ggcgccgcgc tcgcccgcca tctcgccgcc accggccgag cacggcatct gctgctgatc 5460 agccgccgtg gcctcgatgc gccaggcgct cccgaactca tcgctgagat cgacgagttg 5520 ggcgcggcga cgaccgtcgc cacctgcgac gtcggcgacc gtgccgcgct cgccgaactg 5580 ctcgggcgga tccccgccga gcacccgctg accgccgtcg tccacgccgc gggcacactc 5640 gacgacgcca cgctcggctc cctcaccgcg cgccacctcg acaccgttct gcccgcgaag 5700 gccgatgccg cctggcatct gcacgagctg acctgccggc tggatctggc cgcgttcgtg 5760 ctgttctcgt ccgccgcggg cgtcctgggc tcgccggggc agggcaacta cgccgccgcc 5820 aatgcctttc tcgacgcgct cgccttccag cgacgggcga tgggactccc cgccgtgtcc 5880 ctggcatggg gactgtggga ggaggccagc gggatgaccg gccacctcga ccagaccgac 5940 cgcacccgca tggcccgcgt cggcctccgg ccactggcca cgaacgaggc cctggcgctg 6000 ttcgacaacg ctctcgtcga tggcccaccg ctgctgctcc cggcccgtat cgacaccaag 6060 gcgctacggg gcaccaccgc accgcccctg ttccagagcc tcgtacgtcc caccaccggc 6120 caccggccac gccccgcgac acccgacggc cgctcctccc tccgagcccg gctcgccggg 6180 ctcgaccctg ccgcacagca cgaggtcctg ctcaccctcg tccgcggcca cgccgccacg 6240 gtcctcggcc acccgagccc cgacgccatc gcccccgagg cggccttccg tgacctcggc 6300 ttcgactccc tcaccgccgt agagctccgc aaccgcctca aggaggcaac cggtctgcgg 6360 ctccccgcca ccctcgtctt cgaccacccc actcctgccg ctctcgccca gcacctgcgg 6420 gacggcctca tcggcggcgc cgatgcggcc accttggctt cggctcctgc tccgagcgag 6480 gtggcgacgg tggcggatga ggccatcgcg atcatcggca tggcctgccg gtatccgggg 6540 ggcgtgcggt cggccgaagg gctgtgggat ctggtcgcct ccggcaccga cgccatgagc 6600 ggattcccca ccgaccgcgg ctgggacctc gaccgcctct acgcccccca ggaccaggac 6660 cggccgggca ccacatacac ccgccacggg ggcttcctcc acgacgcggg caagttcgac 6720 gcgggattct tcggcatcgg cccacgtgag gcgctggcga tggatccaca gcagcggctg 6780 ctgctggaga cctcctggga ggttttcgaa cacgcgggaa tcgacccctc gtcggtacgg 6840 cggagccgga ccggagtctt cgccggtgtg atgccgacgg actacggccc ccggctgcaa 6900 gacaccgtgg ccgaggtcga gggctatgtc ctcaccggaa actccggcag cgtcgcctcg 6960 ggccgtatcg cctacacctt cggtctggaa ggccccgcgg tgtcggtgga cacggcgtgt 7020 tcgtcgtctc tggtggcgtt gcatctggcg tgtcaggcgc tgcgtgcggg ggagtgctcc 7080 atggcgctgg ccggcggggt gacggtgatg gcgacgcctg gtgccttcgt ggagtttgcg 7140 cggcagcggg ggttgtcggt ggatgggcgg tgcaaggcgt ttggggtggg tgcggatggt 7200 acggggtggg cggagggggt ggggatgctg ttggtggagc ggttgtctga tgcgcggcgg 7260 ttggggcatc gggtgttggc ggtggtgcgg ggttctgcgg tgaatcagga cggggcgagc 7320 aatggtttga cggcgccgaa tggtccgtcg cagcagcggg tgatccggca ggcgttggcc 7380 agtgcgcggg ttggtggggc ggatgtggat gtggtggagg ggcacggtac ggggacgcgg 7440 ctgggtgatc cgatcgaggc gcaggcgttg ctggcgacct acggtcagga gcggtcgggg 7500 gatgaaccgt tgtggttggg gtcggtgaag tcgaatatcg ggcatgcgca ggctgcggcg 7560 ggtgttgcgg gtgtcatcaa gatggtgatg gcgatgcggt gtggggtgtt gccgcggacg 7620 ttgcatgtgc aggagccgtc gccgcatgtg gactggtcct cgggtggggt gcggctgctg 7680 acggaggcgg tgccgtggcc ggagacgggt cgtgcgcggc gtgcgggggt gtcgtcgttc 7740 ggggtcagcg gcaccaacgc gcacatcatc ctcgaacagg caccgccgga ggagcacgac 7800 gatccggcgg acgtttcgtc cgggtcgttt ccgtggatgg tgtcggccaa gtccgaacag 7860 gcactacagg cacaggcagc gcagctgcgc gcgtatctgg cggcacgtcc cggggtgggg 7920 ctggctgatg tcgggtatgc gctggccgcc ggccgtaccg ccttcgacca ccgtgccgtg 7980 ctcctgggcc cggaccgcga agccttcctc gaagggctgg gggctctggg ggccggtgag 8040 gaacacgccg ggctcgtacg gggcgtggcg acgggtgcgg ggaagctggc gttcgtgtgt 8100 tccgggcagg gcacgcagcg ccctcgtatg gggcacgagc tgtaccgcgc cttcccgctg 8160 ttcgccgcag ccatggacga agcctgcgca tacctggacc cgcatctcga ccggcctctg 8220 cgggatgtcg tgttcgccga gccggactcc ggtacggccc ggctgctgca gcagacgcgc 8280 tatgcccagc ccgcgctgtt cgccctccag gtcgccctgc atcgcctggt caccgaacac 8340 tacggcctca cgccccacta ctacgcgggc cattccctgg gggagatcac cgcggcccac 8400 ctcgccggga tcctgaccct ctgcgacgcg gcgcgtctgg tcaccacccg cgcccgcctg 8460 atgcagtctc tccccgccac cggcgcgatg accaccctcc aagcagaccc cgacgaactc 8520 cacgaacacc tcgcacgatg cgagggacgg gtgtcgctcg cggccgtgaa cgcgcctggg 8580 tccgtggtca tcagcggtga ccgccacgac gtagacgcca cggccgaaaa cttccgcgcc 8640 atggggcgca agaccacccc gttgaaggtc agcggcgcct tccactcaca ccacatcgac 8700 ccactcctcg acgaactccg cgccaccgcc gaaaccctca cctaccaccc accccacacc 8760 cccctcatca cgaccgacct gaccgaccag gaccccacca cacctggcta ttgggtccgg 8820 caaacacgcg agaccgtcca ctacgcccac accacccaac aactccacac ccacggcgtc 8880 accgcctacc tcgaactcgg ccccgacacc acactcacca ccctcaccca ccacaacctc 8940 ccccaccaca cccccctagc catccccctc ctccaccccg accaacccga aacccacacc 9000 acccacaccg ccctcgccca cctccacacc cacggccacc ccaccacctg gcaccaccac 9060 cacaccccca cccaccacca cccaaacctc cccacctacc ccttccaaca ccaccactac 9120 tggctcaaca ccaccactgc caccggtgat atgtcggcgg caggccttga gccggcgcgg 9180 catcccctgt tgggcgcggc ggtcgagttg gccgatggtg aggggttgct gttcactggg 9240 cggatttcac tccgtacgca tccctggttg gccgaccacg ccgtcggcgg cgccgtgttg 9300 ctccccggta cggcctttct cgaactcgcc ctcgaagccg ccgcccatgt cgactgccat 9360 cggatcgagg agcttacgct ccacaccccg ctcgtcgtac cggagagcgg cggcgtagtg 9420 ctgcaggtga ccgtggccgg gccgaacgaa gcaggaaacc gggcggtgga tatctactcg 9480 cgaatcgatg tcggcggcct caccgccgat tcggtgggcg agccgtggac gcgccatgcc 9540 gccgggtacc ttgccgacaa gcctggccca gactgcggtg actcggcgga tggtgtcatg 9600 cctgcgggcg catggccgcc gccgggtgcg gtcgccgtgg atctggagga actgtacgag 9660 cagctggccg aggggggttt ccactacggt gcggccttcc gttgcctgga cgccgcctgg 9720 caacgcggcg acgaggtctt cgcgactgtg catatgtcag agaatcagct gggcgacacg 9780 gccgcggctc ggttcgcgct gcaccccgcg ctgctggatt ccgcactgca caccattcca 9840 ctcctcccct ccctgcaggg acaacaggac agcgggctgc cgttcacgtg ggcaggagtc 9900 accctgcgcg catccggggc cacggccctg cgcgtccggc tgaggccgga tggccatggc 9960 ccgggggcgg tgtccgtcga cgtgtccgac gaggcgggtg agcccgtagc atcagttcgg 10020 tcgttggccc tgcggccggt gaccagggtc gagttgcata cggccgagtt gcgcacagcc 10080 gccccagttg ccccccatag ctcgctcttc gaggtgcgat gggaacccgt cccccagccc 10140 tcagcggccg aagaagccga tccatgggtg atgatcggga ccggaccgac gctgcgcccg 10200 gacgaggact tcgccactcc gccggagcgg acgtacgccg acctggccgc gctgtgcgcg 10260 gcagtcgccg atggcgcgcc cgttccccgg acggtcgtgg cctggtccca ggccgggagc 10320 gaagacgagt cgagtgaggc gctgcgccac gccacacacc acatgctggg cctactgcag 10380 cagtggttgg cggacagccg gttcgtcgac agtcgcctgg tgatcctcac ccgagccgcg 10440 gtggccactg cgccggagga ggaggtaaaa gacctggcgg gagcggcgac gcggggtctg 10500 atccgctccg cccagtcgga gcaccccgac cgattcgtcc tgctcgacct ggacgaccgt 10560 cccgctgacg cgaaagacca cgaccgaatg ctgtcggtgg ccctggcctg cggggaaccg 10620 gaagtggccg tacgcgatgg agccctgcgc acaccccggc tgagcccgct tgccggcacc 10680 gccaccgagg ccatggacga gcatccctgg gatccggacg gcaccgtact catcaccggc 10740 ggcaccggca gcctcggcgc catgctcgcc cgccacttgg tggccaccca tggcgtacgg 10800 catctgctgc tgatcagccg acgtggcctc gacgccccgg gggccaggcg acaggggaac 10860 gaactcgtcg agctcggagc gcagttgacc atcgccgcgt gcgatgccgc agaccaaagg 10920 caacttgcaa acgcattgtc ggagatctcc gtcgaccatc cgctgaccgc tgtggtgcat 10980 gcggcaggcg tactggacga cggggtgatc acatccctca caccggagga cctgacccat 11040 gtcctgcggg ccaaggtcga ttcggcgctc aatctccacc agctcacacg cgacctgccg 11100 ctgtccgcgt ttgtgctctt ctcctcgctg gccggggtga tgggttcggc agggcagggc 11160 aactacgccg ccgccaacgc cgccctggac gcgctggcga gtcaccgcag ggccactcgg 11220 ctgccggcgg tgtccctggc ctggggagtt tgggagcaga ccgagggcat gaccgggcag 11280 ttggaggcca cgggccacgc gaggctccgc cgctcgggcc tgaggccgct ggccaccagc 11340 gagggcctgg agctcttcga caaggccttg agctgtggac acgccctggt ggtgcccgcc 11400 gcactcagca cgaaggagct tcagacatcc ggatccgtcc caccattcct gcgccacgtg 11460 acgggcgtcg ctccggcccg gccgtcccgg acccgcgacg cctcggccgg tgagccgacc 11520 cccctgcggc ggcggttgac cggcctcggg ccggaagagc ggctacgcga ggtgctgcgg 11580 ctggtgcgct cccgggcggc tgcggtgctg gggcacggca cggccgaagc ggtcccggcg 11640 gactcggcgt tccgcgacct ggggttcgac tccctcgccg cggtggacct gcggaaccgg 11700 ttgcagcagg ccaccgggct gcgcctgccg gccggcttga tcttcgaccg gccgcgtccg 11760 gacgtactcg cccgtttcct gtgtgacgag ttggccggtg tcggcggtac gtcggcggcc 11820 acggccgccc cacccgttgc ggccgtcggc ggggcagccg gcgagccggt ggccatcgtc 11880 ggcatggcat gccggtttcc gggaggtgtg cggtcggccg agggcctgtg ggatctggtc 11940 gcctccggta tggacgcggt gggtgacttc cccacagacc gaggctggga ggtggaacgg 12000 ctctacgacc ccgacccgga ccgaaccggc acctcctata cccggcaagg cgggttcctc 12060 tacgacgcgg gtgagttcga cgcggcgttc ttcgggattg gcccgcgtga ggcggtggcg 12120 atggatccac agcagcggct gctgctggag atttcctggg aggcgctgga acgggcggga 12180 atcgacccgg cgtcgctgcg ggggagttcg actggagtgt tcgctggggt gatgtaccac 12240 gactacggca cccgcttgcg cgagatccca gagggctacg agggctatat cggcaatgga 12300 aacgcgggca gcgtcgcttc gggacgtgtc tcctacactt tcggcctgga ggggccggcg 12360 gtcaccgtgg acacggcgtg ttcgtcgtcc ctggtcgccc tgcatctggc ctgccaggcg 12420 ctgcggtcag gggagtgctc catggcgctg gcgggcgggg tcaccgtcat gtccaccccc 12480 accacttttg tcgagttctc gcgccaacgg ggactggccc cggacgggcg gtgcaagtcc 12540 ttcggggccg gcgcggacgg aacgggctgg gcggagggcg cggggatgct cctggtggag 12600 cggctttcgg acgcccggcg caacggccac cgggtcctgg cggtggtacg ggggagcgcg 12660 gtcaaccagg acggggcgag caatgggctg acggcgccga acggcccgtc gcaagagcgg 12720 gtgatccgcc aggcgtgggc aaatgcgggt gtggccgcga tggacatcga cgcggtggag 12780 ggacacggca cggggacgac gctcggtgac cccattgagg cccaggcgct gctggggacg 12840 tatggacagg gacggtcggc cgatcggccg ttgtggttgg gatcgatcaa gtccaacgtc 12900 ggacacaccc aggccgccgc gggggtgggc ggcgtcatca agatggtgat ggccatgcgc 12960 cacgggctgc tcccgcagac cctgcacgcc gaggagccct cacctcatgt ggactggtcg 13020 ggcgggacgg tgcggttgct gaccgagccg gtggcctggc ctgagcgggg gcggatgcgc 13080 cgcgcaggcg tctcctcttt cggtgtcagc ggtaccaacg cccacgtcat cttggaacaa 13140 gcaccaccta acgcggagac ccacgaaccg gcagagcccc acaccgcgcc aggcccactg 13200 ccctggacga tctccgcgaa gagcccgcaa gcgctacgtg cccaggcgcg tcagttgcac 13260 acgtacctga ccaacacccc cgaggcgaac cccgccgacg tcggccacac cctcgcgatg 13320 ggccgcgcct ctttcgagca tcgtgcggtg gttatcggct ccgatcgagg ggagtttctg 13380 ggtggtctgg atgctgtggc ggcagatgag gcccactctg ctgtggtcac gggtatcgcg 13440 aggaaggccg gtgacctggg gaaggtggtg ttcgtcttcc ccgggcaggg tggtcagtgg 13500 gccgggatgg gactgcggct gctcaagacc tcgcccgtct tcgcgcaatc catccaggcc 13560 tgcgaacaag ccctcgcccc ccacaccgac tggaccctga ccgacatcct gcaccgcccc 13620 cacaccgacc ccctgtggca gcgcgccgac gtcatccagc ccgccctctt cgccctcatg 13680 acctccctca ccaccctctg gcaatcccac ggcctcaacc ccgacgccgt catcggccac 13740 tcccaaggcg aaatcaccgc cgcccacgcc tgcggagcac tgagcctgga agacgccgcg 13800 aaaatcgtcg ccctccgcag ccagaccctg caaaccctcc aaggctcagg cggcatggcc 13860 tccgtaccac tgcccgcaga ccaggtcacc gcactgctgc acaccatgtg gcccgaccag 13920 ctatgggtcg ccgccatcaa cgcccccacc accacagtca tctccggcga cacacaagcc 13980 ctcacacaag cgctgaacca ctaccgggac caagacatcg acgcgaaacg catcccggtc 14040 gactacgcct cccactgccc ccacatccag gccgtccaac acgaactctc agacctgttg 14100 caggacatca ccccacgggc cgcgaccacc cccttctact ccaccaccga caaccaatgg 14160 accgacacca ccaccctcaa cgcccactac tggtaccgaa acctccgcca acccgtccac 14220 ctcaccaacg ccatcaccaa cctcacccac caaggccacc acacctacat cgaaatcagc 14280 ccccacccca ccctcacccc cgccatccag gaaaccaccc acaccaccca cacccccacc 14340 accgtcatca gcacactccg ccgcaaccac aacgacaccc accaactcct ccacgccctc 14400 gcccacgccc acaccaccgg ccaccccatc aactggcacc ccacccacca acaccacacc 14460 ccaacccccc aacacaccga cctccccacc taccccttcc aacaccaacg ctactggctc 14520 aacaccccca cccaaacagg agacgcagca gccatcggcc tggacccggc acatcacccg 14580 ctgctcggcg cggcggtcgc agtggccgag ggggagggct atctgctcac cggtcggctc 14640 gccctgtcca cccacccctg gcttgccgat cacaccatcg cgggcgcggt cgtccttccc 14700 ggaactgccc ttcttgagat cgcccttcag gcgggccatc gtgtggactg ccatcgcatc 14760 gaagaactca ccctccaatc gccgctgttc atcccggaag agggagcagt acaggtgcag 14820 gcatgggtgg cggcgccgga tgagaacggg taccgaagcc tgacggtgtc ctcccgacgt 14880 gagggtacgt acgaggacgc cacgtgggtg cgccatgcca cgggccgggt cggtcccgca 14940 ccggccgacc aggatgatgc catcgcgcgg ctcaccgacc cacaaggcga cggagcggcg 15000 gcggtctggc caccgcaggg cgctgtcgcg ttcacagcag acgatctgga gggcctgtac 15060 gacgggtacg cggcgcgggg attcgagtac ggcccggtgt tccgaggact gcgggcggcc 15120 tggcgacgtg gcgaggacat cttcgccgag gtgcgccttc ccgacacggc ggacggcgac 15180 gcctcccagt tctccgtaca ccccgccctg ctggacgccg ccctgcacgc cgccgccttc 15240 cgcccggccg acgaactccc gcacggggct ctgcccttct ccttcagcgg ggtgaggctg 15300 cacgggcccg gagcgtcgac cctgcgggtg cgcctcaccc cggatggcca ggcgcgggac 15360 acgcacgcat ggtcggtcgc ggtggtcgac ggcgaggggc ggccggtggc ctcgatcgcg 15420 tcgctcgcgg tccgcccggt gtcgacgcag gagttgctgg cggcctccgg tacggcgcgg 15480 cgggactcgc tcttcgcggt cgagtgggtg accgccccgg cgccgacctc gtcgtccgct 15540 ccgcgacgcc tggccacggt ggggcccagc gaccgcctcc cctcggcaga cgcgtacgcg 15600 aacctcgccg acctggccgc cgcagtgctg gaggcggagg ccccggcgcc cgatgcggtc 15660 gtggtcgact gcggccgccg cgacgcgcgc gccacggccg tggcggagga cgtacggacc 15720 ctcacccggc gcatcctggg tctgctgcag gagtggctgg cggacgagag gccggcctcg 15780 agccggatgg tcgtactgac ccgtggtgcg gtggccacca caccggggga ggacgtggcg 15840 gacctggcgg gcgcggcggt gtgcggcatg gtgcggtccg cgcagtcgga acatcccggc 15900 cggttcgtcc tgctggacct cgaccccgac ccggacctcg acggcgggga agtgccaccg 15960 accgtcgtac cggcggctct cgcctgtggt gagccgcaga tcgcggtgcg tgcgaaccgg 16020 cacctggtgc cccggctgac ccgcgttccg gtgtccgtcc ccgtccccgg gcctgttccc 16080 gttcccgccg ccgaggcagc cgaccaggac accacgccca cggcgttcga ccccgacggc 16140 accgtactga tcaccggcgg caccggcacc ctcggcgcgg tgctcgcgcg ccatctggtc 16200 agccgtcacg gcgtacggca cctgctgctg gcatcgcgac gcgggcccga cgcacccggc 16260 gccaccgagc tgcgggcgga actggccgag ctcggggccg aggcgacggt gcgcgcttgt 16320 gacaccggtg accgaggcgc gctggcggat ctcatcgcgg ggattcccac cggccaccct 16380 ttgaccggtg tggtccacgc cgcgggcgtc ctggatgacg ccaccgtcgc ctccctcacc 16440 ccccgacacc tggacaccgc gctgacaccc aaggccgacg ccgccttcca tctgcacgag 16500 ctcacccgcc acgcccggcc gcgcgccttc gtcctgttct cctcggccgc cggtgtcctc 16560 ggcgcagccg ggcagggcaa ctacgctgcc gccaacgcct tcctcgacgc cctcgccgaa 16620 caccgcaggg cgcagggcct gccggccttg tcgctcgcgt ggggcttgtg ggagcagggc 16680 agcggcatga ccgggcatct cgaccgcacc gaccgggccc gcatcaaccg ctccggactc 16740 gcccccctcg ccaccgagga cgctctcgcg ctcttcgacg ccgccctcgc cggcgatcgg 16800 ccgttcctgg tgcccgcccg gctggaccta cggggttcaa gcgccgccga gaccccggcg 16860 ccgctgttct ccaggatcgc cccggctcgt acgacccggg gccgtacccc cggcgctgag 16920 ggcgccgctg accttcgtac ccgtctcgcg gcccaggatg ccaccgagca gcgcgacacg 16980 cttctcacga tcgtccgcac ccacaccgcc gccgtcctgg ggcatgacac ggctgccgcc 17040 gtgcggccgg acgcggcctt ccgtgagctg ggtttcgact ccctcgccgc cgtggaactc 17100 cgtaaccgcc ttcaaacgac caccgccctc accctgcccg cgaccaccgt tttcgaccac 17160 cccacgcccg ctgccctcgc cgatcatctg cgtactcagc tctgccagga cgctccgtcc 17220 ccggcggcgg ccacggccat ggcggcgatg gcggagctgg ccaggctgga gtccgccgtc 17280 tccgattcgg cggcgctcga cgacgacacg cgcagcggcc tcgcggagcg cctgcggtcc 17340 ctcgcccgca agatgagcag tggccgtgtc gtcgaccaca acggcggcgg cgctgcgggc 17400 ctggatctcc agtcggccac ggacgatgag atgttcgagc tgatcgacaa ggaggtcagc 17460 cgagactga 17469 <210> 14 <211> 5822 <212> PRT <213> Artificial Sequence <220> <223> meiA3 protein of Streptomyces nanchangensis <400> 14 Met Glu Ile Pro Met Ala Ala Gly His Asp Lys Val Ile Glu Ala Leu 1 5 10 15 Arg Ala Ser Leu Lys Thr Asn Glu Arg Gln Arg Glu Gln Ile His Arg 20 25 30 Leu Thr Thr Ala Ala Arg Glu Pro Ile Ala Ile Ile Gly Met Ala Cys 35 40 45 Arg Tyr Pro Gly Gly Val Gly Ser Pro Glu Asp Leu Trp Glu Leu Val 50 55 60 Ala Ala Gly Arg Asp Ala Ile Gly Thr Phe Pro Glu Asp Arg Gly Trp 65 70 75 80 Asp Ala Ala Arg Leu Tyr Asp Pro Asp Pro Glu Arg Ala Gly Thr Ser 85 90 95 Tyr Thr Gln His Gly Gly Phe Leu Tyr Gln Ala Gly Glu Phe Asp Pro 100 105 110 Gly Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln 115 120 125 Gln Arg Leu Leu Leu Glu Ile Ser Trp Glu Ala Phe Glu Arg Ala Gly 130 135 140 Ile Asp Pro Ala Ser Val Arg Gly Ser Arg Thr Gly Val Phe Ala Gly 145 150 155 160 Val Met Tyr His Asp Tyr Gly Ser Arg Leu His Thr Val Pro Glu Gly 165 170 175 Phe Glu Gly Tyr Val Gly Asn Gly Ser Gly Gly Gly Val Ala Ser Gly 180 185 190 Arg Val Ala Tyr Thr Leu Gly Leu Glu Gly Pro Ala Val Thr Val Asp 195 200 205 Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala 210 215 220 Leu Arg Ala Gly Glu Cys Ser Leu Ala Leu Ala Gly Gly Val Thr Val 225 230 235 240 Met Ser Thr Pro Ser Leu Phe Val Glu Tyr Ser Arg Gln Arg Ala Leu 245 250 255 Ala Ala Asp Gly Arg Cys Lys Ala Tyr Gly Ala Gly Ala Asp Gly Thr 260 265 270 Gly Trp Ala Glu Gly Ala Gly Met Leu Leu Val Glu Arg Leu Thr Asp 275 280 285 Ala Gln Arg Leu Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala 290 295 300 Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro 305 310 315 320 Ala Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Ser Ala Gly Val Ser 325 330 335 Ala Ser Glu Val Asp Ala Val Glu Gly His Gly Thr Gly Thr Arg Leu 340 345 350 Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gln 355 360 365 Arg Pro Ala Asp Arg Pro Leu Trp Leu Gly Ser Met Lys Ser Asn Val 370 375 380 Gly His Ala Gln Ala Ala Ala Gly Val Gly Gly Ile Ile Lys Met Val 385 390 395 400 Met Ala Met Arg Ser Gly Thr Leu Pro Arg Thr Leu His Ala Asp Glu 405 410 415 Pro Ser Pro His Ile Asp Trp Asp Ser Gly Ala Val Arg Leu Leu Thr 420 425 430 Glu Pro Val Ala Trp Pro Glu Arg Asp Arg Pro Arg Arg Ala Ala Val 435 440 445 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Ala 450 455 460 Ala Ser Gln Thr Ala Pro His Thr Glu Ser Ala Ser Gln Thr Glu Thr 465 470 475 480 Asp Asp Ala Pro Ala Pro His Gly Ala Pro Gly His Ala Val Ala Gly 485 490 495 Pro Leu Pro Trp Pro Leu Ser Gly Ala Thr Ala Glu Ala Leu Arg Ala 500 505 510 Gln Ala Arg Glu Leu Arg Arg Phe Val Ala Ala Asp Glu Leu Leu Arg 515 520 525 Pro Ala Asp Val Gly His Thr Leu Val Leu Gly Arg Ser Asp Leu Ala 530 535 540 His Arg Ala Val Val Leu Gly Ser Asp Arg Glu Thr Leu Leu Arg Gly 545 550 555 560 Leu Asp Thr Leu Thr Gly Glu Gly Pro Asp Gly Gly Ser Val Val Arg 565 570 575 Gly Val Ala Ala Ala Gly Ala Gly Ala Gly Val Val Phe Val Phe Pro 580 585 590 Gly Gln Gly Gly Gln Trp Ala Gly Met Gly Leu Arg Leu Leu Glu Thr 595 600 605 Ser Ser Phe Phe Ala Glu Arg Met Ala Glu Cys Glu Ala Ala Leu Ala 610 615 620 Pro Tyr Val Asp Trp Ser Leu Leu Asp Val Leu Arg Arg Asp Pro Gly 625 630 635 640 Asp Pro Val Trp Glu Arg Ala Asp Val Val Gln Pro Met Leu Phe Ser 645 650 655 Val Met Val Ser Leu Ala Gln Leu Trp Arg Ser Tyr Gly Val Glu Pro 660 665 670 Asp Ala Val Leu Gly His Ser Gln Gly Glu Ile Ala Ala Ala His Ile 675 680 685 Cys Gly Ala Leu Thr Leu Asp Asp Ala Ala Lys Val Val Ala Leu Arg 690 695 700 Ser Arg Ala Leu Gln Thr Leu Arg Gly Ser Gly Gly Met Ala Ser Val 705 710 715 720 Pro Leu Thr Ala Asp Glu Val Ala Gly Leu Leu Arg Thr Ala Trp Pro 725 730 735 Asp Arg Leu Trp Val Ala Ala Val Asn Ala Pro Thr Ala Thr Val Ile 740 745 750 Ser Gly Asp Ala Asp Ser Leu Ala Glu Ala Leu Glu His Tyr Arg Asp 755 760 765 Gln Gly Val Asp Ala Lys Arg Val Pro Val Asp Tyr Ala Ser His Cys 770 775 780 Pro His Ile Glu Ala Val Glu Gln Glu Leu Leu Ser Leu Leu Arg Gly 785 790 795 800 Ile Ala Pro Arg Ala Ala Asp Ile Pro Phe Tyr Ser Thr Val Asp Asn 805 810 815 Gln Trp Ala Asp Thr Met Gly Leu Asp Ala Arg Tyr Trp Tyr Arg Asn 820 825 830 Leu Arg Arg Pro Val Arg Phe Ala Glu Ala Leu Arg Ala Leu Gly Ala 835 840 845 Ala Glu Tyr Arg Ser Tyr Val Glu Val Gly Pro His Pro Thr Leu Thr 850 855 860 Pro Ala Ile Glu Asp Thr Thr Glu Ala Ala Gly Ala Ala Ala Thr Val 865 870 875 880 Val Gly Ser Leu Arg Arg Gly Glu Asp Asp Ala His Arg Ile Leu Thr 885 890 895 Ser Leu Ala Arg Ala His Ile His Gly Leu Pro Val Ala Trp Asp Arg 900 905 910 His Tyr Arg Ala Leu Ala Pro Glu Ala Asn His Val Asp Leu Pro Thr 915 920 925 Tyr Ala Phe Gln Arg Arg Arg Tyr Trp Leu Asp Ala Pro Ala Thr Thr 930 935 940 Gly Asp Val Thr Ala Ala Gly Leu Ala Pro Val Gly His Pro Leu Leu 945 950 955 960 Gly Ala Ala Val Gly Leu Ala Glu Gly Asp Gly Tyr Leu Leu Thr Gly 965 970 975 Arg Leu Ala Pro His Thr His Pro Trp Leu Thr Asp His Ala Val Ala 980 985 990 Gly Thr Val Leu Leu Pro Gly Thr Ala Tyr Val Glu Leu Ala Val His 995 1000 1005 Val Gly Glu His Leu Gly Cys Pro Arg Leu Glu Glu Leu Thr Leu His 1010 1015 1020 Ala Pro Leu Val Leu Pro Asp Thr Gly Gly Val Ala Leu Gln Val Ala 1025 1030 1035 1040 Val Gly Ala Pro Asp Glu Thr Gly Arg Arg Ala Leu Ser Val Tyr Ala 1045 1050 1055 Gln Arg Asp Asp Asp Pro Thr Trp Glu Gly Ala Ala Arg Gly Ala Trp 1060 1065 1070 Thr Arg His Ala Thr Gly Thr Leu Ala Ala Glu Ala Ala Thr Asp Gly 1075 1080 1085 Ile Asn Gly Ala Asp Gly Ala Gly Pro Leu Ala Gly Ala Trp Pro Pro 1090 1095 1100 Pro Gly Ala Glu Pro Leu Asp Ile Ser Gly Leu Tyr Asp Thr Leu Ala 1105 1110 1115 1120 Ala Ala Asp Phe Gly Tyr Gly Pro Ala Phe Gln Gly Leu Arg Ala Val 1125 1130 1135 Trp Arg His Gly Glu Glu Thr Tyr Ala Glu Val Arg Leu Pro Asp Gln 1140 1145 1150 Val Ala Ala Asp Ala Pro Arg Phe Cys Leu His Pro Ala Leu Leu Asp 1155 1160 1165 Ala Ala Leu His Pro Leu Ala Leu Asp Ser Gly Arg Ser Glu Glu Asn 1170 1175 1180 Pro Ala Gly His Gly Leu Leu Pro Phe Ala Trp Arg Gly Val Ser Leu 1185 1190 1195 1200 Arg Ser Pro Gly Thr Pro Thr Leu Arg Val Arg Leu Arg Pro Gln Gly 1205 1210 1215 Pro Asp Ser Ile Ala Val Asp Val Ala Asp Glu Thr Gly Ala Ser Val 1220 1225 1230 Val Ser Ala Glu Ser Leu Thr Leu Arg Pro Val Ala Leu Glu Asp Leu 1235 1240 1245 Arg Val Leu Gly Gly Gln Ala Asn Asp Pro Leu Tyr Ala Leu Glu Trp 1250 1255 1260 Thr Ala Ala Pro Glu Pro Leu Thr Thr Ala Leu Gly Arg Cys Ala Val 1265 1270 1275 1280 Leu Gly His Ala Thr Pro Gly Trp Ala Ala Ala Leu Glu Thr Ala Ala 1285 1290 1295 Ala Glu Pro Val Arg Arg Tyr Pro Asp Leu Ala Gly Leu Val Ala Ala 1300 1305 1310 Leu Asp Ala Gly Asp Pro Pro Pro Asp Leu Val Phe Val Gly Cys Pro 1315 1320 1325 Pro Ala Ala Ala Gly Pro Asp Asp Thr Thr Val Ala Asp Val His Thr 1330 1335 1340 Thr Arg Thr Arg Val Arg Thr Arg Gln Ala Leu Glu Leu Leu Gln Gly 1345 1350 1355 1360 Trp Leu Gly Glu Ala Arg Leu Ala Gly Ala Arg Leu Val Leu Val Thr 1365 1370 1375 Arg Gly Ala Val Ala Thr Gly Pro Ala Gly Gly Gly Met Asp Leu Ala 1380 1385 1390 Gly Ala Ala Ile Cys Gly Leu Val Arg Ser Ala Gln Ala Glu Glu Pro 1395 1400 1405 Asp Arg Ile Leu Leu Val Asp Leu Asp Thr Ala Glu Glu Ser Trp Ala 1410 1415 1420 Ala Leu Pro Arg Ala Val Ala Leu Gly Glu Pro Gln Met Ala Ile Arg 1425 1430 1435 1440 Ala Gly Gln Pro His Met Ala Arg Leu Val Arg Ala Asp Thr Glu Arg 1445 1450 1455 Asp Ala Leu Leu Thr Pro Pro Arg Gly Ser Gly Gly Trp Arg Leu Asp 1460 1465 1470 Cys Ala Asp Ala Gly Thr Leu Gln Gly Leu Ala Pro Val Ala Ser Ser 1475 1480 1485 Ala Asp His Asp Pro Leu Gly Pro Gln Gln Val Arg Ile Glu Val Arg 1490 1495 1500 Ala Ala Gly Leu Asn Phe Arg Asp Val Leu Val Ala Leu Gly Met Val 1505 1510 1515 1520 Pro Gly Gln Gln Gly Leu Gly Ser Glu Gly Ala Gly Val Val Leu Glu 1525 1530 1535 Ala Gly Pro Glu Val Ala Asp Leu Ala Pro Gly Asp Arg Val Met Gly 1540 1545 1550 Val Phe Ala Asp Ala Phe Gly Pro Phe Ala Ile Ala Asp Arg Ala Thr 1555 1560 1565 Val Ile Arg Val Pro Glu His Trp Thr Phe Ala Gln Ala Ala Ala Val 1570 1575 1580 Pro Val Val Phe Ala Thr Ala Tyr Tyr Gly Leu Val Asp Leu Ala Gly 1585 1590 1595 1600 Leu Arg Pro Gly Glu Ser Val Leu Val His Ala Ala Ala Gly Gly Val 1605 1610 1615 Gly Leu Ala Ala Val Gln Leu Ala Arg His Leu Gly Ala Glu Val Tyr 1620 1625 1630 Ala Thr Ala Ser Pro Gly Lys Trp Asp Thr Leu Arg Ala His Gly Ile 1635 1640 1645 Pro Pro Glu Arg Ile Ala Ser Ser Arg Thr Leu Asp Phe Glu Ser Arg 1650 1655 1660 Phe Thr Gly Arg Asn Ile Asp Val Val Leu Asn Ser Leu Ala His Glu 1665 1670 1675 1680 Tyr Val Asp Ala Ser Leu Arg Leu Val Ser Gly Asp Ser Gly Arg Phe 1685 1690 1695 Leu Glu Met Gly Lys Thr Asp Leu Arg Asp Pro Glu Glu Val Ala Glu 1700 1705 1710 Ala Tyr Pro Gly Val Ala Tyr Arg Ala Tyr Asp Leu Met Glu Ala Gly 1715 1720 1725 Pro Glu Arg Ile Gly Glu Ile Leu Arg Thr Val Leu Arg Leu Phe Asp 1730 1735 1740 Glu Gly Val Leu Thr Pro Leu Pro Leu Thr Cys Trp Asp Ile Arg Gln 1745 1750 1755 1760 Ala Arg Asp Ala Phe Arg Gln Leu Gln Gln Gly Arg Thr Val Gly Lys 1765 1770 1775 Asn Val Leu Thr Leu Asp Arg Thr Pro Asp Pro Asp Gly Thr Val Leu 1780 1785 1790 Ile Thr Gly Gly Thr Gly Thr Leu Gly Ala Ala Leu Ala Arg His Leu 1795 1800 1805 Ala Ala Thr Gly Arg Ala Arg His Leu Leu Leu Ile Ser Arg Arg Gly 1810 1815 1820 Leu Asp Ala Pro Gly Ala Pro Glu Leu Ile Ala Glu Ile Asp Glu Leu 1825 1830 1835 1840 Gly Ala Ala Thr Thr Val Ala Thr Cys Asp Val Gly Asp Arg Ala Ala 1845 1850 1855 Leu Ala Glu Leu Leu Gly Arg Ile Pro Ala Glu His Pro Leu Thr Ala 1860 1865 1870 Val Val His Ala Ala Gly Thr Leu Asp Asp Ala Thr Leu Gly Ser Leu 1875 1880 1885 Thr Ala Arg His Leu Asp Thr Val Leu Pro Ala Lys Ala Asp Ala Ala 1890 1895 1900 Trp His Leu His Glu Leu Thr Cys Arg Leu Asp Leu Ala Ala Phe Val 1905 1910 1915 1920 Leu Phe Ser Ser Ala Ala Gly Val Leu Gly Ser Pro Gly Gln Gly Asn 1925 1930 1935 Tyr Ala Ala Ala Asn Ala Phe Leu Asp Ala Leu Ala Phe Gln Arg Arg 1940 1945 1950 Ala Met Gly Leu Pro Ala Val Ser Leu Ala Trp Gly Leu Trp Glu Glu 1955 1960 1965 Ala Ser Gly Met Thr Gly His Leu Asp Gln Thr Asp Arg Thr Arg Met 1970 1975 1980 Ala Arg Val Gly Leu Arg Pro Leu Ala Thr Asn Glu Ala Leu Ala Leu 1985 1990 1995 2000 Phe Asp Asn Ala Leu Val Asp Gly Pro Pro Leu Leu Leu Pro Ala Arg 2005 2010 2015 Ile Asp Thr Lys Ala Leu Arg Gly Thr Thr Ala Pro Pro Leu Phe Gln 2020 2025 2030 Ser Leu Val Arg Pro Thr Thr Gly His Arg Pro Arg Pro Ala Thr Pro 2035 2040 2045 Asp Gly Arg Ser Ser Leu Arg Ala Arg Leu Ala Gly Leu Asp Pro Ala 2050 2055 2060 Ala Gln His Glu Val Leu Leu Thr Leu Val Arg Gly His Ala Ala Thr 2065 2070 2075 2080 Val Leu Gly His Pro Ser Pro Asp Ala Ile Ala Pro Glu Ala Ala Phe 2085 2090 2095 Arg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg Asn Arg 2100 2105 2110 Leu Lys Glu Ala Thr Gly Leu Arg Leu Pro Ala Thr Leu Val Phe Asp 2115 2120 2125 His Pro Thr Pro Ala Ala Leu Ala Gln His Leu Arg Asp Gly Leu Ile 2130 2135 2140 Gly Gly Ala Asp Ala Ala Thr Leu Ala Ser Ala Pro Ala Pro Ser Glu 2145 2150 2155 2160 Val Ala Thr Val Ala Asp Glu Ala Ile Ala Ile Ile Gly Met Ala Cys 2165 2170 2175 Arg Tyr Pro Gly Gly Val Arg Ser Ala Glu Gly Leu Trp Asp Leu Val 2180 2185 2190 Ala Ser Gly Thr Asp Ala Met Ser Gly Phe Pro Thr Asp Arg Gly Trp 2195 2200 2205 Asp Leu Asp Arg Leu Tyr Ala Pro Gln Asp Gln Asp Arg Pro Gly Thr 2210 2215 2220 Thr Tyr Thr Arg His Gly Gly Phe Leu His Asp Ala Gly Lys Phe Asp 2225 2230 2235 2240 Ala Gly Phe Phe Gly Ile Gly Pro Arg Glu Ala Leu Ala Met Asp Pro 2245 2250 2255 Gln Gln Arg Leu Leu Leu Glu Thr Ser Trp Glu Val Phe Glu His Ala 2260 2265 2270 Gly Ile Asp Pro Ser Ser Val Arg Arg Ser Arg Thr Gly Val Phe Ala 2275 2280 2285 Gly Val Met Pro Thr Asp Tyr Gly Pro Arg Leu Gln Asp Thr Val Ala 2290 2295 2300 Glu Val Glu Gly Tyr Val Leu Thr Gly Asn Ser Gly Ser Val Ala Ser 2305 2310 2315 2320 Gly Arg Ile Ala Tyr Thr Phe Gly Leu Glu Gly Pro Ala Val Ser Val 2325 2330 2335 Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln 2340 2345 2350 Ala Leu Arg Ala Gly Glu Cys Ser Met Ala Leu Ala Gly Gly Val Thr 2355 2360 2365 Val Met Ala Thr Pro Gly Ala Phe Val Glu Phe Ala Arg Gln Arg Gly 2370 2375 2380 Leu Ser Val Asp Gly Arg Cys Lys Ala Phe Gly Val Gly Ala Asp Gly 2385 2390 2395 2400 Thr Gly Trp Ala Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser 2405 2410 2415 Asp Ala Arg Arg Leu Gly His Arg Val Leu Ala Val Val Arg Gly Ser 2420 2425 2430 Ala Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly 2435 2440 2445 Pro Ser Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Ser Ala Arg Val 2450 2455 2460 Gly Gly Ala Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr Arg 2465 2470 2475 2480 Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln 2485 2490 2495 Glu Arg Ser Gly Asp Glu Pro Leu Trp Leu Gly Ser Val Lys Ser Asn 2500 2505 2510 Ile Gly His Ala Gln Ala Ala Ala Gly Val Ala Gly Val Ile Lys Met 2515 2520 2525 Val Met Ala Met Arg Cys Gly Val Leu Pro Arg Thr Leu His Val Gln 2530 2535 2540 Glu Pro Ser Pro His Val Asp Trp Ser Ser Gly Gly Val Arg Leu Leu 2545 2550 2555 2560 Thr Glu Ala Val Pro Trp Pro Glu Thr Gly Arg Ala Arg Arg Ala Gly 2565 2570 2575 Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Ile Ile Leu Glu 2580 2585 2590 Gln Ala Pro Pro Glu Glu His Asp Asp Pro Ala Asp Val Ser Ser Gly 2595 2600 2605 Ser Phe Pro Trp Met Val Ser Ala Lys Ser Glu Gln Ala Leu Gln Ala 2610 2615 2620 Gln Ala Ala Gln Leu Arg Ala Tyr Leu Ala Ala Arg Pro Gly Val Gly 2625 2630 2635 2640 Leu Ala Asp Val Gly Tyr Ala Leu Ala Ala Gly Arg Thr Ala Phe Asp 2645 2650 2655 His Arg Ala Val Leu Leu Gly Pro Asp Arg Glu Ala Phe Leu Glu Gly 2660 2665 2670 Leu Gly Ala Leu Gly Ala Gly Glu Glu His Ala Gly Leu Val Arg Gly 2675 2680 2685 Val Ala Thr Gly Ala Gly Lys Leu Ala Phe Val Cys Ser Gly Gln Gly 2690 2695 2700 Thr Gln Arg Pro Arg Met Gly His Glu Leu Tyr Arg Ala Phe Pro Leu 2705 2710 2715 2720 Phe Ala Ala Ala Met Asp Glu Ala Cys Ala Tyr Leu Asp Pro His Leu 2725 2730 2735 Asp Arg Pro Leu Arg Asp Val Val Phe Ala Glu Pro Asp Ser Gly Thr 2740 2745 2750 Ala Arg Leu Leu Gln Gln Thr Arg Tyr Ala Gln Pro Ala Leu Phe Ala 2755 2760 2765 Leu Gln Val Ala Leu His Arg Leu Val Thr Glu His Tyr Gly Leu Thr 2770 2775 2780 Pro His Tyr Tyr Ala Gly His Ser Leu Gly Glu Ile Thr Ala Ala His 2785 2790 2795 2800 Leu Ala Gly Ile Leu Thr Leu Cys Asp Ala Ala Arg Leu Val Thr Thr 2805 2810 2815 Arg Ala Arg Leu Met Gln Ser Leu Pro Ala Thr Gly Ala Met Thr Thr 2820 2825 2830 Leu Gln Ala Asp Pro Asp Glu Leu His Glu His Leu Ala Arg Cys Glu 2835 2840 2845 Gly Arg Val Ser Leu Ala Ala Val Asn Ala Pro Gly Ser Val Val Ile 2850 2855 2860 Ser Gly Asp Arg His Asp Val Asp Ala Thr Ala Glu Asn Phe Arg Ala 2865 2870 2875 2880 Met Gly Arg Lys Thr Thr Pro Leu Lys Val Ser Gly Ala Phe His Ser 2885 2890 2895 His His Ile Asp Pro Leu Leu Asp Glu Leu Arg Ala Thr Ala Glu Thr 2900 2905 2910 Leu Thr Tyr His Pro Pro His Thr Pro Leu Ile Thr Thr Asp Leu Thr 2915 2920 2925 Asp Gln Asp Pro Thr Thr Pro Gly Tyr Trp Val Arg Gln Thr Arg Glu 2930 2935 2940 Thr Val His Tyr Ala His Thr Thr Gln Gln Leu His Thr His Gly Val 2945 2950 2955 2960 Thr Ala Tyr Leu Glu Leu Gly Pro Asp Thr Thr Leu Thr Thr Leu Thr 2965 2970 2975 His His Asn Leu Pro His His Thr Pro Leu Ala Ile Pro Leu Leu His 2980 2985 2990 Pro Asp Gln Pro Glu Thr His Thr Thr His Thr Ala Leu Ala His Leu 2995 3000 3005 His Thr His Gly His Pro Thr Thr Trp His His His His Thr Pro Thr 3010 3015 3020 His His His Pro Asn Leu Pro Thr Tyr Pro Phe Gln His His His Tyr 3025 3030 3035 3040 Trp Leu Asn Thr Thr Thr Ala Thr Gly Asp Met Ser Ala Ala Gly Leu 3045 3050 3055 Glu Pro Ala Arg His Pro Leu Leu Gly Ala Ala Val Glu Leu Ala Asp 3060 3065 3070 Gly Glu Gly Leu Leu Phe Thr Gly Arg Ile Ser Leu Arg Thr His Pro 3075 3080 3085 Trp Leu Ala Asp His Ala Val Gly Gly Ala Val Leu Leu Pro Gly Thr 3090 3095 3100 Ala Phe Leu Glu Leu Ala Leu Glu Ala Ala Ala His Val Asp Cys His 3105 3110 3115 3120 Arg Ile Glu Glu Leu Thr Leu His Thr Pro Leu Val Val Pro Glu Ser 3125 3130 3135 Gly Gly Val Val Leu Gln Val Thr Val Ala Gly Pro Asn Glu Ala Gly 3140 3145 3150 Asn Arg Ala Val Asp Ile Tyr Ser Arg Ile Asp Val Gly Gly Leu Thr 3155 3160 3165 Ala Asp Ser Val Gly Glu Pro Trp Thr Arg His Ala Ala Gly Tyr Leu 3170 3175 3180 Ala Asp Lys Pro Gly Pro Asp Cys Gly Asp Ser Ala Asp Gly Val Met 3185 3190 3195 3200 Pro Ala Gly Ala Trp Pro Pro Pro Gly Ala Val Ala Val Asp Leu Glu 3205 3210 3215 Glu Leu Tyr Glu Gln Leu Ala Glu Gly Gly Phe His Tyr Gly Ala Ala 3220 3225 3230 Phe Arg Cys Leu Asp Ala Ala Trp Gln Arg Gly Asp Glu Val Phe Ala 3235 3240 3245 Thr Val His Met Ser Glu Asn Gln Leu Gly Asp Thr Ala Ala Ala Arg 3250 3255 3260 Phe Ala Leu His Pro Ala Leu Leu Asp Ser Ala Leu His Thr Ile Pro 3265 3270 3275 3280 Leu Leu Pro Ser Leu Gln Gly Gln Gln Asp Ser Gly Leu Pro Phe Thr 3285 3290 3295 Trp Ala Gly Val Thr Leu Arg Ala Ser Gly Ala Thr Ala Leu Arg Val 3300 3305 3310 Arg Leu Arg Pro Asp Gly His Gly Pro Gly Ala Val Ser Val Asp Val 3315 3320 3325 Ser Asp Glu Ala Gly Glu Pro Val Ala Ser Val Arg Ser Leu Ala Leu 3330 3335 3340 Arg Pro Val Thr Arg Val Glu Leu His Thr Ala Glu Leu Arg Thr Ala 3345 3350 3355 3360 Ala Pro Val Ala Pro His Ser Ser Leu Phe Glu Val Arg Trp Glu Pro 3365 3370 3375 Val Pro Gln Pro Ser Ala Ala Glu Glu Ala Asp Pro Trp Val Met Ile 3380 3385 3390 Gly Thr Gly Pro Thr Leu Arg Pro Asp Glu Asp Phe Ala Thr Pro Pro 3395 3400 3405 Glu Arg Thr Tyr Ala Asp Leu Ala Ala Leu Cys Ala Ala Val Ala Asp 3410 3415 3420 Gly Ala Pro Val Pro Arg Thr Val Val Ala Trp Ser Gln Ala Gly Ser 3425 3430 3435 3440 Glu Asp Glu Ser Ser Glu Ala Leu Arg His Ala Thr His His Met Leu 3445 3450 3455 Gly Leu Leu Gln Gln Trp Leu Ala Asp Ser Arg Phe Val Asp Ser Arg 3460 3465 3470 Leu Val Ile Leu Thr Arg Ala Ala Val Ala Thr Ala Pro Glu Glu Glu 3475 3480 3485 Val Lys Asp Leu Ala Gly Ala Ala Thr Arg Gly Leu Ile Arg Ser Ala 3490 3495 3500 Gln Ser Glu His Pro Asp Arg Phe Val Leu Leu Asp Leu Asp Asp Arg 3505 3510 3515 3520 Pro Ala Asp Ala Lys Asp His Asp Arg Met Leu Ser Val Ala Leu Ala 3525 3530 3535 Cys Gly Glu Pro Glu Val Ala Val Arg Asp Gly Ala Leu Arg Thr Pro 3540 3545 3550 Arg Leu Ser Pro Leu Ala Gly Thr Ala Thr Glu Ala Met Asp Glu His 3555 3560 3565 Pro Trp Asp Pro Asp Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Ser 3570 3575 3580 Leu Gly Ala Met Leu Ala Arg His Leu Val Ala Thr His Gly Val Arg 3585 3590 3595 3600 His Leu Leu Leu Ile Ser Arg Arg Gly Leu Asp Ala Pro Gly Ala Arg 3605 3610 3615 Arg Gln Gly Asn Glu Leu Val Glu Leu Gly Ala Gln Leu Thr Ile Ala 3620 3625 3630 Ala Cys Asp Ala Ala Asp Gln Arg Gln Leu Ala Asn Ala Leu Ser Glu 3635 3640 3645 Ile Ser Val Asp His Pro Leu Thr Ala Val Val His Ala Ala Gly Val 3650 3655 3660 Leu Asp Asp Gly Val Ile Thr Ser Leu Thr Pro Glu Asp Leu Thr His 3665 3670 3675 3680 Val Leu Arg Ala Lys Val Asp Ser Ala Leu Asn Leu His Gln Leu Thr 3685 3690 3695 Arg Asp Leu Pro Leu Ser Ala Phe Val Leu Phe Ser Ser Leu Ala Gly 3700 3705 3710 Val Met Gly Ser Ala Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala 3715 3720 3725 Leu Asp Ala Leu Ala Ser His Arg Arg Ala Thr Arg Leu Pro Ala Val 3730 3735 3740 Ser Leu Ala Trp Gly Val Trp Glu Gln Thr Glu Gly Met Thr Gly Gln 3745 3750 3755 3760 Leu Glu Ala Thr Gly His Ala Arg Leu Arg Arg Ser Gly Leu Arg Pro 3765 3770 3775 Leu Ala Thr Ser Glu Gly Leu Glu Leu Phe Asp Lys Ala Leu Ser Cys 3780 3785 3790 Gly His Ala Leu Val Val Pro Ala Ala Leu Ser Thr Lys Glu Leu Gln 3795 3800 3805 Thr Ser Gly Ser Val Pro Pro Phe Leu Arg His Val Thr Gly Val Ala 3810 3815 3820 Pro Ala Arg Pro Ser Arg Thr Arg Asp Ala Ser Ala Gly Glu Pro Thr 3825 3830 3835 3840 Pro Leu Arg Arg Arg Leu Thr Gly Leu Gly Pro Glu Glu Arg Leu Arg 3845 3850 3855 Glu Val Leu Arg Leu Val Arg Ser Arg Ala Ala Ala Val Leu Gly His 3860 3865 3870 Gly Thr Ala Glu Ala Val Pro Ala Asp Ser Ala Phe Arg Asp Leu Gly 3875 3880 3885 Phe Asp Ser Leu Ala Ala Val Asp Leu Arg Asn Arg Leu Gln Gln Ala 3890 3895 3900 Thr Gly Leu Arg Leu Pro Ala Gly Leu Ile Phe Asp Arg Pro Arg Pro 3905 3910 3915 3920 Asp Val Leu Ala Arg Phe Leu Cys Asp Glu Leu Ala Gly Val Gly Gly 3925 3930 3935 Thr Ser Ala Ala Thr Ala Ala Pro Pro Val Ala Ala Val Gly Gly Ala 3940 3945 3950 Ala Gly Glu Pro Val Ala Ile Val Gly Met Ala Cys Arg Phe Pro Gly 3955 3960 3965 Gly Val Arg Ser Ala Glu Gly Leu Trp Asp Leu Val Ala Ser Gly Met 3970 3975 3980 Asp Ala Val Gly Asp Phe Pro Thr Asp Arg Gly Trp Glu Val Glu Arg 3985 3990 3995 4000 Leu Tyr Asp Pro Asp Pro Asp Arg Thr Gly Thr Ser Tyr Thr Arg Gln 4005 4010 4015 Gly Gly Phe Leu Tyr Asp Ala Gly Glu Phe Asp Ala Ala Phe Phe Gly 4020 4025 4030 Ile Gly Pro Arg Glu Ala Val Ala Met Asp Pro Gln Gln Arg Leu Leu 4035 4040 4045 Leu Glu Ile Ser Trp Glu Ala Leu Glu Arg Ala Gly Ile Asp Pro Ala 4050 4055 4060 Ser Leu Arg Gly Ser Ser Thr Gly Val Phe Ala Gly Val Met Tyr His 4065 4070 4075 4080 Asp Tyr Gly Thr Arg Leu Arg Glu Ile Pro Glu Gly Tyr Glu Gly Tyr 4085 4090 4095 Ile Gly Asn Gly Asn Ala Gly Ser Val Ala Ser Gly Arg Val Ser Tyr 4100 4105 4110 Thr Phe Gly Leu Glu Gly Pro Ala Val Thr Val Asp Thr Ala Cys Ser 4115 4120 4125 Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ser Gly 4130 4135 4140 Glu Cys Ser Met Ala Leu Ala Gly Gly Val Thr Val Met Ser Thr Pro 4145 4150 4155 4160 Thr Thr Phe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala Pro Asp Gly 4165 4170 4175 Arg Cys Lys Ser Phe Gly Ala Gly Ala Asp Gly Thr Gly Trp Ala Glu 4180 4185 4190 Gly Ala Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Asn 4195 4200 4205 Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp 4210 4215 4220 Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ser Gln Glu Arg 4225 4230 4235 4240 Val Ile Arg Gln Ala Trp Ala Asn Ala Gly Val Ala Ala Met Asp Ile 4245 4250 4255 Asp Ala Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile 4260 4265 4270 Glu Ala Gln Ala Leu Leu Gly Thr Tyr Gly Gln Gly Arg Ser Ala Asp 4275 4280 4285 Arg Pro Leu Trp Leu Gly Ser Ile Lys Ser Asn Val Gly His Thr Gln 4290 4295 4300 Ala Ala Ala Gly Val Gly Gly Val Ile Lys Met Val Met Ala Met Arg 4305 4310 4315 4320 His Gly Leu Leu Pro Gln Thr Leu His Ala Glu Glu Pro Ser Pro His 4325 4330 4335 Val Asp Trp Ser Gly Gly Thr Val Arg Leu Leu Thr Glu Pro Val Ala 4340 4345 4350 Trp Pro Glu Arg Gly Arg Met Arg Arg Ala Gly Val Ser Ser Phe Gly 4355 4360 4365 Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Gln Ala Pro Pro Asn 4370 4375 4380 Ala Glu Thr His Glu Pro Ala Glu Pro His Thr Ala Pro Gly Pro Leu 4385 4390 4395 4400 Pro Trp Thr Ile Ser Ala Lys Ser Pro Gln Ala Leu Arg Ala Gln Ala 4405 4410 4415 Arg Gln Leu His Thr Tyr Leu Thr Asn Thr Pro Glu Ala Asn Pro Ala 4420 4425 4430 Asp Val Gly His Thr Leu Ala Met Gly Arg Ala Ser Phe Glu His Arg 4435 4440 4445 Ala Val Val Ile Gly Ser Asp Arg Gly Glu Phe Leu Gly Gly Leu Asp 4450 4455 4460 Ala Val Ala Ala Asp Glu Ala His Ser Ala Val Val Thr Gly Ile Ala 4465 4470 4475 4480 Arg Lys Ala Gly Asp Leu Gly Lys Val Val Phe Val Phe Pro Gly Gln 4485 4490 4495 Gly Gly Gln Trp Ala Gly Met Gly Leu Arg Leu Leu Lys Thr Ser Pro 4500 4505 4510 Val Phe Ala Gln Ser Ile Gln Ala Cys Glu Gln Ala Leu Ala Pro His 4515 4520 4525 Thr Asp Trp Thr Leu Thr Asp Ile Leu His Arg Pro His Thr Asp Pro 4530 4535 4540 Leu Trp Gln Arg Ala Asp Val Ile Gln Pro Ala Leu Phe Ala Leu Met 4545 4550 4555 4560 Thr Ser Leu Thr Thr Leu Trp Gln Ser His Gly Leu Asn Pro Asp Ala 4565 4570 4575 Val Ile Gly His Ser Gln Gly Glu Ile Thr Ala Ala His Ala Cys Gly 4580 4585 4590 Ala Leu Ser Leu Glu Asp Ala Ala Lys Ile Val Ala Leu Arg Ser Gln 4595 4600 4605 Thr Leu Gln Thr Leu Gln Gly Ser Gly Gly Met Ala Ser Val Pro Leu 4610 4615 4620 Pro Ala Asp Gln Val Thr Ala Leu Leu His Thr Met Trp Pro Asp Gln 4625 4630 4635 4640 Leu Trp Val Ala Ala Ile Asn Ala Pro Thr Thr Thr Val Ile Ser Gly 4645 4650 4655 Asp Thr Gln Ala Leu Thr Gln Ala Leu Asn His Tyr Arg Asp Gln Asp 4660 4665 4670 Ile Asp Ala Lys Arg Ile Pro Val Asp Tyr Ala Ser His Cys Pro His 4675 4680 4685 Ile Gln Ala Val Gln His Glu Leu Ser Asp Leu Leu Gln Asp Ile Thr 4690 4695 4700 Pro Arg Ala Ala Thr Thr Pro Phe Tyr Ser Thr Thr Asp Asn Gln Trp 4705 4710 4715 4720 Thr Asp Thr Thr Thr Leu Asn Ala His Tyr Trp Tyr Arg Asn Leu Arg 4725 4730 4735 Gln Pro Val His Leu Thr Asn Ala Ile Thr Asn Leu Thr His Gln Gly 4740 4745 4750 His His Thr Tyr Ile Glu Ile Ser Pro His Pro Thr Leu Thr Pro Ala 4755 4760 4765 Ile Gln Glu Thr Thr His Thr Thr His Thr Pro Thr Thr Val Ile Ser 4770 4775 4780 Thr Leu Arg Arg Asn His Asn Asp Thr His Gln Leu Leu His Ala Leu 4785 4790 4795 4800 Ala His Ala His Thr Thr Gly His Pro Ile Asn Trp His Pro Thr His 4805 4810 4815 Gln His His Thr Pro Thr Pro Gln His Thr Asp Leu Pro Thr Tyr Pro 4820 4825 4830 Phe Gln His Gln Arg Tyr Trp Leu Asn Thr Pro Thr Gln Thr Gly Asp 4835 4840 4845 Ala Ala Ala Ile Gly Leu Asp Pro Ala His His Pro Leu Leu Gly Ala 4850 4855 4860 Ala Val Ala Val Ala Glu Gly Glu Gly Tyr Leu Leu Thr Gly Arg Leu 4865 4870 4875 4880 Ala Leu Ser Thr His Pro Trp Leu Ala Asp His Thr Ile Ala Gly Ala 4885 4890 4895 Val Val Leu Pro Gly Thr Ala Leu Leu Glu Ile Ala Leu Gln Ala Gly 4900 4905 4910 His Arg Val Asp Cys His Arg Ile Glu Glu Leu Thr Leu Gln Ser Pro 4915 4920 4925 Leu Phe Ile Pro Glu Glu Gly Ala Val Gln Val Gln Ala Trp Val Ala 4930 4935 4940 Ala Pro Asp Glu Asn Gly Tyr Arg Ser Leu Thr Val Ser Ser Arg Arg 4945 4950 4955 4960 Glu Gly Thr Tyr Glu Asp Ala Thr Trp Val Arg His Ala Thr Gly Arg 4965 4970 4975 Val Gly Pro Ala Pro Ala Asp Gln Asp Asp Ala Ile Ala Arg Leu Thr 4980 4985 4990 Asp Pro Gln Gly Asp Gly Ala Ala Ala Val Trp Pro Pro Gln Gly Ala 4995 5000 5005 Val Ala Phe Thr Ala Asp Asp Leu Glu Gly Leu Tyr Asp Gly Tyr Ala 5010 5015 5020 Ala Arg Gly Phe Glu Tyr Gly Pro Val Phe Arg Gly Leu Arg Ala Ala 5025 5030 5035 5040 Trp Arg Arg Gly Glu Asp Ile Phe Ala Glu Val Arg Leu Pro Asp Thr 5045 5050 5055 Ala Asp Gly Asp Ala Ser Gln Phe Ser Val His Pro Ala Leu Leu Asp 5060 5065 5070 Ala Ala Leu His Ala Ala Ala Phe Arg Pro Ala Asp Glu Leu Pro His 5075 5080 5085 Gly Ala Leu Pro Phe Ser Phe Ser Gly Val Arg Leu His Gly Pro Gly 5090 5095 5100 Ala Ser Thr Leu Arg Val Arg Leu Thr Pro Asp Gly Gln Ala Arg Asp 5105 5110 5115 5120 Thr His Ala Trp Ser Val Ala Val Val Asp Gly Glu Gly Arg Pro Val 5125 5130 5135 Ala Ser Ile Ala Ser Leu Ala Val Arg Pro Val Ser Thr Gln Glu Leu 5140 5145 5150 Leu Ala Ala Ser Gly Thr Ala Arg Arg Asp Ser Leu Phe Ala Val Glu 5155 5160 5165 Trp Val Thr Ala Pro Ala Pro Thr Ser Ser Ser Ala Pro Arg Arg Leu 5170 5175 5180 Ala Thr Val Gly Pro Ser Asp Arg Leu Pro Ser Ala Asp Ala Tyr Ala 5185 5190 5195 5200 Asn Leu Ala Asp Leu Ala Ala Ala Val Leu Glu Ala Glu Ala Pro Ala 5205 5210 5215 Pro Asp Ala Val Val Val Asp Cys Gly Arg Arg Asp Ala Arg Ala Thr 5220 5225 5230 Ala Val Ala Glu Asp Val Arg Thr Leu Thr Arg Arg Ile Leu Gly Leu 5235 5240 5245 Leu Gln Glu Trp Leu Ala Asp Glu Arg Pro Ala Ser Ser Arg Met Val 5250 5255 5260 Val Leu Thr Arg Gly Ala Val Ala Thr Thr Pro Gly Glu Asp Val Ala 5265 5270 5275 5280 Asp Leu Ala Gly Ala Ala Val Cys Gly Met Val Arg Ser Ala Gln Ser 5285 5290 5295 Glu His Pro Gly Arg Phe Val Leu Leu Asp Leu Asp Pro Asp Pro Asp 5300 5305 5310 Leu Asp Gly Gly Glu Val Pro Pro Thr Val Val Pro Ala Ala Leu Ala 5315 5320 5325 Cys Gly Glu Pro Gln Ile Ala Val Arg Ala Asn Arg His Leu Val Pro 5330 5335 5340 Arg Leu Thr Arg Val Pro Val Ser Val Pro Val Pro Gly Pro Val Pro 5345 5350 5355 5360 Val Pro Ala Ala Glu Ala Ala Asp Gln Asp Thr Thr Pro Thr Ala Phe 5365 5370 5375 Asp Pro Asp Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Thr Leu Gly 5380 5385 5390 Ala Val Leu Ala Arg His Leu Val Ser Arg His Gly Val Arg His Leu 5395 5400 5405 Leu Leu Ala Ser Arg Arg Gly Pro Asp Ala Pro Gly Ala Thr Glu Leu 5410 5415 5420 Arg Ala Glu Leu Ala Glu Leu Gly Ala Glu Ala Thr Val Arg Ala Cys 5425 5430 5435 5440 Asp Thr Gly Asp Arg Gly Ala Leu Ala Asp Leu Ile Ala Gly Ile Pro 5445 5450 5455 Thr Gly His Pro Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp 5460 5465 5470 Asp Ala Thr Val Ala Ser Leu Thr Pro Arg His Leu Asp Thr Ala Leu 5475 5480 5485 Thr Pro Lys Ala Asp Ala Ala Phe His Leu His Glu Leu Thr Arg His 5490 5495 5500 Ala Arg Pro Arg Ala Phe Val Leu Phe Ser Ser Ala Ala Gly Val Leu 5505 5510 5515 5520 Gly Ala Ala Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Phe Leu Asp 5525 5530 5535 Ala Leu Ala Glu His Arg Arg Ala Gln Gly Leu Pro Ala Leu Ser Leu 5540 5545 5550 Ala Trp Gly Leu Trp Glu Gln Gly Ser Gly Met Thr Gly His Leu Asp 5555 5560 5565 Arg Thr Asp Arg Ala Arg Ile Asn Arg Ser Gly Leu Ala Pro Leu Ala 5570 5575 5580 Thr Glu Asp Ala Leu Ala Leu Phe Asp Ala Ala Leu Ala Gly Asp Arg 5585 5590 5595 5600 Pro Phe Leu Val Pro Ala Arg Leu Asp Leu Arg Gly Ser Ser Ala Ala 5605 5610 5615 Glu Thr Pro Ala Pro Leu Phe Ser Arg Ile Ala Pro Ala Arg Thr Thr 5620 5625 5630 Arg Gly Arg Thr Pro Gly Ala Glu Gly Ala Ala Asp Leu Arg Thr Arg 5635 5640 5645 Leu Ala Ala Gln Asp Ala Thr Glu Gln Arg Asp Thr Leu Leu Thr Ile 5650 5655 5660 Val Arg Thr His Thr Ala Ala Val Leu Gly His Asp Thr Ala Ala Ala 5665 5670 5675 5680 Val Arg Pro Asp Ala Ala Phe Arg Glu Leu Gly Phe Asp Ser Leu Ala 5685 5690 5695 Ala Val Glu Leu Arg Asn Arg Leu Gln Thr Thr Thr Ala Leu Thr Leu 5700 5705 5710 Pro Ala Thr Thr Val Phe Asp His Pro Thr Pro Ala Ala Leu Ala Asp 5715 5720 5725 His Leu Arg Thr Gln Leu Cys Gln Asp Ala Pro Ser Pro Ala Ala Ala 5730 5735 5740 Thr Ala Met Ala Ala Met Ala Glu Leu Ala Arg Leu Glu Ser Ala Val 5745 5750 5755 5760 Ser Asp Ser Ala Ala Leu Asp Asp Asp Thr Arg Ser Gly Leu Ala Glu 5765 5770 5775 Arg Leu Arg Ser Leu Ala Arg Lys Met Ser Ser Gly Arg Val Val Asp 5780 5785 5790 His Asn Gly Gly Gly Ala Ala Gly Leu Asp Leu Gln Ser Ala Thr Asp 5795 5800 5805 Asp Glu Met Phe Glu Leu Ile Asp Lys Glu Val Ser Arg Asp 5810 5815 5820 <210> 15 <211> 17481 <212> DNA <213> Artificial Sequence <220> <223> milA3 gene of Streptomyces bingchenggensis <400> 15 atggccgctg gccacgacaa ggtgatcgag gcgctgcggg cgtccctcaa gaccaacgag 60 cggcagaggg aacagatcca ccggctcact acggcggcgc gggaacccat cgccatcatc 120 ggcatggcct gccgctatcc gggcggagtg ggatcgccgg aggacctgtg ggagctggtg 180 gccgccggtc gtgacgccat cggcaccttc cccgaggacc ggggctggga cgtggagcgg 240 ctgtacgacc ccgatccgga gcgggccggc acctcgtgta cccagcatgg cggattcctg 300 taccaggcag gggagttcga ccccggtttc ttcgggatca gcccgcgcga ggcgctggcg 360 atggacccgc agcagcggct gctgctggag atctcctggg aggtgttcga gcgggccggg 420 atcgacccgg cctcggtgcg cggcagccgc accggggtgt tcgcgggcgt catgtaccac 480 gactacggct cccggctgca caccgtcccc gaaggcttcg agggctatgt cggcaacggc 540 agcggcggcg gcgtggcgtc cggccgggtc gcctacaccc tcggcctcga aggcccggcc 600 gtgaccgtgg acaccgcctg ctcctcctcg ttggtcgccc tgcacctggc ctgccaggcg 660 ctgcgggccg gcgagtgctc actcgccctg gcgggcgggg tgacggtgat gtccaccccc 720 agcctgttcg tcgagtactc ccggcagcgc gcgctcgcgg cagacggccg gtgcaaggcg 780 tacggggcgg gggcggacgg caccggctgg gcagaaggcg ccgggatgct gctggtggaa 840 cggctcacgg acgcacagcg cctcggccac cgggtgctgg cggtggtccg gggcagcgcg 900 gtcaaccagg acggcgcgag caacggcctc accgccccca acggccccgc gcaacaacgg 960 gccatccggc aggcactggc gagcgccggg gtgtcggcgt ccgaggtcga cgccgtggag 1020 gggcatggga cggggacgcg gctgggcgat ccgatcgagg cgcaggcgtt gctggcgacc 1080 tacggtcagc agcggcccgc ggaccggccg ctgtggctcg ggtcgatgaa gtccaacgtc 1140 ggccatgcgc aggcggccgc cggcgtgggc gggatcatca agatggtgat ggccatgcgg 1200 agcgggacgc tgccgcgcac cctgcacgcg gacgagccgt cgccacacat cgactgggac 1260 tcgggcgcgg tacggctgct gaccgagccg gtcgcctggc cggagcgcga ccggccccgc 1320 cgcgccgcgg tgtcctcctt cggggtcagc ggcaccaacg cccatgtgat cctcgaggcc 1380 gcatcgcaga cggcgccgca gacggattcc gcgtcgcagg cggaaaccga cgacgctccc 1440 gcaccgcacg gcgcgccggg ccatgccgtg gcggggccgc tgctctggcc cttgtcgggc 1500 gcgacggccg aggcgctgcg ggcccaggcc ggggagctgc gtcgcttcgt ggcggccgat 1560 gagctgctgc gccccgccga cgtcgggcac accctggtct tcggccgctc ggacctcgca 1620 caccgcgcag tcgtcctcgg ctccgaccgg gaaaccctgc tgcgcgctct ggacactctg 1680 gcaggggagg ggccggacga cggctcggtc gtacggggca tggcggccgc cggggccggt 1740 gcgggcgtgg tgttcgtctt cccgggacag ggcggccagt gggccggcat ggggctgcgg 1800 ctgctggaga cctcgtcgtt cttcgccgag cggatggcgg agtgcgaggc ggcgttggca 1860 ccgtatgccg actggtcgct gctcgacgtt ctgcgccggg accccgggga cccggtctgg 1920 gagcgggccg atgtcgtcca gccgatgctg ttctcggtga tggtgtcgct ggcgcagctg 1980 tggcgctcgt acggcgtcga accggacgcc gtactcggcc actcccaggg cgagatcgcc 2040 gccgcccaca tctgcggcgc gctgaccctg gacgacgccg cgaaggttgt cgcgctgcgc 2100 agccgggccc tgcagaccct gcgcggttcg ggcggcatgg cctccgtacc actgccggcg 2160 gacgaggtca ccgggctgct gcggaccgac tctctgtggg tggccgccgt caacgccccc 2220 acggccacgg tgatctccgg cgacgcggac tctctggcgg aggcgctgga acactaccgg 2280 gaccagggcg tcgaagcgaa gcgggtcccg gtcgactacg cctcccactg cccgcatatc 2340 gaagccgtgg agcaggagct gctgggcctg ttgcggggga tcgctccaag ggccgccgac 2400 atccccttct actccaccgt ggacaaccag tgggccgaca ccatgggact cgacgcccgg 2460 tactggtacc gcaatctgcg ccggcccgta cgcttcgccg aagcgctccg cgccctcggc 2520 gccgccgagt accggacgta tgtcgaggtc ggcccgcacc ccaccctcac ccccgccatc 2580 gaggacacca ctgaggccgc cggcgtcgcg gccacggttg tcggatccct gcgccgcggc 2640 gaggacgacg cccaccgcat cctgacctcg ctggcccggg ctcatattca tggcctgccc 2700 gtggcgtggg accgccacta ccgggcgctc gcccccgagg cgaaccatgt cgacctgccc 2760 acctacgcct tccagcgccg ccgctactgg ctggacgccc cggcgaccac cggggacgtg 2820 acggccgcgg ggctggcccc ggtcggacac ccactgctcg gcgcggcggt cggactcgcc 2880 gagggcgacg gatatctgct caccggccgg ctcgccccgc acacccaccc ctggctcacc 2940 gaccacgcgg tcgccggcac cgtcctgctg ccgggcaccg catacgtgga actggccgtg 3000 cacgtcggcg gacacctcgg ctgcccccgg ctggaggagc tcaccctgca cgccccgctc 3060 gtcctccccg acaccggcgg cgtggcgctc caggtggccg tcggggcacc ggacgagacc 3120 ggccgccgcg cactgagcgt ctacgcacag cgcgacgacg accccgcgtg ggagggggcg 3180 gcccggggcg cgtggacacg gcatgcgacc ggcacactgg cggccgaggc cccgactgat 3240 ggcatcagcg gtgccgacgg tgccgggacc ctggcggggg cgtggcctcc gccgggcgcg 3300 gagcccctgg acatcagcgg cctctacgac acgctggccg ccgcagactt cggctacggc 3360 ccggccttcc aggggctgcg cgccgtctgg cggcaaggcg aggagaccta cgccgaggtg 3420 cggctccccg accaggtggc cgccgacgcc ccacgcttct gcctccaccc cgcgctgctc 3480 gacgccgcgc tccacccgct ggcactcgac agcggccgaa gcgaggagaa tccagcggga 3540 catggcctgc tgccgttcgc ctggcgcggc gtcagcctgc gctccccggg cacaccgacg 3600 ctgcgcgtac ggctgcggcc gcagggcccg gactcgattg ccgtcgacgt ggccgacgag 3660 acgggcgcgc cggtggcctc ggccgaatcg ctcacgctgc ggccggtggc cctggaggac 3720 ctgcgggccc tcggcggcca ggcgggcgac accctctacg ccctggagtg gaccgccgcg 3780 cccgagcccc cggcgacggc cctcgggcgg tgcgctgtga ttggccaagc cattcctgga 3840 tgggctgccg cgctggagac ggcggcagcg gggcccgtac ggcggtaccc ggaccttgcc 3900 ggactggtga cggccctgga cgcgggcgat ccgcctccgg acctggtgtt cgtgggctgc 3960 cctccggctg ccgccgggcc cgacgacacg acggtcgccg acgtccacac cgcccgtacc 4020 cgtgtccgta cccgacaagc gctggacctg cttcagggct ggctcggcga agcgcggctg 4080 gccggcgcga ggctggtgct ggtcacctgc ggcgcggtgg ccaccgggcc ggcggaggga 4140 gtgatggacc tggcgggcgc ggcgatctgc ggactggtgc gatccgcgca ggccgaggag 4200 cccgaccgta tcctcctggt ggacctggac gcggccgagg agtcgtgggc ggcgctacca 4260 cgggcggtcg cgctgggcga accgcagatg gccatccggg ccggccagcc gcacatggcc 4320 cggctggttc gagccgacac cgaggggggc gccctgctca cgccgccaca ggggagcggc 4380 ggctggcggc tcgactgcgc cgacgcgggc acggtccagg ggctggcgcc tgtggcgtcc 4440 tcggccgacc gcgacccgct gggcccgcac caggtacgga tcgaggtgcg tgcggccggg 4500 ctgaacttcc gcgatgtcct ggtggccctg gggatggtcc ctgggcagcg ggggctgggc 4560 agcgagggcg ccggggtggt gctcgaagcc gggcctgaag tggccgacct ggcgcccggg 4620 gaccgggtga tgggcgtgtt cgcggatgcg ttcggcccgt tcgcgatcgc cgaccgggcc 4680 accgtgatcc gcgtccccga ccactggacc ttcggccagg ccgccgccgt ccccgtcgtg 4740 ttcgccaccg cctattacgg gctggtggac ctggcaggac tgcgcccggg tgagtcggtg 4800 ctggtgcacg ctgcggccgg cggagtggga ctggccgctg tccaactggc ccgccacctg 4860 ggcgctgagg tctacgccac ggcgagcccc ggcaaatggg acaccctacg cgcccacggc 4920 atccccccgg agcgcatcgc ctcgtcccgc accctcgact tcgagagccg gttcaccggc 4980 cggaacatcg acgtcgtcct caactccctg gcccatgagt acgtcgacgc ctcgctgcgc 5040 ctggtgtccg gcgacagcgg ccggttcctg gagatgggca agaccgacct ccgcgacccg 5100 gaggaggtgg cgcaggcgta ccccggtgtc gcctaccggg cgtacgacct gatggaggcc 5160 ggacccgagc gcatcgggga gatcctgcgc accgtgttgc ggctgttcga cgagggcgtg 5220 ctcaccccgc tgccgctcac ctgctgggac atccggcagg ccagggatgc cttccgccaa 5280 ctccagcagg gccgcaccgt cggaaagaat gtgctcacgc tggaccgcac ccccgacccc 5340 gacggcaccg tcctcatcac cggtggcacc ggtaccctcg gcgccgcgct cgcccgccat 5400 ctcgccgcca ccggccgagc acggcatctg ctactgatca gccgccgtgg cctcgatgcg 5460 ccaggcgctc ccgaactcat cgctgagatt gacgagttgg gcgccacggc gaccgtcgcc 5520 acctgcgacg tcggcgaccg tgccgcgctc gccgaactgc tcgggcggat ccccgccgag 5580 cacccgctga ccgccgtcgt ccacgccgcg ggcaccctcg acgacgccac gctcggctcc 5640 ctcaccgcgc gccacctcga caccgttctg cccgcgaagg ccgatgccgc ctggcatctg 5700 cacgacctga cctgccggct ggatctggcc gcgttcgtgc tgttctcgtc cgccgcgggt 5760 gtcctgggct cgccggggca gggcaactac gccgccgcca acgcctttct cgacgcgctc 5820 gccttccagc gacgggcgat gggactcccc gccgtgtccc tggcatgggg actgtgggag 5880 gaggccagcg gaatgaccgg ccacctcgac cagaccgacc gcacccgcat ggcccgcgtc 5940 ggcctccggc cactggccac ggacgaggcc ctggcgctgt tcgacaacgc tctcgtcgac 6000 ggcccaccgc tgctgctccc ggcccgtatc gacaccaagg cgctacgggg caccaccgca 6060 ccgcccctgt tccagagcct cgtacgcccc accaccggcc accggccacg ccccgcgaca 6120 cccgacggcc gctcctccct ccgagcccgg ctcgccgggc tcgaccccgc cgcacagcac 6180 gaggtcctgc tcaccctcgt ccgcggccac gccgccacgg tcctcggcca cccgagcccc 6240 gacgccatcg cccgcgaggc ggccttccgt gacctcggct tcgactccct caccgccgtg 6300 gagctccgca accgcctcaa ggaggcaacc ggcctgcggc tccccccccc cccccgcctc 6360 aaggaggcaa ccggcctgcg gctccccgcc accatcgtct tcgaccatcc cactcctgcc 6420 gctctcgccc agcacctgcg ggacggcctc atcggcggcg ccgatacggt caccctggct 6480 gcggctcctg ctccgagcaa ggtggcgatg gtggcggatg aggccatcgc gatcatcggc 6540 atggcctgcc ggtatccggg gggcgtgcgg tcggccgagg ggctgtggga tctggtcgcc 6600 tccggcaccg acgccatgag cggattcccc agcgaccgcg gctgggacct cgaccgcctc 6660 tacgcccccc aggaccagga cgtgccgggc accacataca cccgccacgg gggcttcctc 6720 cacgacgcgg gcaagttcga cgcgggattc ttcggcatcg gcccacgtga ggcgctggcg 6780 atggatccgc agcagcggct gctgctggag acctcctggg aggttttcga acacgcggga 6840 atcgacccct cgtcggtacg gcggagccgg accggagtct tcgccggtgt gatgccgacg 6900 gactacggcc cccggctgca agacaccgtg gccgaggtcg agggctatgt cctcaccgga 6960 aactccggca gcgtcgcctc gggccgtatc gcctacacct tcggcctgga aggccccgcg 7020 gtgtcggtgg acacggcgtg ttcgtcgtct ctggtggcgt tgcatctggc gtgtcaggcg 7080 ctgcgtgcgg gggagtgctc catggcgctg gccggcgggg tgacggtgat ggcgacgcct 7140 ggtgccttcg tggagtttgc gcggcagcgg gggttgtcgg tggatgggcg gtgcaaggcg 7200 tttggggtgg gtgcggatgg tacggggtgg gcggaggggg tggggatgct gttggtggag 7260 cggttgtctg atgcgcggcg gttggggcat cgggtgttgg cggtggtgcg gggttctgcg 7320 gtgaatcagg atggtgcgtc gaatggtttg acggcgccga atggtccgtc gcagcagcgg 7380 gtgatccggc aggcgttggc cagtgcgcgg gttggcgggg cggatgtgga tgtggtggag 7440 gggcacggta cggggacgcg gctgggtgat ccgatcgagg cgcaggcgtt gctggcgacc 7500 tacggtcagg aacgccctga tgatcgacct gtctggttgg ggtcggtgaa gtcgaatatc 7560 gggcatgcgc aggccgcggc gggggttgcg ggtgtcatca agatggtgat ggcgatgcgg 7620 tatggggtgt tgccgcggac gttgcatgtg caggagccgt cgccgcatgt ggactggtcc 7680 tcgggcgggg tgcggctgct gacggaggcg gtgccgtggc cggagacggg gcgtgcgcgg 7740 cgtgcggggg tgtcgtcgtt cggggtcagt ggcaccaacg cgcacatcat cctcgaacag 7800 gcgccgcctg aggagcacga cgatccggcg gacgtctcgt ccgggtcgtt tccgtggatg 7860 gtgtcggcca agtccgaaca ggcactacag gcgcaggcag cacagttgcg cgcgtatctg 7920 gcggcacatc ctgagctggg gctggctgat gtcgggtatg cgctggcctc cggccgcacg 7980 gccttcggcc accgtgccgt gctcctgggc ccggaccgcg aagccttcgt cgaagagctg 8040 ggagctctgg aggccggtga ggaacacgcc gggctggtac ggggcgtggc gacgggtgcg 8100 gggaagctgg cgtttgtgtg ttccgggcag ggaacgcaac gtccccgtat gggacacggg 8160 ctgtactcgc cttcccgctg ttcgccgcag ccatggacga agcctgcgca cacctggacc 8220 cacacctcga ccatcccctg cgggatgtca tgttcgccga gccgggcacc gacaccgccc 8280 agctgctcca ccagacccgc tacgcccagc ccgcgctgtt cgccctccag gtcgccctgc 8340 accgcctggt caccgaacac cacggcctta ccccccacta ctacgccggc cattccctcg 8400 gagagatcac cgcggcccac ctcgccggga tcctcaccct ccccgacgcg gcccgcctgg 8460 tcaccacccg cgcccgcctc atgcaatctc tccccgccac cggcgccaat gaccaccctc 8520 caagcagacc ccgacgaact ccacgaacac ctcacacgat gcgaaggacg ggtctcactc 8580 gcggccgtga acgcgcccgg gtccgtggtc atcagcggtg atcgccacga cgtagacgct 8640 acggccgaaa acctccgcgc catgggacgc aagaccactg cgctgaaggt cagcggcgct 8700 ttccactcac accacatcga cccactcctc aacgaactcc gcaacacggc agaaaccctc 8760 acctaccacc caccccacac ccccctcatc accaccaacc ccaccgacca cgaccccacc 8820 acaccccact actgggtccg gcaagcgcgc gagacggtcc actacgccca caccacccaa 8880 caactccaca cccacggcgt caccgcctac ctcgaactcg gccccgacca caccctcacc 8940 gccctcaccc accacaacct ccccgaccac accccgctag ccgtcccgct tctccacccc 9000 gaccaatccg agacccacac cacccacacc gccctcgccc acctccacac ccacggccac 9060 cccaccacct ggcaccacca tcacaccccc acccactacc acccaaacct ccccacctac 9120 cccttccaac accaccacta ctggctcaac accaccactg ccaccggtga tatgtcggct 9180 gcaggccttg agccggcgcg gcatcccctg ttgggcgcgg cggtcgggtt ggccgatggt 9240 gaggggttgc tgttcactgg gcggatttct ctccgtacgc atccctggct ggccgaccac 9300 gccgtcggcg gcgccgtgtt gctccccggt acggcctttc tcgaactcgc cctccaagcc 9360 gccgcccatg ccgactgccg tcgggtcgag gagcttacgc tccacacccc gctcgtcgta 9420 ccggatagcg ccggcgtagt gctgcaggtc actgtggccg cgccgaacga agcaggaaac 9480 cgggcggtgg atatctactc gcgaatcgat gtcggcggcc tcaccgccga ttcggctggc 9540 gagccgtgga cgcgccatgc cgccgggtac cttgccgaca agcctgaccc agactgcggt 9600 gactcggcgg atggtgtcat gcccgcgggc gcatggccgc cgccgggtgc ggtcgccgtg 9660 gatctggagg gactgtacga gcaactggcc gaggggggtt tccactacgg tgcggccttc 9720 cgttgcctgg acgccgcctg gcaacgcggg gacgaggtct tcgcgaccgc gtatatgtca 9780 gaggatcagc tgggcgacac ggctgcggct cggttcgcgc tgcaccccgc gctgctggat 9840 tccgcactgc acaccattcc acttttgccc tccctacggg gacaacagga cagcgggctg 9900 ccgttcacgt ggacaggagt caccctgcgt gcatccgggg cgacggctct gcgcgtccgg 9960 ctgaggccgg acggccatgg cccgggggcg gtgtcggtcg acgtgtccga cgaggcgggt 10020 gagcccgtag catcggtccg gtcgttggcc ctgcggccgg tgaccagggc cgagttgcat 10080 acggccgagt tgcgcacagc cgccccggtt gccccccatg gctcgctctt cgaggtgcga 10140 tgggaacccg tcccccagcc ttcagcggcc gaagaagccg ccccatgggt gatgatcggg 10200 accgggccga cgctgcgccc ggtcgaggac ttcgtcactc cgccggagcg gacgtacgcc 10260 gacctggccg cgctgtgcgt ggcaatcgcc gatgacgcgc ccgttccccg gacggtcgtg 10320 gcctggtccc cagccgggag cgaagacgag tcgagtgagg cgctgcgcca ggccacacac 10380 cacatgctgg gcctactgca gcagtggttg gcggacagcc ggttcgccga cagtcgcctg 10440 gtgatcctca cccgagccgc ggtggccact gcgccggacg aggaggtaga agacctggcg 10500 ggagcggcgg cgcggggtct gatccgctcc gcccagtcgg agcaccctga ccgattcgtc 10560 ctgctcgacc tggacgaccg tcccgctgac gcgaaagacc acgaccgaat gctgtcgatg 10620 gccctggcct gcggggaacc ggaagtggcc gtacgcgatg gagccctgcg cacaccccgg 10680 ctgagcccgc tggccggcac cgccaccgag gccatggacg agcatccctg ggatcaggac 10740 ggcaccgtac tcatcaccgg cggcaccggc agcctcggcg ccatgcttgc ccgccacttg 10800 gtggccaccc atggcgtacg gcatctgatg ctgatcagcc gacgtggcct cgacgccccg 10860 ggggccaggc gactgggggt cgaacttgcg gagctcgggg cgcaggtgac gatcaccgcg 10920 tgcgatgccg cagaccaaag gcaacttgcg aacgtattgt cggagatctc cgtcgaccat 10980 ccgctgaccg ctgtggtgca tgcggcaggc gtactggacg acggggtgat cacatccctc 11040 acaccggagg gcctgaccca tgtcctgcgg gccaaggtcg attcggcgct caatctccac 11100 cagctcacac gcgacctgcc gctgtccgcg tttgtgctct tctcctcgct ggccggggtg 11160 atgggttcgg cagggcaggg caactacgcc gccgccaacg cagccctgga cgcgctggcg 11220 agtcaccgga gggccgctcg gctgccggcg gtgtccttgg cctggggagt ttgggagcag 11280 accgagggca tgaccgggca gttggaggcc acggaccacg cgcggctccg ccgctcgggc 11340 ctgaggccgc tggccatcag cgagggcctg gagctcttcg acaaggccct gagctgtgga 11400 cacgccctgg tggtgcccgc cgcactcagc acgagggagc ttcagacatc cggatccgtc 11460 ccgccattcc tgcgccacct gacgggtgtc gctccggccc ggccgtcccg gacccgcgac 11520 gcctcggccg gtgagccgac ctccctgcgg cggcggttga ccggcctcgg gccggaagaa 11580 cggctacgcg aggtgctgcg gctggtgcgc tcccgggcgg ctgcggtgct ggggcacggc 11640 acggccgaat cggtcccggc ggactcggcg ttccgcgacc tggggttcga ctccctcgcc 11700 gcggtggacc tgcggaaccg gttgcagcag gccaccgggc tgcgcctgcc ggccggcttg 11760 atcttcgacc ggccgcgtcc ggacgtgctc gcccgtttcc tgtgtgacga gttggccggc 11820 gccggcggta cgtcggcggc cacggccgcc ccacccgttg cggccggcgg gggggggggc 11880 cgcgggggag ccggtggcca tcgtcggcat ggcatgccgg tttccgggag gtgtgcggtc 11940 ggccgagggc ctgtgggatc tggtcgcctc cggtatggac gcgtgggtga cttccccgca 12000 gaccgaggct gggaggtgga acggctctac gaccccgacc cggaccgaac cggcacctcc 12060 tacacccggc aaggcgggtt cctctacgac gcgggtgagt tcgacgcggc attcttcggg 12120 atcggcccgc gtgaggcggt agccatggat ccacagcagc ggctgctgct ggagatctcc 12180 tgggaggcgc tggaacgtgc ggggatcgac ccggcgtcgc tgcgggggag ttcgaccggg 12240 gtgttcgctg gggtgatgta ccacgactac ggcacccgcc tgcgcgagat cccagagggc 12300 tacgagggct atatcggcaa tggaaacgcg ggcagcgtcg cgtcgggacg tgtcgcctac 12360 accttcggcc tggaggggcc ggcggtcacc gtggacacgg cgtgttcgtc gtccctggtc 12420 gccctgcatc tggcctgcca ggcgctgcgg tcaggggagt gctccatggc gctggccggc 12480 ggggtcaccg tcatgtccac ccccaccact tttgtcgagt tctcgcgcca gcggggactg 12540 gccccggacg ggcggtgcaa gtccttcggg gccggcgcgg acggaacagg ctgggcggag 12600 ggggcgggga tgctcctggt ggaacggctt tcggacgccc ggcgcaacgg ccaccgggtc 12660 ctggcggtgg tacgggggag tgcggtcaac caggacgggg cgagcaatgg gctgacggcg 12720 ccgaacggcc cgtcgcaaga gcgggtgatc cgccaggcgt gggcaaacgc gggtgtggcc 12780 gcgatggaca tcgacgcggt ggagggacac ggcacgggga cgacgctcgg tgaccccatc 12840 gaggcccagg cgctgctggg gacgtacgga cagggacggt cggccgatcg gccgttgtgg 12900 ttgggatcga tcaagtccaa cgtcggacac acccaggccg ccgcgggggt gggcggcgtc 12960 atcaagatgg tgatggccat gcgccacggg ctgctcccgc agaccctgca cgccgaggag 13020 ccctcacctc atgtggactg gtcgggcggg acggtgcggt tgctgaccga gtcggtggcc 13080 tggcccgagc aggggcggat gcgccgtgcg ggcgtctcct ctttcggtgt cagcggtacc 13140 aacgcccacg tcatcctgga acaagcaccg cctgccgcgg agacccacga accggcagag 13200 cccaacaccg cgccaggccc actgccctgg gcgatctccg cgaagagccc gcaagcgcta 13260 cgtgcccagg cgcgccaact gcacacgtac ctgaccaacg cccccgaggc gaaccccgcc 13320 gacgtcggcc acaccctcgc gacgggccgc gcctctttcg agcatcgtgc tgtggtcatc 13380 ggctccgacc gagcggagtt cctgggtggc ctggatgctc tggcggccga cgaggcccac 13440 accgccgtcg tcacggggat cgcgaggaag gccggtgacc agggcaaggt ggtgttcgtg 13500 ttccccgggc agggcggtca gtgggccggg atgggactgc ggctgcttaa gacctcaccc 13560 gtcttcgccc aatcgatcca ggcctgcgaa caagccctcg ccccccacac cgactggacc 13620 ctgaccgaca tcctgcaccg gccccacacc gaccccctgt ggcagcgcgc cgacgtcatc 13680 cagcccgtcc tcttcgccct catgacctcc ctcgccgccc tctggcaatc ccacggcctt 13740 aaccccgacg ccgtcatcgg ccactcccaa ggcgaaatca ccgccgccca catcagcgga 13800 gcgctgagcc tggaggacgc cgcgaaaacc gtcgcgctgc gcagccgggc cctgcagacc 13860 ctgcgcggtt cgggcggcat ggcctccgta ccactgccgg cggacgaggt caccgggctg 13920 ctgcggaccg gactctctgg cggaggcgcc cccccccccg ccacggtgat ctccggcaac 13980 gcggaagctc tcacacaggc gctggaacac taccgggacc aaggcgtcga cgcgaaacgg 14040 atcccggtcg actacgcctc ccactgcccc cacatccagg ccgtggaaca ggaactgtca 14100 cggctgttgc ggggcatcac cccacgggcc gccaccaccc ccttctactc caccaccgac 14160 aaccaatgga ccgacaccac caccctcaac gcccactact ggtaccgaaa cctccgccaa 14220 cccgtccacc tcgccgacgc catcaccaac ctcacccacc aaggccacca caccttcatc 14280 gaaatcagcc cccaccccac cctcaccccc gccatccaag aaaccaccga caccacccac 14340 acccccacca ccgtcatcag cacactccgc cgcaaccaca acgacaccca ccaaatcctc 14400 cacgccctcg cccacgccca caccaccggc caccccatca actggcacac cacccaccaa 14460 caccacaccc caacccccca acacatcgac ctacccacct accccttcca acaccaccac 14520 tactggctca acacccccac ccagacaggg gatgcggcgg ccgtcggcct ggacccggca 14580 catcacccgt tgctgggcgc ggcggtcgcg gtggccgagg gggagggcta tctgctcacc 14640 ggtcggctcg ccctgtccac ccacccctgg ctcgccgatc acaccatcgc cggcgcggtt 14700 gtcctccctg gaactgccct tctcgagatc gcccttcagg cgggccatcg tgtggactgc 14760 tggcgcatcg aagaactcac cctccaatca ccgctgttca tcccggaaga gggagcagta 14820 caggtgcagg catgggtggc ggcaccggat gagaacgggt gccgaagcct gacggtgtcc 14880 tcccgacgcg agggtacgta cgaggacgcc acgtgggtgc gccatgccac gggccgggtc 14940 ggccccgcac cggccgacca ggatgaagcc atcgcacggc tcaccgaccc acaaggcgac 15000 ggagcggcgg cggcggtctg gccaccgcag ggcgctgtcg cgttcaccgc agacgatctg 15060 gagggcctgt acgacgggta cgcggcgcgg ggattcgagt acggcccggt gttccgaggc 15120 ctgcgggcgg cctggcgacg tggcgaggac atcttcgccg aggtgcgcct tcccgacacg 15180 gcggacggcg acgcctccca gttctccgta caccccgccc tgctggacgc cgcactgcac 15240 gccgcggcct tccgcccggc cgacaaactc ccgcacggcg ccctgccgtt ctccttcagc 15300 ggggtgaggc tgcacgggcc cggagcgtcg accctgcggg tgcgcctcac cccggacggc 15360 caggcgcggg acacgcacgc atggtcggtc gcggtggtcg acggcgaggg gcggccggtg 15420 gcctcgatcg catcgctcgc ggtccgcccg gtgtcgacgc aggagttgct ggcggcctcc 15480 ggtacggcgc ggcgggactc gctcttcgcg gtcgagtggg tgaccgccct ggcgccgacc 15540 tcgtcgtccg ttccgcaacg cctggccacg gtggggccca gcgaccgcct cccctcggca 15600 gacgcgtacg cgaacctcgc cgacctggcc gccgcagtgc tggaggcggg ggccccggcg 15660 cccgatgcgg tcgtggtcga ctgcggccgc cgcgatgcgc gcgccaccgc cgtgccggag 15720 gacgtaagga ccctcacccg gcgcatcctg ggtctgctgc aggagtggct ggcggacgag 15780 aggccggcct cgagccggat ggtcgtactg acccgtggtg cggtggccac cactccgggg 15840 gaggacgtgg cggacctggc gggcgcggcg gtgtgcggca tggtgcgctc cgcgcagtcg 15900 gaacatcccg gccggttcgt cctgctggac ctcgaccccg acccggacct cgacggcggg 15960 gaagtgccac cgaccgtcgt tccggcggct ctcgcctgtg gtgagccgca gatcgcggtg 16020 cgtgcgaacc ggcacctggt gccccggctg acccgcgttc cggcgtccgt ccccgtcccc 16080 gggcgtgttc ccgttcccgc cgccgaggca gccgacccgg acaccacgcc cacggcgttc 16140 gaccccgacg gcaccgtagt gatcaccggc ggcaccggca cccttggcgc gatgctcgcg 16200 cgccatctgg tcagccgtca cggtgtacga cacctcctgc tggcatcgcg acgcggaccc 16260 gacgcacccg gcgccaccga gctgcgggcg gaactggccg agctcggcgc cgaggtgacg 16320 gtgcgcgctt gtgacaccgg tgaccgaggc gcgctggcgg atctcatcgc ggggattccc 16380 accggccacc ctttgaccgg tgtggtccac gctgcgggcg tcctggacga cgccaccgtc 16440 gcctcgctca ccccccgaca cctggacacc gcgctgacac ccaaggccga cgccgccttc 16500 catctgcacg agctcacccg ccacgcccgg ccgcgcgcct tcgtcctgtt ctcctcggcc 16560 gccggtgtcc tcggcgcagc cgggcagggc aactatgcgg ccgccaacgc tttcctcgac 16620 gccctcgccg aacaccgcag ggcgcagggc ctgccggcct tgtcgctcgc gtggggcctg 16680 tgggagcagg gcagcggcat gaccgggcat ctcgaccgca ccgaccgggc ccgcatcaac 16740 cgctccggac tcgcccccct cgccacggag gacgctctcg cgctcttcga cgccgccctc 16800 gccggcgatc ggccgttcct ggtgcccgcc cggctggacc tgcggggttc aagcgccgcc 16860 gagaccccgg cgccgctgtt ctccaggatc gccccggctc gtacgacccg gggccggtcc 16920 cccggcgccg agggcgccgc tgaccttcgt acccgtctcg cggcccagga cgccgccgag 16980 cagcgcgaca cgcttctcac gatcgtccgc acccacaccg ccgccgtcct ggggcatgac 17040 acggctgccg ccgtgcggcc ggacggggcc ttccgtgaac tgggtttcga ctccctcgcc 17100 gccgtggaac tccgtaaccg ccttcaaacg accaccgccc tcaccctgcc cgcgaccacc 17160 gtcttcgacc accccacccc cgctgccctc gccgatcatc tgcgtactca gctctgccag 17220 gacgctcagt cctcggcggc ggccacggcc atggcggcga tggcggagct ggccaggctg 17280 gagtccgccg tctccgattc ggtggcgctc gacgacgaca cgcgcagcgg cctcgcggag 17340 cgcctgcggt ccctcgcccg caagatgagc agtggccgtg tcgtcgacca cgacggcggc 17400 ggcgctgcgg acctggatct tcagtcggtc acggacgatg agatgttcga gctgatcgac 17460 aaggaggtca gccgagactg a 17481 <210> 16 <211> 5826 <212> PRT <213> Artificial Sequence <220> <223> milA3 protein of Streptomyces bingchenggensis <400> 16 Met Ala Ala Gly His Asp Lys Val Ile Glu Ala Leu Arg Ala Ser Leu 1 5 10 15 Lys Thr Asn Glu Arg Gln Arg Glu Gln Ile His Arg Leu Thr Thr Ala 20 25 30 Ala Arg Glu Pro Ile Ala Ile Ile Gly Met Ala Cys Arg Tyr Pro Gly 35 40 45 Gly Val Gly Ser Pro Glu Asp Leu Trp Glu Leu Val Ala Ala Gly Arg 50 55 60 Asp Ala Ile Gly Thr Phe Pro Glu Asp Arg Gly Trp Asp Val Glu Arg 65 70 75 80 Leu Tyr Asp Pro Asp Pro Glu Arg Ala Gly Thr Ser Cys Thr Gln His 85 90 95 Gly Gly Phe Leu Tyr Gln Ala Gly Glu Phe Asp Pro Gly Phe Phe Gly 100 105 110 Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu 115 120 125 Leu Glu Ile Ser Trp Glu Val Phe Glu Arg Ala Gly Ile Asp Pro Ala 130 135 140 Ser Val Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Val Met Tyr His 145 150 155 160 Asp Tyr Gly Ser Arg Leu His Thr Val Pro Glu Gly Phe Glu Gly Tyr 165 170 175 Val Gly Asn Gly Ser Gly Gly Gly Val Ala Ser Gly Arg Val Ala Tyr 180 185 190 Thr Leu Gly Leu Glu Gly Pro Ala Val Thr Val Asp Thr Ala Cys Ser 195 200 205 Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ala Gly 210 215 220 Glu Cys Ser Leu Ala Leu Ala Gly Gly Val Thr Val Met Ser Thr Pro 225 230 235 240 Ser Leu Phe Val Glu Tyr Ser Arg Gln Arg Ala Leu Ala Ala Asp Gly 245 250 255 Arg Cys Lys Ala Tyr Gly Ala Gly Ala Asp Gly Thr Gly Trp Ala Glu 260 265 270 Gly Ala Gly Met Leu Leu Val Glu Arg Leu Thr Asp Ala Gln Arg Leu 275 280 285 Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp 290 295 300 Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ala Gln Gln Arg 305 310 315 320 Ala Ile Arg Gln Ala Leu Ala Ser Ala Gly Val Ser Ala Ser Glu Val 325 330 335 Asp Ala Val Glu Gly His Gly Thr Gly Thr Arg Leu Gly Asp Pro Ile 340 345 350 Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gln Arg Pro Ala Asp 355 360 365 Arg Pro Leu Trp Leu Gly Ser Met Lys Ser Asn Val Gly His Ala Gln 370 375 380 Ala Ala Ala Gly Val Gly Gly Ile Ile Lys Met Val Met Ala Met Arg 385 390 395 400 Ser Gly Thr Leu Pro Arg Thr Leu His Ala Asp Glu Pro Ser Pro His 405 410 415 Ile Asp Trp Asp Ser Gly Ala Val Arg Leu Leu Thr Glu Pro Val Ala 420 425 430 Trp Pro Glu Arg Asp Arg Pro Arg Arg Ala Ala Val Ser Ser Phe Gly 435 440 445 Val Ser Gly Thr Asn Ala His Val Ile Leu Glu Ala Ala Ser Gln Thr 450 455 460 Ala Pro Gln Thr Asp Ser Ala Ser Gln Ala Glu Thr Asp Asp Ala Pro 465 470 475 480 Ala Pro His Gly Ala Pro Gly His Ala Val Ala Gly Pro Leu Leu Trp 485 490 495 Pro Leu Ser Gly Ala Thr Ala Glu Ala Leu Arg Ala Gln Ala Gly Glu 500 505 510 Leu Arg Arg Phe Val Ala Ala Asp Glu Leu Leu Arg Pro Ala Asp Val 515 520 525 Gly His Thr Leu Val Phe Gly Arg Ser Asp Leu Ala His Arg Ala Val 530 535 540 Val Leu Gly Ser Asp Arg Glu Thr Leu Leu Arg Ala Leu Asp Thr Leu 545 550 555 560 Ala Gly Glu Gly Pro Asp Asp Gly Ser Val Val Arg Gly Met Ala Ala 565 570 575 Ala Gly Ala Gly Ala Gly Val Val Phe Val Phe Pro Gly Gln Gly Gly 580 585 590 Gln Trp Ala Gly Met Gly Leu Arg Leu Leu Glu Thr Ser Ser Phe Phe 595 600 605 Ala Glu Arg Met Ala Glu Cys Glu Ala Ala Leu Ala Pro Tyr Ala Asp 610 615 620 Trp Ser Leu Leu Asp Val Leu Arg Arg Asp Pro Gly Asp Pro Val Trp 625 630 635 640 Glu Arg Ala Asp Val Val Gln Pro Met Leu Phe Ser Val Met Val Ser 645 650 655 Leu Ala Gln Leu Trp Arg Ser Tyr Gly Val Glu Pro Asp Ala Val Leu 660 665 670 Gly His Ser Gln Gly Glu Ile Ala Ala Ala His Ile Cys Gly Ala Leu 675 680 685 Thr Leu Asp Asp Ala Ala Lys Val Val Ala Leu Arg Ser Arg Ala Leu 690 695 700 Gln Thr Leu Arg Gly Ser Gly Gly Met Ala Ser Val Pro Leu Pro Ala 705 710 715 720 Asp Glu Val Thr Gly Leu Leu Arg Thr Asp Ser Leu Trp Val Ala Ala 725 730 735 Val Asn Ala Pro Thr Ala Thr Val Ile Ser Gly Asp Ala Asp Ser Leu 740 745 750 Ala Glu Ala Leu Glu His Tyr Arg Asp Gln Gly Val Glu Ala Lys Arg 755 760 765 Val Pro Val Asp Tyr Ala Ser His Cys Pro His Ile Glu Ala Val Glu 770 775 780 Gln Glu Leu Leu Gly Leu Leu Arg Gly Ile Ala Pro Arg Ala Ala Asp 785 790 795 800 Ile Pro Phe Tyr Ser Thr Val Asp Asn Gln Trp Ala Asp Thr Met Gly 805 810 815 Leu Asp Ala Arg Tyr Trp Tyr Arg Asn Leu Arg Arg Pro Val Arg Phe 820 825 830 Ala Glu Ala Leu Arg Ala Leu Gly Ala Ala Glu Tyr Arg Thr Tyr Val 835 840 845 Glu Val Gly Pro His Pro Thr Leu Thr Pro Ala Ile Glu Asp Thr Thr 850 855 860 Glu Ala Ala Gly Val Ala Ala Thr Val Val Gly Ser Leu Arg Arg Gly 865 870 875 880 Glu Asp Asp Ala His Arg Ile Leu Thr Ser Leu Ala Arg Ala His Ile 885 890 895 His Gly Leu Pro Val Ala Trp Asp Arg His Tyr Arg Ala Leu Ala Pro 900 905 910 Glu Ala Asn His Val Asp Leu Pro Thr Tyr Ala Phe Gln Arg Arg Arg 915 920 925 Tyr Trp Leu Asp Ala Pro Ala Thr Thr Gly Asp Val Thr Ala Ala Gly 930 935 940 Leu Ala Pro Val Gly His Pro Leu Leu Gly Ala Ala Val Gly Leu Ala 945 950 955 960 Glu Gly Asp Gly Tyr Leu Leu Thr Gly Arg Leu Ala Pro His Thr His 965 970 975 Pro Trp Leu Thr Asp His Ala Val Ala Gly Thr Val Leu Leu Pro Gly 980 985 990 Thr Ala Tyr Val Glu Leu Ala Val His Val Gly Gly His Leu Gly Cys 995 1000 1005 Pro Arg Leu Glu Glu Leu Thr Leu His Ala Pro Leu Val Leu Pro Asp 1010 1015 1020 Thr Gly Gly Val Ala Leu Gln Val Ala Val Gly Ala Pro Asp Glu Thr 1025 1030 1035 1040 Gly Arg Arg Ala Leu Ser Val Tyr Ala Gln Arg Asp Asp Asp Pro Ala 1045 1050 1055 Trp Glu Gly Ala Ala Arg Gly Ala Trp Thr Arg His Ala Thr Gly Thr 1060 1065 1070 Leu Ala Ala Glu Ala Pro Thr Asp Gly Ile Ser Gly Ala Asp Gly Ala 1075 1080 1085 Gly Thr Leu Ala Gly Ala Trp Pro Pro Pro Gly Ala Glu Pro Leu Asp 1090 1095 1100 Ile Ser Gly Leu Tyr Asp Thr Leu Ala Ala Ala Asp Phe Gly Tyr Gly 1105 1110 1115 1120 Pro Ala Phe Gln Gly Leu Arg Ala Val Trp Arg Gln Gly Glu Glu Thr 1125 1130 1135 Tyr Ala Glu Val Arg Leu Pro Asp Gln Val Ala Ala Asp Ala Pro Arg 1140 1145 1150 Phe Cys Leu His Pro Ala Leu Leu Asp Ala Ala Leu His Pro Leu Ala 1155 1160 1165 Leu Asp Ser Gly Arg Ser Glu Glu Asn Pro Ala Gly His Gly Leu Leu 1170 1175 1180 Pro Phe Ala Trp Arg Gly Val Ser Leu Arg Ser Pro Gly Thr Pro Thr 1185 1190 1195 1200 Leu Arg Val Arg Leu Arg Pro Gln Gly Pro Asp Ser Ile Ala Val Asp 1205 1210 1215 Val Ala Asp Glu Thr Gly Ala Pro Val Ala Ser Ala Glu Ser Leu Thr 1220 1225 1230 Leu Arg Pro Val Ala Leu Glu Asp Leu Arg Ala Leu Gly Gly Gln Ala 1235 1240 1245 Gly Asp Thr Leu Tyr Ala Leu Glu Trp Thr Ala Ala Pro Glu Pro Pro 1250 1255 1260 Ala Thr Ala Leu Gly Arg Cys Ala Val Ile Gly Gln Ala Ile Pro Gly 1265 1270 1275 1280 Trp Ala Ala Ala Leu Glu Thr Ala Ala Ala Gly Pro Val Arg Arg Tyr 1285 1290 1295 Pro Asp Leu Ala Gly Leu Val Thr Ala Leu Asp Ala Gly Asp Pro Pro 1300 1305 1310 Pro Asp Leu Val Phe Val Gly Cys Pro Pro Ala Ala Ala Gly Pro Asp 1315 1320 1325 Asp Thr Thr Val Ala Asp Val His Thr Ala Arg Thr Arg Val Arg Thr 1330 1335 1340 Arg Gln Ala Leu Asp Leu Leu Gln Gly Trp Leu Gly Glu Ala Arg Leu 1345 1350 1355 1360 Ala Gly Ala Arg Leu Val Leu Val Thr Cys Gly Ala Val Ala Thr Gly 1365 1370 1375 Pro Ala Glu Gly Val Met Asp Leu Ala Gly Ala Ala Ile Cys Gly Leu 1380 1385 1390 Val Arg Ser Ala Gln Ala Glu Glu Pro Asp Arg Ile Leu Leu Val Asp 1395 1400 1405 Leu Asp Ala Ala Glu Glu Ser Trp Ala Ala Leu Pro Arg Ala Val Ala 1410 1415 1420 Leu Gly Glu Pro Gln Met Ala Ile Arg Ala Gly Gln Pro His Met Ala 1425 1430 1435 1440 Arg Leu Val Arg Ala Asp Thr Glu Gly Gly Ala Leu Leu Thr Pro Pro 1445 1450 1455 Gln Gly Ser Gly Gly Trp Arg Leu Asp Cys Ala Asp Ala Gly Thr Val 1460 1465 1470 Gln Gly Leu Ala Pro Val Ala Ser Ser Ala Asp Arg Asp Pro Leu Gly 1475 1480 1485 Pro His Gln Val Arg Ile Glu Val Arg Ala Ala Gly Leu Asn Phe Arg 1490 1495 1500 Asp Val Leu Val Ala Leu Gly Met Val Pro Gly Gln Arg Gly Leu Gly 1505 1510 1515 1520 Ser Glu Gly Ala Gly Val Val Leu Glu Ala Gly Pro Glu Val Ala Asp 1525 1530 1535 Leu Ala Pro Gly Asp Arg Val Met Gly Val Phe Ala Asp Ala Phe Gly 1540 1545 1550 Pro Phe Ala Ile Ala Asp Arg Ala Thr Val Ile Arg Val Pro Asp His 1555 1560 1565 Trp Thr Phe Gly Gln Ala Ala Ala Val Pro Val Val Phe Ala Thr Ala 1570 1575 1580 Tyr Tyr Gly Leu Val Asp Leu Ala Gly Leu Arg Pro Gly Glu Ser Val 1585 1590 1595 1600 Leu Val His Ala Ala Ala Gly Gly Val Gly Leu Ala Ala Val Gln Leu 1605 1610 1615 Ala Arg His Leu Gly Ala Glu Val Tyr Ala Thr Ala Ser Pro Gly Lys 1620 1625 1630 Trp Asp Thr Leu Arg Ala His Gly Ile Pro Pro Glu Arg Ile Ala Ser 1635 1640 1645 Ser Arg Thr Leu Asp Phe Glu Ser Arg Phe Thr Gly Arg Asn Ile Asp 1650 1655 1660 Val Val Leu Asn Ser Leu Ala His Glu Tyr Val Asp Ala Ser Leu Arg 1665 1670 1675 1680 Leu Val Ser Gly Asp Ser Gly Arg Phe Leu Glu Met Gly Lys Thr Asp 1685 1690 1695 Leu Arg Asp Pro Glu Glu Val Ala Gln Ala Tyr Pro Gly Val Ala Tyr 1700 1705 1710 Arg Ala Tyr Asp Leu Met Glu Ala Gly Pro Glu Arg Ile Gly Glu Ile 1715 1720 1725 Leu Arg Thr Val Leu Arg Leu Phe Asp Glu Gly Val Leu Thr Pro Leu 1730 1735 1740 Pro Leu Thr Cys Trp Asp Ile Arg Gln Ala Arg Asp Ala Phe Arg Gln 1745 1750 1755 1760 Leu Gln Gln Gly Arg Thr Val Gly Lys Asn Val Leu Thr Leu Asp Arg 1765 1770 1775 Thr Pro Asp Pro Asp Gly Thr Val Leu Ile Thr Gly Gly Thr Gly Thr 1780 1785 1790 Leu Gly Ala Ala Leu Ala Arg His Leu Ala Ala Thr Gly Arg Ala Arg 1795 1800 1805 His Leu Leu Leu Ile Ser Arg Arg Gly Leu Asp Ala Pro Gly Ala Pro 1810 1815 1820 Glu Leu Ile Ala Glu Ile Asp Glu Leu Gly Ala Thr Ala Thr Val Ala 1825 1830 1835 1840 Thr Cys Asp Val Gly Asp Arg Ala Ala Leu Ala Glu Leu Leu Gly Arg 1845 1850 1855 Ile Pro Ala Glu His Pro Leu Thr Ala Val Val His Ala Ala Gly Thr 1860 1865 1870 Leu Asp Asp Ala Thr Leu Gly Ser Leu Thr Ala Arg His Leu Asp Thr 1875 1880 1885 Val Leu Pro Ala Lys Ala Asp Ala Ala Trp His Leu His Asp Leu Thr 1890 1895 1900 Cys Arg Leu Asp Leu Ala Ala Phe Val Leu Phe Ser Ser Ala Ala Gly 1905 1910 1915 1920 Val Leu Gly Ser Pro Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Phe 1925 1930 1935 Leu Asp Ala Leu Ala Phe Gln Arg Arg Ala Met Gly Leu Pro Ala Val 1940 1945 1950 Ser Leu Ala Trp Gly Leu Trp Glu Glu Ala Ser Gly Met Thr Gly His 1955 1960 1965 Leu Asp Gln Thr Asp Arg Thr Arg Met Ala Arg Val Gly Leu Arg Pro 1970 1975 1980 Leu Ala Thr Asp Glu Ala Leu Ala Leu Phe Asp Asn Ala Leu Val Asp 1985 1990 1995 2000 Gly Pro Pro Leu Leu Leu Pro Ala Arg Ile Asp Thr Lys Ala Leu Arg 2005 2010 2015 Gly Thr Thr Ala Pro Pro Leu Phe Gln Ser Leu Val Arg Pro Thr Thr 2020 2025 2030 Gly His Arg Pro Arg Pro Ala Thr Pro Asp Gly Arg Ser Ser Leu Arg 2035 2040 2045 Ala Arg Leu Ala Gly Leu Asp Pro Ala Ala Gln His Glu Val Leu Leu 2050 2055 2060 Thr Leu Val Arg Gly His Ala Ala Thr Val Leu Gly His Pro Ser Pro 2065 2070 2075 2080 Asp Ala Ile Ala Arg Glu Ala Ala Phe Arg Asp Leu Gly Phe Asp Ser 2085 2090 2095 Leu Thr Ala Val Glu Leu Arg Asn Arg Leu Lys Glu Ala Thr Gly Leu 2100 2105 2110 Arg Leu Pro Pro Pro Pro Arg Leu Lys Glu Ala Thr Gly Leu Arg Leu 2115 2120 2125 Pro Ala Thr Ile Val Phe Asp His Pro Thr Pro Ala Ala Leu Ala Gln 2130 2135 2140 His Leu Arg Asp Gly Leu Ile Gly Gly Ala Asp Thr Val Thr Leu Ala 2145 2150 2155 2160 Ala Ala Pro Ala Pro Ser Lys Val Ala Met Val Ala Asp Glu Ala Ile 2165 2170 2175 Ala Ile Ile Gly Met Ala Cys Arg Tyr Pro Gly Gly Val Arg Ser Ala 2180 2185 2190 Glu Gly Leu Trp Asp Leu Val Ala Ser Gly Thr Asp Ala Met Ser Gly 2195 2200 2205 Phe Pro Ser Asp Arg Gly Trp Asp Leu Asp Arg Leu Tyr Ala Pro Gln 2210 2215 2220 Asp Gln Asp Val Pro Gly Thr Thr Tyr Thr Arg His Gly Gly Phe Leu 2225 2230 2235 2240 His Asp Ala Gly Lys Phe Asp Ala Gly Phe Phe Gly Ile Gly Pro Arg 2245 2250 2255 Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser 2260 2265 2270 Trp Glu Val Phe Glu His Ala Gly Ile Asp Pro Ser Ser Val Arg Arg 2275 2280 2285 Ser Arg Thr Gly Val Phe Ala Gly Val Met Pro Thr Asp Tyr Gly Pro 2290 2295 2300 Arg Leu Gln Asp Thr Val Ala Glu Val Glu Gly Tyr Val Leu Thr Gly 2305 2310 2315 2320 Asn Ser Gly Ser Val Ala Ser Gly Arg Ile Ala Tyr Thr Phe Gly Leu 2325 2330 2335 Glu Gly Pro Ala Val Ser Val Asp Thr Ala Cys Ser Ser Ser Leu Val 2340 2345 2350 Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ala Gly Glu Cys Ser Met 2355 2360 2365 Ala Leu Ala Gly Gly Val Thr Val Met Ala Thr Pro Gly Ala Phe Val 2370 2375 2380 Glu Phe Ala Arg Gln Arg Gly Leu Ser Val Asp Gly Arg Cys Lys Ala 2385 2390 2395 2400 Phe Gly Val Gly Ala Asp Gly Thr Gly Trp Ala Glu Gly Val Gly Met 2405 2410 2415 Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Leu Gly His Arg Val 2420 2425 2430 Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn 2435 2440 2445 Gly Leu Thr Ala Pro Asn Gly Pro Ser Gln Gln Arg Val Ile Arg Gln 2450 2455 2460 Ala Leu Ala Ser Ala Arg Val Gly Gly Ala Asp Val Asp Val Val Glu 2465 2470 2475 2480 Gly His Gly Thr Gly Thr Arg Leu Gly Asp Pro Ile Glu Ala Gln Ala 2485 2490 2495 Leu Leu Ala Thr Tyr Gly Gln Glu Arg Pro Asp Asp Arg Pro Val Trp 2500 2505 2510 Leu Gly Ser Val Lys Ser Asn Ile Gly His Ala Gln Ala Ala Ala Gly 2515 2520 2525 Val Ala Gly Val Ile Lys Met Val Met Ala Met Arg Tyr Gly Val Leu 2530 2535 2540 Pro Arg Thr Leu His Val Gln Glu Pro Ser Pro His Val Asp Trp Ser 2545 2550 2555 2560 Ser Gly Gly Val Arg Leu Leu Thr Glu Ala Val Pro Trp Pro Glu Thr 2565 2570 2575 Gly Arg Ala Arg Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr 2580 2585 2590 Asn Ala His Ile Ile Leu Glu Gln Ala Pro Pro Glu Glu His Asp Asp 2595 2600 2605 Pro Ala Asp Val Ser Ser Gly Ser Phe Pro Trp Met Val Ser Ala Lys 2610 2615 2620 Ser Glu Gln Ala Leu Gln Ala Gln Ala Ala Gln Leu Arg Ala Tyr Leu 2625 2630 2635 2640 Ala Ala His Pro Glu Leu Gly Leu Ala Asp Val Gly Tyr Ala Leu Ala 2645 2650 2655 Ser Gly Arg Thr Ala Phe Gly His Arg Ala Val Leu Leu Gly Pro Asp 2660 2665 2670 Arg Glu Ala Phe Val Glu Glu Leu Gly Ala Leu Glu Ala Gly Glu Glu 2675 2680 2685 His Ala Gly Leu Val Arg Gly Val Ala Thr Gly Ala Gly Lys Leu Ala 2690 2695 2700 Phe Val Cys Ser Gly Gln Gly Thr Gln Arg Pro Arg Met Gly His Gly 2705 2710 2715 2720 Leu Tyr Ser Pro Ser Arg Cys Ser Pro Gln Pro Trp Thr Lys Pro Ala 2725 2730 2735 His Thr Trp Thr His Thr Ser Thr Ile Pro Cys Gly Met Ser Cys Ser 2740 2745 2750 Pro Ser Arg Ala Pro Thr Pro Pro Ser Cys Ser Thr Arg Pro Ala Thr 2755 2760 2765 Pro Ser Pro Arg Cys Ser Pro Ser Arg Ser Pro Cys Thr Ala Trp Ser 2770 2775 2780 Pro Asn Thr Thr Ala Leu Pro Pro Thr Thr Thr Pro Ala Ile Pro Ser 2785 2790 2795 2800 Glu Arg Ser Pro Arg Pro Thr Ser Pro Gly Ser Ser Pro Ser Pro Thr 2805 2810 2815 Arg Pro Ala Trp Ser Pro Pro Ala Pro Ala Ser Cys Asn Leu Ser Pro 2820 2825 2830 Pro Pro Ala Pro Met Thr Thr Leu Gln Ala Asp Pro Asp Glu Leu His 2835 2840 2845 Glu His Leu Thr Arg Cys Glu Gly Arg Val Ser Leu Ala Ala Val Asn 2850 2855 2860 Ala Pro Gly Ser Val Val Ile Ser Gly Asp Arg His Asp Val Asp Ala 2865 2870 2875 2880 Thr Ala Glu Asn Leu Arg Ala Met Gly Arg Lys Thr Thr Ala Leu Lys 2885 2890 2895 Val Ser Gly Ala Phe His Ser His His Ile Asp Pro Leu Leu Asn Glu 2900 2905 2910 Leu Arg Asn Thr Ala Glu Thr Leu Thr Tyr His Pro Pro His Thr Pro 2915 2920 2925 Leu Ile Thr Thr Asn Pro Thr Asp His Asp Pro Thr Thr Pro His Tyr 2930 2935 2940 Trp Val Arg Gln Ala Arg Glu Thr Val His Tyr Ala His Thr Thr Gln 2945 2950 2955 2960 Gln Leu His Thr His Gly Val Thr Ala Tyr Leu Glu Leu Gly Pro Asp 2965 2970 2975 His Thr Leu Thr Ala Leu Thr His His Asn Leu Pro Asp His Thr Pro 2980 2985 2990 Leu Ala Val Pro Leu Leu His Pro Asp Gln Ser Glu Thr His Thr Thr 2995 3000 3005 His Thr Ala Leu Ala His Leu His Thr His Gly His Pro Thr Thr Trp 3010 3015 3020 His His His His Thr Pro Thr His Tyr His Pro Asn Leu Pro Thr Tyr 3025 3030 3035 3040 Pro Phe Gln His His His Tyr Trp Leu Asn Thr Thr Thr Ala Thr Gly 3045 3050 3055 Asp Met Ser Ala Ala Gly Leu Glu Pro Ala Arg His Pro Leu Leu Gly 3060 3065 3070 Ala Ala Val Gly Leu Ala Asp Gly Glu Gly Leu Leu Phe Thr Gly Arg 3075 3080 3085 Ile Ser Leu Arg Thr His Pro Trp Leu Ala Asp His Ala Val Gly Gly 3090 3095 3100 Ala Val Leu Leu Pro Gly Thr Ala Phe Leu Glu Leu Ala Leu Gln Ala 3105 3110 3115 3120 Ala Ala His Ala Asp Cys Arg Arg Val Glu Glu Leu Thr Leu His Thr 3125 3130 3135 Pro Leu Val Val Pro Asp Ser Ala Gly Val Val Leu Gln Val Thr Val 3140 3145 3150 Ala Ala Pro Asn Glu Ala Gly Asn Arg Ala Val Asp Ile Tyr Ser Arg 3155 3160 3165 Ile Asp Val Gly Gly Leu Thr Ala Asp Ser Ala Gly Glu Pro Trp Thr 3170 3175 3180 Arg His Ala Ala Gly Tyr Leu Ala Asp Lys Pro Asp Pro Asp Cys Gly 3185 3190 3195 3200 Asp Ser Ala Asp Gly Val Met Pro Ala Gly Ala Trp Pro Pro Pro Gly 3205 3210 3215 Ala Val Ala Val Asp Leu Glu Gly Leu Tyr Glu Gln Leu Ala Glu Gly 3220 3225 3230 Gly Phe His Tyr Gly Ala Ala Phe Arg Cys Leu Asp Ala Ala Trp Gln 3235 3240 3245 Arg Gly Asp Glu Val Phe Ala Thr Ala Tyr Met Ser Glu Asp Gln Leu 3250 3255 3260 Gly Asp Thr Ala Ala Ala Arg Phe Ala Leu His Pro Ala Leu Leu Asp 3265 3270 3275 3280 Ser Ala Leu His Thr Ile Pro Leu Leu Pro Ser Leu Arg Gly Gln Gln 3285 3290 3295 Asp Ser Gly Leu Pro Phe Thr Trp Thr Gly Val Thr Leu Arg Ala Ser 3300 3305 3310 Gly Ala Thr Ala Leu Arg Val Arg Leu Arg Pro Asp Gly His Gly Pro 3315 3320 3325 Gly Ala Val Ser Val Asp Val Ser Asp Glu Ala Gly Glu Pro Val Ala 3330 3335 3340 Ser Val Arg Ser Leu Ala Leu Arg Pro Val Thr Arg Ala Glu Leu His 3345 3350 3355 3360 Thr Ala Glu Leu Arg Thr Ala Ala Pro Val Ala Pro His Gly Ser Leu 3365 3370 3375 Phe Glu Val Arg Trp Glu Pro Val Pro Gln Pro Ser Ala Ala Glu Glu 3380 3385 3390 Ala Ala Pro Trp Val Met Ile Gly Thr Gly Pro Thr Leu Arg Pro Val 3395 3400 3405 Glu Asp Phe Val Thr Pro Pro Glu Arg Thr Tyr Ala Asp Leu Ala Ala 3410 3415 3420 Leu Cys Val Ala Ile Ala Asp Asp Ala Pro Val Pro Arg Thr Val Val 3425 3430 3435 3440 Ala Trp Ser Pro Ala Gly Ser Glu Asp Glu Ser Ser Glu Ala Leu Arg 3445 3450 3455 Gln Ala Thr His His Met Leu Gly Leu Leu Gln Gln Trp Leu Ala Asp 3460 3465 3470 Ser Arg Phe Ala Asp Ser Arg Leu Val Ile Leu Thr Arg Ala Ala Val 3475 3480 3485 Ala Thr Ala Pro Asp Glu Glu Val Glu Asp Leu Ala Gly Ala Ala Ala 3490 3495 3500 Arg Gly Leu Ile Arg Ser Ala Gln Ser Glu His Pro Asp Arg Phe Val 3505 3510 3515 3520 Leu Leu Asp Leu Asp Asp Arg Pro Ala Asp Ala Lys Asp His Asp Arg 3525 3530 3535 Met Leu Ser Met Ala Leu Ala Cys Gly Glu Pro Glu Val Ala Val Arg 3540 3545 3550 Asp Gly Ala Leu Arg Thr Pro Arg Leu Ser Pro Leu Ala Gly Thr Ala 3555 3560 3565 Thr Glu Ala Met Asp Glu His Pro Trp Asp Gln Asp Gly Thr Val Leu 3570 3575 3580 Ile Thr Gly Gly Thr Gly Ser Leu Gly Ala Met Leu Ala Arg His Leu 3585 3590 3595 3600 Val Ala Thr His Gly Val Arg His Leu Met Leu Ile Ser Arg Arg Gly 3605 3610 3615 Leu Asp Ala Pro Gly Ala Arg Arg Leu Gly Val Glu Leu Ala Glu Leu 3620 3625 3630 Gly Ala Gln Val Thr Ile Thr Ala Cys Asp Ala Ala Asp Gln Arg Gln 3635 3640 3645 Leu Ala Asn Val Leu Ser Glu Ile Ser Val Asp His Pro Leu Thr Ala 3650 3655 3660 Val Val His Ala Ala Gly Val Leu Asp Asp Gly Val Ile Thr Ser Leu 3665 3670 3675 3680 Thr Pro Glu Gly Leu Thr His Val Leu Arg Ala Lys Val Asp Ser Ala 3685 3690 3695 Leu Asn Leu His Gln Leu Thr Arg Asp Leu Pro Leu Ser Ala Phe Val 3700 3705 3710 Leu Phe Ser Ser Leu Ala Gly Val Met Gly Ser Ala Gly Gln Gly Asn 3715 3720 3725 Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala Ser His Arg Arg 3730 3735 3740 Ala Ala Arg Leu Pro Ala Val Ser Leu Ala Trp Gly Val Trp Glu Gln 3745 3750 3755 3760 Thr Glu Gly Met Thr Gly Gln Leu Glu Ala Thr Asp His Ala Arg Leu 3765 3770 3775 Arg Arg Ser Gly Leu Arg Pro Leu Ala Ile Ser Glu Gly Leu Glu Leu 3780 3785 3790 Phe Asp Lys Ala Leu Ser Cys Gly His Ala Leu Val Val Pro Ala Ala 3795 3800 3805 Leu Ser Thr Arg Glu Leu Gln Thr Ser Gly Ser Val Pro Pro Phe Leu 3810 3815 3820 Arg His Leu Thr Gly Val Ala Pro Ala Arg Pro Ser Arg Thr Arg Asp 3825 3830 3835 3840 Ala Ser Ala Gly Glu Pro Thr Ser Leu Arg Arg Arg Leu Thr Gly Leu 3845 3850 3855 Gly Pro Glu Glu Arg Leu Arg Glu Val Leu Arg Leu Val Arg Ser Arg 3860 3865 3870 Ala Ala Ala Val Leu Gly His Gly Thr Ala Glu Ser Val Pro Ala Asp 3875 3880 3885 Ser Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu Ala Ala Val Asp Leu 3890 3895 3900 Arg Asn Arg Leu Gln Gln Ala Thr Gly Leu Arg Leu Pro Ala Gly Leu 3905 3910 3915 3920 Ile Phe Asp Arg Pro Arg Pro Asp Val Leu Ala Arg Phe Leu Cys Asp 3925 3930 3935 Glu Leu Ala Gly Ala Gly Gly Thr Ser Ala Ala Thr Ala Ala Pro Pro 3940 3945 3950 Val Ala Ala Gly Gly Gly Gly Gly Arg Gly Gly Ala Gly Gly His Arg 3955 3960 3965 Arg His Gly Met Pro Val Ser Gly Arg Cys Ala Val Gly Arg Gly Pro 3970 3975 3980 Val Gly Ser Gly Arg Leu Arg Tyr Gly Arg Val Gly Asp Phe Pro Ala 3985 3990 3995 4000 Asp Arg Gly Trp Glu Val Glu Arg Leu Tyr Asp Pro Asp Pro Asp Arg 4005 4010 4015 Thr Gly Thr Ser Tyr Thr Arg Gln Gly Gly Phe Leu Tyr Asp Ala Gly 4020 4025 4030 Glu Phe Asp Ala Ala Phe Phe Gly Ile Gly Pro Arg Glu Ala Val Ala 4035 4040 4045 Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Ile Ser Trp Glu Ala Leu 4050 4055 4060 Glu Arg Ala Gly Ile Asp Pro Ala Ser Leu Arg Gly Ser Ser Thr Gly 4065 4070 4075 4080 Val Phe Ala Gly Val Met Tyr His Asp Tyr Gly Thr Arg Leu Arg Glu 4085 4090 4095 Ile Pro Glu Gly Tyr Glu Gly Tyr Ile Gly Asn Gly Asn Ala Gly Ser 4100 4105 4110 Val Ala Ser Gly Arg Val Ala Tyr Thr Phe Gly Leu Glu Gly Pro Ala 4115 4120 4125 Val Thr Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu 4130 4135 4140 Ala Cys Gln Ala Leu Arg Ser Gly Glu Cys Ser Met Ala Leu Ala Gly 4145 4150 4155 4160 Gly Val Thr Val Met Ser Thr Pro Thr Thr Phe Val Glu Phe Ser Arg 4165 4170 4175 Gln Arg Gly Leu Ala Pro Asp Gly Arg Cys Lys Ser Phe Gly Ala Gly 4180 4185 4190 Ala Asp Gly Thr Gly Trp Ala Glu Gly Ala Gly Met Leu Leu Val Glu 4195 4200 4205 Arg Leu Ser Asp Ala Arg Arg Asn Gly His Arg Val Leu Ala Val Val 4210 4215 4220 Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala 4225 4230 4235 4240 Pro Asn Gly Pro Ser Gln Glu Arg Val Ile Arg Gln Ala Trp Ala Asn 4245 4250 4255 Ala Gly Val Ala Ala Met Asp Ile Asp Ala Val Glu Gly His Gly Thr 4260 4265 4270 Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Gly Thr 4275 4280 4285 Tyr Gly Gln Gly Arg Ser Ala Asp Arg Pro Leu Trp Leu Gly Ser Ile 4290 4295 4300 Lys Ser Asn Val Gly His Thr Gln Ala Ala Ala Gly Val Gly Gly Val 4305 4310 4315 4320 Ile Lys Met Val Met Ala Met Arg His Gly Leu Leu Pro Gln Thr Leu 4325 4330 4335 His Ala Glu Glu Pro Ser Pro His Val Asp Trp Ser Gly Gly Thr Val 4340 4345 4350 Arg Leu Leu Thr Glu Ser Val Ala Trp Pro Glu Gln Gly Arg Met Arg 4355 4360 4365 Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val 4370 4375 4380 Ile Leu Glu Gln Ala Pro Pro Ala Ala Glu Thr His Glu Pro Ala Glu 4385 4390 4395 4400 Pro Asn Thr Ala Pro Gly Pro Leu Pro Trp Ala Ile Ser Ala Lys Ser 4405 4410 4415 Pro Gln Ala Leu Arg Ala Gln Ala Arg Gln Leu His Thr Tyr Leu Thr 4420 4425 4430 Asn Ala Pro Glu Ala Asn Pro Ala Asp Val Gly His Thr Leu Ala Thr 4435 4440 4445 Gly Arg Ala Ser Phe Glu His Arg Ala Val Val Ile Gly Ser Asp Arg 4450 4455 4460 Ala Glu Phe Leu Gly Gly Leu Asp Ala Leu Ala Ala Asp Glu Ala His 4465 4470 4475 4480 Thr Ala Val Val Thr Gly Ile Ala Arg Lys Ala Gly Asp Gln Gly Lys 4485 4490 4495 Val Val Phe Val Phe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met Gly 4500 4505 4510 Leu Arg Leu Leu Lys Thr Ser Pro Val Phe Ala Gln Ser Ile Gln Ala 4515 4520 4525 Cys Glu Gln Ala Leu Ala Pro His Thr Asp Trp Thr Leu Thr Asp Ile 4530 4535 4540 Leu His Arg Pro His Thr Asp Pro Leu Trp Gln Arg Ala Asp Val Ile 4545 4550 4555 4560 Gln Pro Val Leu Phe Ala Leu Met Thr Ser Leu Ala Ala Leu Trp Gln 4565 4570 4575 Ser His Gly Leu Asn Pro Asp Ala Val Ile Gly His Ser Gln Gly Glu 4580 4585 4590 Ile Thr Ala Ala His Ile Ser Gly Ala Leu Ser Leu Glu Asp Ala Ala 4595 4600 4605 Lys Thr Val Ala Leu Arg Ser Arg Ala Leu Gln Thr Leu Arg Gly Ser 4610 4615 4620 Gly Gly Met Ala Ser Val Pro Leu Pro Ala Asp Glu Val Thr Gly Leu 4625 4630 4635 4640 Leu Arg Thr Gly Leu Ser Gly Gly Gly Ala Pro Pro Pro Ala Thr Val 4645 4650 4655 Ile Ser Gly Asn Ala Glu Ala Leu Thr Gln Ala Leu Glu His Tyr Arg 4660 4665 4670 Asp Gln Gly Val Asp Ala Lys Arg Ile Pro Val Asp Tyr Ala Ser His 4675 4680 4685 Cys Pro His Ile Gln Ala Val Glu Gln Glu Leu Ser Arg Leu Leu Arg 4690 4695 4700 Gly Ile Thr Pro Arg Ala Ala Thr Thr Pro Phe Tyr Ser Thr Thr Asp 4705 4710 4715 4720 Asn Gln Trp Thr Asp Thr Thr Thr Leu Asn Ala His Tyr Trp Tyr Arg 4725 4730 4735 Asn Leu Arg Gln Pro Val His Leu Ala Asp Ala Ile Thr Asn Leu Thr 4740 4745 4750 His Gln Gly His His Thr Phe Ile Glu Ile Ser Pro His Pro Thr Leu 4755 4760 4765 Thr Pro Ala Ile Gln Glu Thr Thr Asp Thr Thr His Thr Pro Thr Thr 4770 4775 4780 Val Ile Ser Thr Leu Arg Arg Asn His Asn Asp Thr His Gln Ile Leu 4785 4790 4795 4800 His Ala Leu Ala His Ala His Thr Thr Gly His Pro Ile Asn Trp His 4805 4810 4815 Thr Thr His Gln His His Thr Pro Thr Pro Gln His Ile Asp Leu Pro 4820 4825 4830 Thr Tyr Pro Phe Gln His His His Tyr Trp Leu Asn Thr Pro Thr Gln 4835 4840 4845 Thr Gly Asp Ala Ala Ala Val Gly Leu Asp Pro Ala His His Pro Leu 4850 4855 4860 Leu Gly Ala Ala Val Ala Val Ala Glu Gly Glu Gly Tyr Leu Leu Thr 4865 4870 4875 4880 Gly Arg Leu Ala Leu Ser Thr His Pro Trp Leu Ala Asp His Thr Ile 4885 4890 4895 Ala Gly Ala Val Val Leu Pro Gly Thr Ala Leu Leu Glu Ile Ala Leu 4900 4905 4910 Gln Ala Gly His Arg Val Asp Cys Trp Arg Ile Glu Glu Leu Thr Leu 4915 4920 4925 Gln Ser Pro Leu Phe Ile Pro Glu Glu Gly Ala Val Gln Val Gln Ala 4930 4935 4940 Trp Val Ala Ala Pro Asp Glu Asn Gly Cys Arg Ser Leu Thr Val Ser 4945 4950 4955 4960 Ser Arg Arg Glu Gly Thr Tyr Glu Asp Ala Thr Trp Val Arg His Ala 4965 4970 4975 Thr Gly Arg Val Gly Pro Ala Pro Ala Asp Gln Asp Glu Ala Ile Ala 4980 4985 4990 Arg Leu Thr Asp Pro Gln Gly Asp Gly Ala Ala Ala Ala Val Trp Pro 4995 5000 5005 Pro Gln Gly Ala Val Ala Phe Thr Ala Asp Asp Leu Glu Gly Leu Tyr 5010 5015 5020 Asp Gly Tyr Ala Ala Arg Gly Phe Glu Tyr Gly Pro Val Phe Arg Gly 5025 5030 5035 5040 Leu Arg Ala Ala Trp Arg Arg Gly Glu Asp Ile Phe Ala Glu Val Arg 5045 5050 5055 Leu Pro Asp Thr Ala Asp Gly Asp Ala Ser Gln Phe Ser Val His Pro 5060 5065 5070 Ala Leu Leu Asp Ala Ala Leu His Ala Ala Ala Phe Arg Pro Ala Asp 5075 5080 5085 Lys Leu Pro His Gly Ala Leu Pro Phe Ser Phe Ser Gly Val Arg Leu 5090 5095 5100 His Gly Pro Gly Ala Ser Thr Leu Arg Val Arg Leu Thr Pro Asp Gly 5105 5110 5115 5120 Gln Ala Arg Asp Thr His Ala Trp Ser Val Ala Val Val Asp Gly Glu 5125 5130 5135 Gly Arg Pro Val Ala Ser Ile Ala Ser Leu Ala Val Arg Pro Val Ser 5140 5145 5150 Thr Gln Glu Leu Leu Ala Ala Ser Gly Thr Ala Arg Arg Asp Ser Leu 5155 5160 5165 Phe Ala Val Glu Trp Val Thr Ala Leu Ala Pro Thr Ser Ser Ser Val 5170 5175 5180 Pro Gln Arg Leu Ala Thr Val Gly Pro Ser Asp Arg Leu Pro Ser Ala 5185 5190 5195 5200 Asp Ala Tyr Ala Asn Leu Ala Asp Leu Ala Ala Ala Val Leu Glu Ala 5205 5210 5215 Gly Ala Pro Ala Pro Asp Ala Val Val Val Asp Cys Gly Arg Arg Asp 5220 5225 5230 Ala Arg Ala Thr Ala Val Pro Glu Asp Val Arg Thr Leu Thr Arg Arg 5235 5240 5245 Ile Leu Gly Leu Leu Gln Glu Trp Leu Ala Asp Glu Arg Pro Ala Ser 5250 5255 5260 Ser Arg Met Val Val Leu Thr Arg Gly Ala Val Ala Thr Thr Pro Gly 5265 5270 5275 5280 Glu Asp Val Ala Asp Leu Ala Gly Ala Ala Val Cys Gly Met Val Arg 5285 5290 5295 Ser Ala Gln Ser Glu His Pro Gly Arg Phe Val Leu Leu Asp Leu Asp 5300 5305 5310 Pro Asp Pro Asp Leu Asp Gly Gly Glu Val Pro Pro Thr Val Val Pro 5315 5320 5325 Ala Ala Leu Ala Cys Gly Glu Pro Gln Ile Ala Val Arg Ala Asn Arg 5330 5335 5340 His Leu Val Pro Arg Leu Thr Arg Val Pro Ala Ser Val Pro Val Pro 5345 5350 5355 5360 Gly Arg Val Pro Val Pro Ala Ala Glu Ala Ala Asp Pro Asp Thr Thr 5365 5370 5375 Pro Thr Ala Phe Asp Pro Asp Gly Thr Val Val Ile Thr Gly Gly Thr 5380 5385 5390 Gly Thr Leu Gly Ala Met Leu Ala Arg His Leu Val Ser Arg His Gly 5395 5400 5405 Val Arg His Leu Leu Leu Ala Ser Arg Arg Gly Pro Asp Ala Pro Gly 5410 5415 5420 Ala Thr Glu Leu Arg Ala Glu Leu Ala Glu Leu Gly Ala Glu Val Thr 5425 5430 5435 5440 Val Arg Ala Cys Asp Thr Gly Asp Arg Gly Ala Leu Ala Asp Leu Ile 5445 5450 5455 Ala Gly Ile Pro Thr Gly His Pro Leu Thr Gly Val Val His Ala Ala 5460 5465 5470 Gly Val Leu Asp Asp Ala Thr Val Ala Ser Leu Thr Pro Arg His Leu 5475 5480 5485 Asp Thr Ala Leu Thr Pro Lys Ala Asp Ala Ala Phe His Leu His Glu 5490 5495 5500 Leu Thr Arg His Ala Arg Pro Arg Ala Phe Val Leu Phe Ser Ser Ala 5505 5510 5515 5520 Ala Gly Val Leu Gly Ala Ala Gly Gln Gly Asn Tyr Ala Ala Ala Asn 5525 5530 5535 Ala Phe Leu Asp Ala Leu Ala Glu His Arg Arg Ala Gln Gly Leu Pro 5540 5545 5550 Ala Leu Ser Leu Ala Trp Gly Leu Trp Glu Gln Gly Ser Gly Met Thr 5555 5560 5565 Gly His Leu Asp Arg Thr Asp Arg Ala Arg Ile Asn Arg Ser Gly Leu 5570 5575 5580 Ala Pro Leu Ala Thr Glu Asp Ala Leu Ala Leu Phe Asp Ala Ala Leu 5585 5590 5595 5600 Ala Gly Asp Arg Pro Phe Leu Val Pro Ala Arg Leu Asp Leu Arg Gly 5605 5610 5615 Ser Ser Ala Ala Glu Thr Pro Ala Pro Leu Phe Ser Arg Ile Ala Pro 5620 5625 5630 Ala Arg Thr Thr Arg Gly Arg Ser Pro Gly Ala Glu Gly Ala Ala Asp 5635 5640 5645 Leu Arg Thr Arg Leu Ala Ala Gln Asp Ala Ala Glu Gln Arg Asp Thr 5650 5655 5660 Leu Leu Thr Ile Val Arg Thr His Thr Ala Ala Val Leu Gly His Asp 5665 5670 5675 5680 Thr Ala Ala Ala Val Arg Pro Asp Gly Ala Phe Arg Glu Leu Gly Phe 5685 5690 5695 Asp Ser Leu Ala Ala Val Glu Leu Arg Asn Arg Leu Gln Thr Thr Thr 5700 5705 5710 Ala Leu Thr Leu Pro Ala Thr Thr Val Phe Asp His Pro Thr Pro Ala 5715 5720 5725 Ala Leu Ala Asp His Leu Arg Thr Gln Leu Cys Gln Asp Ala Gln Ser 5730 5735 5740 Ser Ala Ala Ala Thr Ala Met Ala Ala Met Ala Glu Leu Ala Arg Leu 5745 5750 5755 5760 Glu Ser Ala Val Ser Asp Ser Val Ala Leu Asp Asp Asp Thr Arg Ser 5765 5770 5775 Gly Leu Ala Glu Arg Leu Arg Ser Leu Ala Arg Lys Met Ser Ser Gly 5780 5785 5790 Arg Val Val Asp His Asp Gly Gly Gly Ala Ala Asp Leu Asp Leu Gln 5795 5800 5805 Ser Val Thr Asp Asp Glu Met Phe Glu Leu Ile Asp Lys Glu Val Ser 5810 5815 5820 Arg Asp 5825 <210> 17 <211> 419 <212> PRT <213> Artificial Sequence <220> <223> mil-AT0 of Streptomyces milbemycinicus <400> 17 Leu Pro Lys Ala Gln Asn Glu Phe Ala Val Ala Gly His Pro Trp Ile 1 5 10 15 Leu Ser Gly His Thr Gly Thr Ala Leu Arg Ala Gln Ala Arg Arg Leu 20 25 30 His Asp His Val Ala Asp His Pro Arg Leu Arg Pro Glu Asp Ile Ala 35 40 45 His Thr Leu Ala Ser Ser Gly Pro Ala Leu Thr His Arg Ala Ala Val 50 55 60 Ile Ala Ala Asp Arg Glu Gly His Leu Arg Gly Leu Asp Ala Val Ala 65 70 75 80 Arg Gly Glu Asp Thr Pro Gly Val Val Arg Gly Thr Ala Ala Ala Gly 85 90 95 Gly Asp Gly Val Ala Phe Val Phe Pro Gly Gln Gly Thr Gln Trp Pro 100 105 110 Gly Met Ala Ala Asp Leu Leu Thr Val Ser Pro Ala Phe Ser Arg Ala 115 120 125 Val Asp Ala Cys Ala Glu Ala Phe Glu Pro Tyr Val Ser Trp Ser Pro 130 135 140 Glu Ala Val Leu Arg Gly Ala Pro Gly Ala Pro Pro Leu Glu Gly Thr 145 150 155 160 Asp Val Val Gln Pro Thr Leu Phe Ala Val Met Val Gly Leu Ala Glu 165 170 175 Leu Trp Arg Thr Leu Gly Val Ser Pro Thr Ser Ile Val Gly His Cys 180 185 190 Ile Gly Glu Ile Ala Ala Ala His Leu Cys Gly Ala Leu Ser Leu Ser 195 200 205 Asp Ala Ala Arg Val Val Ile Glu Ser Ser Arg Ala Gln Ala Thr Leu 210 215 220 Ser Gly Ser Gly Ala Leu Ile Ala Val Ala Arg Ser Glu Ala Gln Leu 225 230 235 240 Leu Pro Leu Leu Arg Arg Trp Pro Gly Arg Leu Thr Ile Ala Ala Val 245 250 255 Asn Gly Pro Met Ala Thr Val Val Ser Gly Asp Arg Pro Ala Ala Asp 260 265 270 Glu Leu Leu Ala Glu Phe Ala Arg Ala Gly Val Arg Ala Arg Glu Val 275 280 285 Ala Ile Asp Ile Pro Ala His Ser Pro Phe Met Ala Pro Leu Arg Asp 290 295 300 Gly Leu Leu Asp Ser Leu Ser Ser Val Thr Ala Gly Ala Ser Arg Leu 305 310 315 320 Pro Phe His Ser Ser Val Ile Gly Gly Pro Leu Glu Thr Gln Gly Leu 325 330 335 Asp Ala Ala Tyr Trp Tyr Arg Asn Leu Ala Asp Thr Val Arg Phe Glu 340 345 350 Ser Val Val Thr Gly Leu Leu Arg Gln Gly Thr Arg Cys Phe Val Glu 355 360 365 Leu Ser Pro His Pro Met Leu Thr Met Cys Val Gln Ala Thr Ala Glu 370 375 380 Glu Val Val Gly Gly Glu Arg Val Val Ile Leu Pro Thr Leu His Arg 385 390 395 400 Gly Gln Ala Ala Val Glu Ser Val Arg Thr Thr Leu Ala Glu Leu Tyr 405 410 415 Val Arg Gly <210> 18 <211> 410 <212> PRT <213> Artificial Sequence <220> <223> mei-AT0 of Streptomyces nanchangensis <400> 18 Val Ala Gly His Pro Trp Ile Leu Ser Gly His Thr Gly Thr Ala Leu 1 5 10 15 Arg Ala Gln Ala Arg Arg Leu His Asp His Val Ala Asp His Pro Leu 20 25 30 Leu Arg Pro Glu Asp Ile Ala His Thr Leu Ala Ser Gly Gly Pro Ala 35 40 45 Leu Thr His Arg Ala Ala Val Ile Ala Ala Asp Arg Glu Gly Tyr Leu 50 55 60 Arg Gly Leu Asp Ala Val Ala Arg Gly Glu Asp Ala Pro Gly Val Val 65 70 75 80 Arg Gly Thr Ala Thr Ala Val Gly Asp Gly Val Ala Phe Val Phe Pro 85 90 95 Gly Gln Gly Thr Gln Trp Pro Gly Met Ala Ala Asp Leu Leu Thr Val 100 105 110 Ser Pro Ala Phe Ser Arg Ala Val Asp Ala Cys Ala Glu Ala Phe Glu 115 120 125 Pro Tyr Val Pro Trp Ser Pro Glu Ala Val Leu Arg Gly Ala Pro Gly 130 135 140 Ala Pro Pro Leu Glu Gly Thr Asp Val Val Gln Pro Thr Leu Phe Ala 145 150 155 160 Val Met Val Gly Leu Ala Glu Leu Trp Arg Thr Leu Gly Val Ser Pro 165 170 175 Thr Thr Ile Val Gly His Cys Ile Gly Glu Ile Ala Ala Ala His Leu 180 185 190 Cys Gly Ala Leu Ser Leu Ser Asp Ala Ala Arg Val Val Ile Glu Ser 195 200 205 Ser Arg Ala Gln Ala Thr Leu Ser Gly Ser Gly Ala Leu Ile Ala Val 210 215 220 Ala Arg Ser Glu Ala Gln Leu Leu Pro Leu Leu Arg Arg Trp Pro Gly 225 230 235 240 Arg Leu Thr Ile Ala Ala Val Asn Gly Pro Met Ala Thr Val Val Ser 245 250 255 Gly Asp Arg Pro Ala Ala Asp Glu Leu Leu Ala Glu Leu Ala Arg Ala 260 265 270 Gly Val Arg Ala Arg Glu Val Ala Ile Asp Ile Pro Ala His Ser Ala 275 280 285 Phe Met Ala Pro Leu Arg Asp Gly Leu Leu Asp Ser Leu Ser Ser Val 290 295 300 Thr Ala Gly Ala Ser Arg Leu Pro Phe His Ser Ser Val Ile Gly Gly 305 310 315 320 Pro Leu Glu Thr Gln Gly Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu 325 330 335 Ala Asp Thr Val Arg Phe Glu Ser Val Val Thr Gly Leu Leu Arg Gln 340 345 350 Gly Thr Arg Cys Phe Val Glu Leu Ser Pro His Pro Met Leu Thr Met 355 360 365 Cys Val Gln Ala Thr Ala Glu Glu Val Val Gly Gly Glu Arg Val Val 370 375 380 Ile Leu Pro Thr Leu His Arg Gly Gln Ala Ala Val Glu Ser Val Arg 385 390 395 400 Thr Thr Leu Ala Glu Leu Tyr Val Arg Gly 405 410 <210> 19 <211> 34 <212> DNA <213> Artificial Sequence <220> <223> AF-XNF primer <400> 19 gccctctaga tgcatagtga cggcaacggg aata 34 <210> 20 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Mm1-HR primer <400> 20 gattacgcca agcttacgta atccgacggc ttg 33 <210> 21 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V292L-F primer <400> 21 cggtcgacct ccccgcgcac tcg 23 <210> 22 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V292L-R primer <400> 22 cggggaggtc gaccgccacc tcg 23 <210> 23 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V292V-F primer <400> 23 cggtcgacgt ccccgcgcac tcg 23 <210> 24 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V292V-R primer <400> 24 cggggacgtc gaccgccacc tcg 23 <210> 25 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V-F primer <400> 25 cggtcgacat ccccgcgcac tcg 23 <210> 26 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V-R primer <400> 26 cggggatgtc gaccgccacc tcg 23 <210> 27 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> 290V292M-F primer <400> 27 cggtcgacat gcccgcgcac tcg 23 <210> 28 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> 290V292M-R primer <400> 28 cggtcgacct ccccgcgcac tc 22 <210> 29 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> M1O408F primer <400> 29 cgaaccgtat gtctcctgg 19

Claims (8)

  1. 스트렙토마이세스 아베르미틸리스 균주에서,
    (1) 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 1번 유전자(aveA1 유전자)가, 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소의 시작 모듈의 변형된 아실트랜스퍼라제 도메인 (AT0 도메인)을 포함하는 변형 밀베마이신 폴리케타이드 합성효소를 암호화하는 변형 폴리케타이드 합성효소 유전자군의 1번 유전자 (m_milA1 유전자)로 치환되고, 이 때, 상기 변형된 AT0 도메인은 (i) 서열번호 17에서 Ile290가 발린(Val)으로 치환되고 Ile292가 발린(Val) 또는 류신(Leu)으로 치환된 아미노산 서열, 또는 (ii) 서열번호 18에서 Ile281이 발린(Val)으로 치환되고 Ile283이 발린(Val) 또는 류신(Leu)으로 치환된 아미노산 서열을 포함하는 것이며,
    (2) 아베멕틴 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자 (aveA3 유전자)의 전부 또는 일부가 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소 유전자군의 3번 유전자의 전부 또는 일부로 치환된,
    재조합 스트렙토마이세스 아베르미틸리스 균주.
  2. 제1항에 있어서, 상기 밀베마이신 생산 균주는 스트렙토마이세스 밀베마이시니쿠스 (Streptomyces milbemycinicus), 스트렙토마이세스 난찬젠시스(Streptomyces nanchangensis), 또는 스트렙토마이세스 빙첸젠시스(Streptomyces bingchenggensis)인, 재조합 스트렙토마이세스 아베르미틸리스 균주.
  3. 다음에서 선택된 재조합 스트렙토마이세스 아베르미틸리스 균주:
    수탁번호 KCTC13325BP의 스트렙토마이세스 아베르미틸리스 LB-50005 균주; 및
    수탁번호 KCTC13326BP의 스트렙토마이세스 아베르미틸리스 LB-50006 균주.
  4. 제1항 내지 제3항 중 어느 한 항의 재조합 스트렙토마이세스 아베르미틸리스 균주를 포함하는, 밀베마이신 생산용 조성물.
  5. 제4항에 있어서, 상기 재조합 스트렙토마이세스 아베르미틸리스 균주가 생산하는 밀베마이신 중의 밀베마이신 D의 비율이 50중량% 이상인, 밀베마이신 생산용 조성물.
  6. 제1항 내지 제3항 중 어느 한 항의 재조합 스트렙토마이세스 아베르미틸리스 균주를 배양하는 단계; 및
    상기 배양된 균주 또는 균주의 배양물로부터 밀베마이신을 수득하는 단계를 포함하는,
    밀베마이신 생산 방법.
  7. 밀베마이신 생산 균주에서 밀베마이신 생합성을 수행하는 폴리케타이드 합성효소에 있어서, 서열번호 17에서 Ile290가 발린(Val)으로 치환되고 Ile292가 발린(Val) 또는 류신(Leu)으로 치환된 아미노산 서열, 또는 서열번호 18에서 Ile281이 발린(Val)으로 치환되고 Ile283이 발린(Val) 또는 류신(Leu)으로 치환된 아미노산 서열을 포함하는 변형 AT0 도메인을 포함하는, 변형 밀베마이신 폴리케타이드 합성효소를 암호화하는 변형 폴리케타이드 합성효소 유전자군의 1번 유전자 (m_milA1 유전자)를 포함하는, 재조합 벡터.
  8. 제7항에 있어서, 상기 밀베마이신 생산 균주는 스트렙토마이세스 밀베마이시니쿠스 (Streptomyces milbemycinicus), 스트렙토마이세스 난찬젠시스(Streptomyces nanchangensis), 또는 스트렙토마이세스 빙첸젠시스(Streptomyces bingchenggensis)인, 재조합 벡터.
KR1020170119833A 2017-09-18 2017-09-18 밀베마이신 d를 생산하는 재조합 미생물 및 밀베마이신 d 생산 방법 KR102017788B1 (ko)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
KR940011630A (ko) * 1992-11-30 1994-06-21 리로이 휘테커 구충제 화합물 제조용의 스트렙토마이세스 균주 및 이의 사용방법
KR20170035346A (ko) * 2015-09-22 2017-03-30 주식회사 팜한농 밀베마이신을 생산하는 재조합 미생물 및 이를 이용한 밀베마이신 생산 방법

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KR940011630A (ko) * 1992-11-30 1994-06-21 리로이 휘테커 구충제 화합물 제조용의 스트렙토마이세스 균주 및 이의 사용방법
KR20170035346A (ko) * 2015-09-22 2017-03-30 주식회사 팜한농 밀베마이신을 생산하는 재조합 미생물 및 이를 이용한 밀베마이신 생산 방법

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