KR20210041049A - 최적화된 3-피타아제, 및 식품 또는 사료에서의 이의 용도 - Google Patents

최적화된 3-피타아제, 및 식품 또는 사료에서의 이의 용도 Download PDF

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KR20210041049A
KR20210041049A KR1020217006844A KR20217006844A KR20210041049A KR 20210041049 A KR20210041049 A KR 20210041049A KR 1020217006844 A KR1020217006844 A KR 1020217006844A KR 20217006844 A KR20217006844 A KR 20217006844A KR 20210041049 A KR20210041049 A KR 20210041049A
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헬게 요헨스
프랑크 발랍
미하엘 회슬
토마스 아이젤
루츠 뢰허
가비 겝하르트-바이들
마틴 그레버
베르너 스튜머
외르그 클라렌
티모시 오코넬
마틴 샤테
크리스토프 라이징어
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Abstract

본 발명은 서열번호 2의 서열과 하나 이상의 돌연변이를 포함하는, 3-피타아제에 대해 적어도 95%의 서열 동일성을 갖는 생물학적 효능이 있는 피타아제 돌연변이체인, 최적화된 3-피타아제(서열번호 1)에 관한 것이다. 또한, 본 발명은 식품 또는 사료 제품의 제조에 있어서 이러한 최적화된 3-피타아제의 용도에 관한 것이다.

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최적화된 3-피타아제, 및 식품 또는 사료에서의 이의 용도
본 발명은 서열번호 2의 서열 및 하나 이상의 돌연변이를 포함하는, 3-피타아제에 대해 적어도 95%의 서열 동일성을 갖는, 생물학적 효능이 있는 피타아제 돌연변이체인, 최적화된 3-피타아제(서열번호 1)에 관한 것이다. 또한, 본 발명은 식품 또는 사료 제품의 제조에 있어서 이러한 최적화된 3-피타아제의 용도에 관한 것이다.
피타아제는 피테이트와 피트산과 같은 유기포스페이트 화합물로부터 각각 포스페이트를 제거하는 효소이다. 여러가지 종류의 피타아제들이 당업계에 공지되어 있고, 이들 중 일부는 옥수수, 밀 및 대두와 같은 동물성 사료 물질 내에 본래 존재하는 피테이트의 대사 및 활용을 개선시키기 위해서 이미 동물성 사료 제품에 첨가제로서 사용되고 있다. 피타아제의 분류는 우선 피테이트 분자의 포스페이트의 절단 출발 위치에 따라 좌우된다. 3-피타아제 (E.C. 3.1.3.8, 다음과 같이 불리기도 함: 1-피타아제; 미오-이노시톨-헥사키스포스페이트 3-포스포하이드롤라제; 피테이트 1-포스파타아제 또는 피테이트 3-포스파타아제)는 피테이트 분자의 3번 위치에서 포스페이트 절단이 시작된다. 6-피타아제는 6번 위치에서 포스페이트 절단이 시작된다. 피타아제의 종류에 따라서, 다른 위치들의 추가의 포스페이트 절단이 일어날 수 있다. 예를 들어, 3-피타아제는 피테이트의 모든 포스페이트기를 절단할 수 있다.
식품 또는 사료에 피타아제를 첨가하게 되면, 포스페이트는 인간 또는 동물의 식이에 있어서 중요한 성분이므로, 해당 식품 또는 사료의 천연 피테이트 물질에 대한 더 우수한 대사작용이 가능할 뿐만 아니라, 배설물에서 잔류 인의 감소를 유도할 수도 있다. 배설물의 높은 인 함량때문에, 통상적으로 배설물의 비료로서의 사용에 대해서는 여러 나라에서 그러하듯이 엄격한 제한을 두고 있는 실정이다.
불충분한 천연 피테이트 대사 및 비용이 많이 드는 식품 또는 사료의 인공적인 인 농축화 (이 역시 비료의 잔류 인 함량을 매우 증가시키는 것으로 알려짐)의 상기 단점을 극복하기 위해서, 위와 소화관에서 피테이트 대사를 증가시키는 방편으로 이미 피타아제를 식품 또는 사료 제품에 도입하여 사용해 왔었다.
현재 시판중인 이러한 피타아제의 예로는 에쉐리키아 콜라이 (Escherichia coli), 시트로박터 브라아키(Citrobacter braakii), 부티아욱셀라 종(Buttiauxella sp.) 및 아스퍼길루스 니거(Aspergillus niger)로부터 유래된다.
이러한 각 피타아제 제품들은 적어도 특유의 활성, 용량 요건, 반응 시간 및 억제성 중간체 화합물의 축적에 있어서 제약이 있다. 이러한 종류의 최초 제품은 목적하는 효과를 달성하기 위해 높은 효소 투여량이 요구되는 진균성 3-피타아제를 포함하였다. 현재 시판중인 시판 사료 제품들은 박테리아 기원의 6-피타아제를 사용함으로써 이러한 효과를 넘어서고자 하였다. 그러나, 이러한 6-피타아제의 심각한 단점은 중간체 화합물인 이노시톨-테트라포스페이트의 축적인데, 이 때문에 효과적인 피테이트 대사에 매우 제약이 따르게 된다. 또한, 피테이트 및 이의 중간체, 특히 이노시톨-테트라포스페이트는 Ca2+, Zn2+ 및 Mg2+와 같은 2가 이온을 갖는 복합체를 형성한다. 추가로, 당업계에 공지된 여러가지 피타아제 제품들은, 인간 또는 동물 위에서 최대 1.5시간의 식품 또는 사료의 실제 임계 체류 시간과 관련하여 충분한 포스페이트 방출을 위해 다량의 피타아제의 사용이 필요하다.
여러가지 요인들이 인간 또는 동물의 소화관에서 피타아제 기능과 이들의 생체내 피타아제 효소 활성에 영향을 미친다. 예컨대 돼지의 경우, 사료용 피타아제는 위와 소장 상부에서 주로 활성인 상태로, 첨가된 피타아제 활성은 회장에서는 복구되지 않는다. 예컨대 가금류에서는, 사료용 피타아제 활성은 소낭, 선위 및 근위를 포함하는 소화관의 상부에서 주로 나타난다. 예를 들어 위가 있는 물고기의 경우, 피타아제 활성은 주로 위에서 나타난다. 여러가지 요인들이 위장관에서 식품 또는 사료 피타아제의 효율성에 영향을 미칠 수 있는데, 이들을 (i) 피타아제 관련; (ii) 식이 관련 및 (iii) 대상체 관련의 3가지의 주요 그룹으로 나눌 수 있다. 피타아제 관련 요인으로는 피타아제의 종류 (예컨대, 3- 또는 6-피타아제; 박테리아 또는 진균성 피타아제 기원), 최적 pH 및 내인성 프로테아제에 대한 해당 피타아제의 내성이 포함된다. 식이 관련 요인은 식이 피테이트 함량, 식품 또는 사료 성분 조성과 식품 또는 사료 가공처리, 및 P, Ca 및 Na 총함량과 주로 관련이 있다. 대상체 관련 요인으로는 해당 대상체의 종, 성별 및 연령을 포함한다 (Yueming Dersjant-Li et al., J. Sci. Food Agric., 2015 Mar 30; 95(5): 878-896).
식품과 사료는 각각, 일반적으로 예컨대 오염도를 줄이기 위해 고온에서 제조되며, 그 결과 식품 및/또는 사료 제조에 사용되는 피타아제는 열안정성이 있어야 한다.
따라서, 광범위한 pH 값에 대하여 작용하여 위 뿐만 아니라 상부 장에서도 활성인 동시에 고온에서도 안정적인 피타아제가 필요한 실정이다.
본 발명은 이러한 간극을 메워서, 예상치 못한 놀라운 온도 및 pH 안정성을 유도하는 돌연변이를 포함하는 3-피타아제 돌연변이체, 예컨대 박테리아 3-피타아제 돌연변이체로서, 상기 3-피타아제가 활성 상태이고 포스페이트 절단에 있어 매우 효율적인 것인, 3-피타아제 돌연변이체를 제공한다.
본 발명은 서열번호 1에 대해 적어도 96.25%의 서열 동일성을 갖는, 3-피타아제 돌연변이체와 같은 생물학적 효능이 있는 피타아제 돌연변이체로서, 상기 돌연변이체가 서열번호 2의 서열과, D149N, S189D, K190N, K191N, R210Q, L211E, L211M, K25E, K25A, G26N, G26S, N193H, N193K, N193S, N193R, D1E, P3T, G26K, K29A, T30S, T30A, T30K, D36N, Q45N, Q45R, V58E, S75C, Q76R, P107S, A112G, D120K, T129K, Q136R, Q144L, D149N, K187E, D189N, G192R, S195R, S195Y, S195T, S195N, N204I, N204T, N204S, S214A, N216D, A230T, M237L, N243K, N248K, R255H, G257S, F264Y, A275P, D276G, K295Y, K295M, Q332D, A352S, V383M, R393H, A395T 및 이들의 조합으로 이루어진 군으로부터 선택된 돌연변이를 포함하는 것인, 피타아제 돌연변이체에 대한 것이다.
본 발명의 생물학적 효능이 있는 피타아제 돌연변이체는, 예를 들어 돌연변이 D149N, S189D, K190N 및 K191N, 또는 R210Q 및 L211M, 또는 K25E 또는 K25A, 및 G26N 또는 G26S, 및 N193S 또는 N193R; 또는 D149N, S189D, K190N, K191N, R210Q, L211M, K25E 또는 K25A, 및 G26N 또는 G26S, 및 N193S 또는 N193R을 포함한다.
본 발명의 생물학적 효능이 있는 피타아제 돌연변이체는 예를 들어 25, 26, 193, 210 및/또는 211번 위치에 돌연변이를 포함한다.
유리한 열안정성을 나타내는 본 발명의 추가의 유리한 피타아제 돌연변이체는 돌연변이 D149N, S189D, K190N 및 K191N을 포함하며, 특히 유리한 피타아제 돌연변이체는 돌연변이 K25E 또는 K25A; N193H, N193S, N193R 또는 N193K 및 L211M 또는 L211E를 추가로 포함한다. 유리한 열안정성을 나타내는 다른 유리한 피타아제 돌연변이체는 돌연변이 D149N, S189D, K190N, K191N, K25E 또는 K25A, G26S 또는 G26N, N193H, N193S, N193R 또는 N193K, R210Q 및 L211M을 포함한다. 유리한 열안정성 및 특히 우수한 포스페이트 방출을 나타내는 본 발명에 따른 특히 적절한 피타아제 돌연변이체는 돌연변이 D149N, S189D, K190N, K191N, K25E, G26S 또는 G26N, N193S, N193R 또는 N193K, R210Q 및 L211M을 포함한다.
본 발명의 생물학적 효능이 있는 피타아제 돌연변이체는, 예를 들어 90℃까지 활성 상태이며, 예를 들어 pH 3 내지 5.5에서 활성 상태이다.
본 발명의 생물학적 효능이 있는 피타아제 돌연변이체는, 예를 들어 인간 및/또는 동물에서, 예를 들어 식품 또는 사료 제품의 제조에 사용된다.
본원에 인용되거나 참조된 모든 문헌들 ("본원에 인용된 문헌들") 및 본원에 인용된 문헌들에 인용되거나 참조된 모든 문헌들은, 본원 또는 본원에 참조로 포함된 임의의 문헌들에 언급된 임의의 제품에 대한 제조업체의 지침서, 기술서, 제품 사양서 및 제품 설명서와 함께, 본원에 참조로 포함되며, 본 발명의 실시에 사용될 수 있다. 보다 구체적으로, 참조된 모든 문헌들은 각 개개의 문헌들이 구체적으로 그리고 개별적으로 참조로 포함되었던 것과 동일한 정도로 본원에 참조로 포함된다.
아래의 도면들은 본 발명을 보다 상세하게 보여주지만, 본 발명은 이러한 도면들에 한정되지는 않는다.
도 1: 서열번호 2의 3-피타아제 돌연변이체의 실제 적용 환경에서의 촉매 성능과 열안정성에 대한 척도인 IC50 값의 개선;
Figure pct00001
- 야생형 서열번호 2,
Figure pct00002
- 서열번호 47, 서열번호 4, 서열번호 6, 서열번호 7, 서열번호 8, 서열번호 10, 서열번호 14, 서열번호 19, 서열번호 20, 서열번호 21, 서열번호 26, 서열번호 28, 서열번호 29, 서열번호 30, 서열번호 31, 서열번호 34, 서열번호 1, 서열번호 37, 서열번호 38, 서열번호 39, 서열번호 40, 서열번호 41, 서열번호 45, 및 서열번호 46의 3-피타아제 돌연변이체.
도 2: pH 2 내지 5.5에서, 야생형 서열번호 2, 및 서열번호 19, 서열번호 20, 서열번호 21, 서열번호 28, 서열번호 30, 서열번호 34, 서열번호 1의 3-피타아제 돌연변이체들의 pH 프로파일
도 3: 서열번호 2와 비교한, 3-피타아제 돌연변이체인 서열번호 1, 서열번호 3, 서열번호 4, 서열번호 5, 서열번호 6, 서열번호 7, 서열번호 8, 서열번호 9, 서열번호 10, 서열번호 11, 서열번호 12, 서열번호 13, 서열번호 14, 서열번호 15, 서열번호 16, 서열번호 17, 서열번호 18, 서열번호 19, 서열번호 20, 서열번호 21, 서열번호 22, 서열번호 23, 서열번호 24, 서열번호 25, 서열번호 26, 서열번호 27, 서열번호 28, 서열번호 29, 서열번호 30, 서열번호 31, 서열번호 32, 서열번호 33, 서열번호 34, 서열번호 35, 서열번호 36, 서열번호 37, 서열번호 38, 서열번호 39, 서열번호 40, 서열번호 41, 서열번호 42, 서열번호 43, 서열번호 44, 서열번호 45, 서열번호 46, 서열번호 47의 생물학적 효능 지수.
본 발명은 피타아제 돌연변이체에 관한 것으로, 예컨대 서열번호 2의 서열 및 하나 이상, 예컨대, 적어도 2개, 적어도 3개, 적어도 4개, 적어도 5개, 적어도 6개, 적어도 7개, 적어도 8개, 적어도 9개 또는 적어도 10개의 돌연변이를 포함하거나 이로 이루어지고, 서열번호 1과 90% 내지 97%, 91% 내지 96%, 92% 내지 95%, 적어도 90%, 적어도 91%, 적어도 92%, 적어도 93%, 적어도 94%, 적어도 95%, 적어도 96.25% 또는 적어도 97%의 서열 동일성을 갖는 3-피타아제 돌연변이체에 관한 것이다.
본 발명에서, "피타아제 돌연변이체"라는 용어는, 자연에서는 그런 것들이 발생하지는 않지만 자연적으로 발생하는 피타아제 효소 서열과 비교하였을 때 적어도 하나의 아미노산의 유전적 변형의 결과로 나타난 임의의 서열을 지칭하는 것으로 이해한다.
본 발명의 3-피타아제와 같은 피타아제의 돌연변이는 D149N, S189D, K190N, K191N, R210Q, L211E, L211M, K25E, K25A, G26N, G26S, N193H, N193K, N193S, N193R, D1E, P3T, G26K, K29A, T30S, T30A, T30K, D36N, Q45N, Q45R, V58E, S75C, Q76R, P107S, A112G, D120K, T129K, Q136R, Q144L, D149N, K187E, D189N, G192R, S195R, S195Y, S195T, S195N, N204I, N204T, N204S, S214A, N216D, A230T, M237L, N243K, N248K, R255H, G257S, F264Y, A275P, D276G, K295Y, K295M, Q332D, A352S, V383M, R393H, A395T 및 이들의 조합으로 이루어진 군으로부터 선택된다. 상기 조합은 하나 이상의 돌연변이를 포함한다.
생성된 피타아제 돌연변이체는 생물학적 효능을 나타내는데, 즉 상기 피타아제 돌연변이체는 본 발명 내의 다양한 조건 하에서, 예를 들어 최대 90℃의 고온 및 예를 들어 pH 2.5 내지 5.5 범위의 산성 내지 염기성 pH 하에 계속 활성 상태로 존재한다.
이하에서는, 본 발명의 성분들을 보다 상세히 설명한다. 이러한 성분들은 특정 실시양태들과 함께 열거하지만, 이들을 임의의 방식과 임의의 수로 조합하여 추가의 실시양태들을 만들 수도 있음을 이해해야 할 것이다. 다양하게 설명된 실시예와 실시양태들은 본 발명을 명시적으로 기술된 실시양태들로만 한정하는 것으로 해석되어서는 안된다. 본 설명은 명시적으로 기술된 실시양태들을 개시된 임의의 수의 성분들과 조합하는 실시양태들을 뒷받침하며 포함하는 것으로 이해되어야 할 것이다. 또한, 본 출원에서 설명된 모든 성분들에 대한 임의의 순열과 조합들은, 문맥상 달리 설명이 있지 않는 한, 본 출원의 상세한 설명에 개시된 것으로 간주되어야 할 것이다.
본 명세서와 청구범위 전반에 걸쳐, 문맥상 달리 해석해야 할 경우가 아니라면, "포함하다"라는 단어와 "포함하는" 또는 "포함하고"와 같은 이의 변형태는, 언급된 구성요소, 정수 또는 단계, 또는 상기 구성요소, 정수 또는 단계들의 그룹을 포함하며, 임의의 다른 구성요소, 정수 또는 단계, 또는 상기 구성요소, 정수 또는 단계들의 그룹을 배제하지는 않음을 의미하는 것으로 이해해야 할 것이다. 본 발명을 설명하는 내용에서 (특히 청구범위의 내용에서) 사용되는 단수 형태 ("a", "an" 및 "the") 및 이와 유사한 언급대상은, 본원에서 달리 명시하지 않는 한, 단수와 복수를 모두 포괄하는 것으로 해석한다. 본원에서 수치 범위에 대한 언급은, 해당 범위에 속하는 각 개별 수치들을 개별적으로 언급하는 것에 대한 편법을 제공하려는 것일 뿐이다. 본원에서 달리 언급하지 않는 한, 각 개별 수치들은 이들이 본원에 개별적으로 언급되는 것처럼 본 명세서 내에 포함된다. 본원에 기술된 모든 방법들은 본원에서 달리 지시하지 않거나 문맥상 명백하게 모순되지 않는 한, 임의의 적절한 순서로 수행될 수 있다. 본원에 제시된 임의의 모든 예, 또는 예시적인 표현 (예: "예컨대", "예를 들어")의 사용은 다만 본 발명을 더 잘 설명하기 위한 것이지 그 이외의 청구된 본 발명의 범위에 제한을 두려는 것은 아니다. 본 명세서에서 어떠한 표현도 본 발명의 실시에 필수적인 임의의 청구되지 않은 구성요소를 가리키는 것으로 이해되어서는 안된다.
예를 들어 식품 또는 사료 제품의 온도, 이에 따른 식품 또는 사료 제품에 포함된 피타아제 돌연변이체의 온도는, 예를 들어 -18℃, 4℃ 또는 실온과 같은 보관 온도에 따라 크게 다른데, 예를 들어 사람 또는 동물과 같은 대상체에서의 온도는 37℃이고, 예를 들어 오염 제거 공정에서 식품 또는 사료 제품의 제조를 위한 온도는 최대 90℃이다. 본 발명의 생물학적 효능이 있는 피타아제 돌연변이체는 4℃, 10℃, 15℃, 20℃, 25℃, 28℃, 30℃, 35℃, 37℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 또는 75℃ 내지 90℃에서 안정하고 활성 상태이거나, 또는 최대 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃ 또는 90℃에서 안정하며 활성 상태이다.
또한, 사람이나 동물의 장관을 통과하는 피타아제는 서로 다른 pH 범위에 노출되는데, 예를 들어 사람의 경우 타액의 pH는 약 6.5 내지 7.5이고, 상부 위의 pH는 약 4.0 내지 6.5이며, 하부 위의 pH는 약 1.5 내지 4.0이고, 십이지장의 pH는 약 7.0 내지 8.5이며, 소장과 대장의 pH는 약 4.0 내지 7.0이다. 피테이트에서 포스페이트의 높은 절단율을 유도하는 3-피타아제 돌연변이체와 같은 고효율 피타아제 돌연변이체는 광범위한 pH 범위에서 활성화 상태이어야 한다. 본 발명의 생물학적 효능이 있는 피타아제 돌연변이체는 pH 2.5 내지 5.5, pH 3.0 내지 5.0, pH 3.5 내지 4.5, pH 3.0 내지 5.5 또는 pH 5.0 내지 5.5의 범위, 및 이전에 개시한 온도들 및 온도 범위들 중 임의의 온도에서 각각 안정하며 활성이다.
본 발명의 피타아제 및 피타아제 돌연변이체의 활성은 특정 pH에서 mmol/L의 피테이트로 나타내는 포스페이트 방출량을 측정함으로써 측정된다. 서열번호 2와 같은 참조기준과 비교하여 서로 다른 pH에서 피타아제 돌연변이체의 활성에 대한 정보를 제공하는 성능 지수는, [(pH X에서 방출된 포스페이트 [mM])돌연변이체/ pH X에서 방출된 포스페이트 [mM])참조기준]×[(pH Y에서 방출된 포스페이트 [mM])돌연변이체 / (pH Y에서 방출된 포스페이트 [mM])참조기준] (여기서, X와 Y는 서로 다른 pH 값임), 즉 예를 들어 [(pH 3에서 방출된 포스페이트 [mM])돌연변이체/ pH 3에서 방출된 포스페이트 [mM])서열번호 2]×[(pH 5에서 방출된 포스페이트 [mM])돌연변이체 / (pH 5에서 방출된 포스페이트 [mM])서열번호 2]로 정의된다.
생물학적 효능 지수는, 서열번호 2와 같은 참조기준과 비교하여 피타아제 돌연변이체의 성능과 열안정성의 상관관계를 알아보는 것으로, IC50(변이체) / IC50(참조기준)×[(pH X에서 방출된 포스페이트 [mM])돌연변이체/ pH X에서 방출된 포스페이트 [mM])참조기준]×[(pH Y에서 방출된 포스페이트 [mM])돌연변이체 / (pH Y에서 방출된 포스페이트 [mM])참조기준] (여기서, X와 Y는 서로 다른 pH 값임), 즉 예를 들어 IC50(변이체) / IC50(서열번호 2)×[(pH 3에서 방출된 포스페이트 [mM])돌연변이체/ pH 3에서 방출된 포스페이트 [mM])서열번호 2]×[(pH 5에서 방출된 포스페이트 [mM])돌연변이체 / (pH 5에서 방출된 포스페이트 [mM])서열번호 2]로 정의된다.
본 발명에 사용되는 "사료" 또는 "사료 제품"이라는 용어는, 임의의 종류의 동물, 예를 들어 포유동물 및 조류, 예컨대 이에 제한되지는 않지만, 반추동물, 돼지, 사슴, 가금류에게 공급하기에 적절한 당업계의 숙련자들에게 공지된 임의의 제품일 뿐만 아니라, 어류 또는 일반적으로 해산물로 지칭하는 다른 수생 가축류도 포함한다. 비반추동물, 예컨대 가금류, 육계, 조류, 닭, 칠면조, 오리, 거위 및 새; 반추동물, 예를 들면, 젖소, 소, 말 및 양; 돼지(pig 또는 swine), 새끼 돼지, 육성돈 및 암퇘지; 이에 제한되는 것은 아니지만 고양이, 개, 설치류 및 토끼를 포함하는 반려 동물; 이에 제한되는 것은 아니지만, 연어, 송어, 틸라피아, 메기 및 잉어를 포함하는 어류; 및 이에 제한되는 것은 아니지만, 새우 및 참새우를 포함하는 갑각류를 위한 사료 제품들이 포함된다.
본 발명에 사용되는 "식품"이라는 용어는, 인간이 소비하기에 적절한 당업계의 숙련가들에게 공지된 임의의 제품을 말한다.
본 발명의 사료 또는 식품은 예를 들어 전분을 함유한다. 전분 함유 사료 성분은 일반적으로 곡류(들), 예컨대 하나 이상의 옥수수, 밀, 보리, 호밀, 쌀, 수수와 기장, 및/또는 덩이줄기, 예컨대 감자, 카사바 및 고구마와 같은 식물성 재료를 포함한다. 상기 식물성 재료는 분쇄된 형태, 예를 들어 습식 또는 건식 분쇄된 곡물, 또는 주정박 고형물일 수 있다.
본 발명의 사료 또는 식품은 대두 (바람직하게는 대두분), 유채씨, 팜 커넬, 목화씨 및 해바라기와 같은 단백질이 풍부한 사료 성분들을 포함한다.
추가로, 사료 또는 식품은, 예를 들어 비타민, 미네랄, 유기산, 프로바이오틱 성분, 유지, 지방, 안료, 성장 인자 및 항균제로 이루어진 군으로부터 선택된 적어도 하나의 화합물을 포함한다.
임의로, 사료 또는 식품은, 박테리아 3-피타아제 돌연변이체 이외에, 적어도 하나 이상의 효소, 예를 들어 해당 사료의 소화율을 개선하고/개선하거나 상기 3-피타아제 돌연변이체에 의해 생성된 중간체 생성물, 예컨대 이노시톨-테트라포스페이트를 분해하는 식품 또는 사료 효소, 예를 들면 6-피타아제와 같은 또 다른 피타아제, 아밀라아제 또는 프로테아제, 아미노펩티다아제, 카보하이드라아제, 카복시펩티다아제, 카탈라아제, 셀룰라아제, 키티나아제, 쿠티나아제, 사이클로덱스트린 글리코실트랜스퍼라아제, 데옥시리보뉴클레아제, 에스테라아제, 알파-갈락토시다아제, 베타-갈락토시다아제, 글루코아밀라아제, 알파-글루코시다아제, 베타-글루코시다아제, 할로퍼옥시다아제, 인버타아제, 락카아제, 리파아제, 만노시다아제, 옥시다아제, 펙틴분해 효소, 펩티도글루타미나아제, 퍼옥시다아제, 폴리페놀옥시다아제, 단백질가수분해 효소, 리보뉴클레아제, 트랜스글루타미나아제, 또는 자일라나아제를 포함한다. 식품 또는 사료 효소(들)는, 예를 들어 박테리아 또는 진균과 같은 미생물에서 유래하거나, 또는 식물 또는 동물로부터 유래한다.
상기 사료 또는 식품은 예를 들어 과립물, 압축물, 압출물 또는 액체 형태로 존재한다.
본 발명의 피타아제 돌연변이체는 대상체에게 예를 들어 식품 또는 사료 제품으로 투여되거나, 또는 식품 또는 사료 제품이 아닌, 예를 들어 정제, 분말, 액체, 압출물 또는 과립물, 예컨대 염, 예를 들면 NaCl, KCl, Na2S04, K2S04 및 MgS04로 이루어진 군으로부터 선택되는 적어도 60% w/w의 염을 포함하는 코팅을 갖는 코팅된 과립물의 형태로 직접 투여된다.
본 발명의 피타아제 돌연변이체는 예를 들어 건조 또는 액체 형태의 곡물, 옥수수, 건초, 당밀 및 짚을 펠릿화시키거나 압출시킨 혼합물과 같은 식품 또는 사료 제품의 제조에 사용된다.
본원에 사용된 "액체 형태"는 예를 들어 완충제, 안정화제 및 항균제와 임의로 적어도 하나의 추가의 효소를 포함하는 조성물을 말하며, 여기서, 상기 효소는 아밀라아제, 셀룰라아제, 락타아제, 리파아제, 프로테아제, 카탈라아제, 자일라나아제, 베타-글루카나아제, 만나나아제, 아밀라아제, 아미다아제, 에폭사이드 하이드롤라아제, 에스테라아제, 포스포리파아제, 트랜스아미나아제, 아민 옥시다아제, 셀로바이오하이드롤라제, 암모니아 리아제, 또는 이들의 임의의 조합이다.
본원에 사용된 "건조 형태"는 예를 들어 다음 성분들: 담체, 완충제, 안정화제, 결합제, 가소화제, 항균제 중 하나 이상을 포함하는 조성물을 말한다. 건조 형태의 식품 또는 사료 제품은 수크로스, 염화나트륨, 소르비톨, 시트르산나트륨, 소르빈산칼륨, 벤조산나트륨, 프로피온산나트륨, 구아검 및/또는 밀가루를 포함한다.
본 발명의 피타아제 돌연변이체의 서열은 예를 들어 다음과 같으며, 이들을 실시예에서 부분적으로 시험하였다:
Figure pct00003
Figure pct00004
Figure pct00005
Figure pct00006
Figure pct00007
Figure pct00008
Figure pct00009
Figure pct00010
Figure pct00011
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Figure pct00014
실시예
이하에서, 본 발명을 실시예로 설명한다. 본 실시예는 본 발명을 예를 들어서 설명할 목적일 뿐이지, 어떠한 측면에서든 본 발명의 범위와 청구범위를 한정하려고 하는 것은 아니다.
실시예 1: 3-피타아제 돌연변이체의 열안정성
3-피타아제 돌연변이체의 열안정성에 대한 특성 분석은 열처리 전후로 아세트산염 완충액 중에서 pH 5.5에서 체적 활성을 측정하여 수행하였다. 열 처리는 서로 다른 온도 (58 내지 85℃)에서 15분간 수행하였고, 효소 활성은 실시예 4에 따른 측광 분석법을 사용하여 서로 다른 시점에서의 포스페이트 방출을 측정함으로써 측정하였다. 열처리 전후의 활성을 이용하여 IC50 값을 측정하였으며, 여기서 IC50은 해당 효소가 25분의 항온배양 후에 50% 잔류 활성을 나타내는 온도로 정의된다. 서열번호 2의 모든 3-피타아제 돌연변이체는 아래에 제시된 바와 같이 야생형 서열번호 2보다 열안정성이 훨씬 더 높다:
Figure pct00015
Figure pct00016
실시예 2: 돌연변이 D149N, S189D, K190N, K191N, R210Q 및 L211M을 포함하는 열안정성 3-피타아제 돌연변이체의 실제 적용 시험에서의 포스페이트 방출
돌연변이 D149N, S189D, K190N, K191N, R210Q 및 L211M을 포함하는, 서열번호 2의 각 3-피타아제 돌연변이체들의 포스페이트 방출을 실제 적용되는 것과 근접한 시험에서 측정하여 야생형 서열번호 2와 비교하였다. 이에 따라, 3-피타아제 돌연변이체들을 피치아 파스토리스 (Pichia pastoris)에서 발현시켜고, 체적 활성은 약간의 변경을 가한 (포맷을 5배 축소시킨) DIN EN ISO 30024:2009 (https://www.iso.org/standard/45787.html)에 따라 측정하였다. 효소들은 실제 적용 시험에서 사료 1 kg당 500 단위로 사용하였다. 여기서, 옥수수와 대두의 70/30 혼합물 15 g을 pH 3과 5에서 60분간 25% 건조물을 사용하여 41℃에서 항온배양하였다. 다음으로, 실시예 4에 따른 몰리브덴산암모늄 분석법을 사용하여 상기 방출된 포스페이트를 측정하였다. 성능 지수는 다음과 같이 계산하였다: [(pH 3에서 방출된 포스페이트 [mM])변이체 / (pH 3에서 방출된 포스페이트 [mM])서열번호 2]×[(pH 5에서 방출된 포스페이트 [mM])변이체 / (pH 5에서 방출된 포스페이트 [mM])서열번호 2]. 모든 3-피타아제 돌연변이체들은 아래 표에 제시되어 있는 바와 같이 야생형 서열번호 2에 비해 개선된 성능 지수를 나타낸다:
Figure pct00017
Figure pct00018
실시예 3: 서열번호 2에 대한 열안정성 3-피타아제 돌연변이체들의 pH 프로파일 측정
3-피타아제 돌연변이체들의 개선된 성능은 낮은 pH로 이동한 pH 프로파일에 의해 주로 입증된다. 따라서, 선택된 서열번호 2에 대한 3-피타아제 돌연변이체의 pH 프로파일은 실시예 4에 따른 측광 분석법을 사용하여 서로 다른 pH 값에서 활성을 측정함으로써 측정하였다. 도 2는 야생형 서열번호 2와 비교한 모든 변이체들에 대해 최적인 pH의 변화를 보여주고 있다.
실시예 4: 3-피타아제 돌연변이체의 효소 활성 측정
(100 mmol/L의 아세트산나트륨 완충액, pH 5.5, 0.05% (w/v)의 Triton X-100 중) 5 μL의 효소 용액을 100 mmol/L의 아세트산나트륨 완충액 (pH 5.5) 중 95 μL의 2,88 mmol/L 피테이트산나트륨 (Sigma 68388, 로트번호 BCBM4006V)를 사용하여 25분간 항온배양하였다. 상기 반응을 100 μL의 10% (w/v) 트리클로로아세트산을 첨가하여 중지시켰다. 다음으로, 100 μL의 상기 중지된 효소 반응물을 100 μL의 몰리브데이트 시약 [1.2% (w/v) 몰리브덴산암모늄; 4.4% (v/v) 황산 및 27 mg/mL (w/v) 황산제1철(ferrous sulfate)의 수용액]과 혼합하여 생성된 용액을 15분간 실온에서 항온배양하였다. 700 nm에서의 흡광도를 측정하고, 방출된 무기 포스페이트의 양을 무기 포스페이트 표준 용액 (0 내지 1.5 mmol/L)을 사용하여 계산하였다. 1 단위의 피타아제 활성은, 37℃에서 분당 1 μmol의 포스페이트를 방출하는 효소의 양으로 정의하였다.
<110> Clariant Produkte (Deutschland) GmbH <120> Optimized 3-phytase and its use in food or feed production <130> 2018DE612-WO-PCT <160> 47 <170> PatentIn version 3.5 <210> 1 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt Sequence (Seq2) <400> 1 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Asn Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Ser Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 2 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> wt sequence of Dickeya zeae phytase with His tag <400> 2 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Lys Gly Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Ser Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asp Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Ser Lys Lys Gly 180 185 190 Asn Ile Ser Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Arg Leu Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 3 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 3 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Asn Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Met Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 4 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 4 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 5 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 5 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Asn Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Ser Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 6 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 6 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Arg Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 7 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 7 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Leu 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 8 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 8 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp His Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 9 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 9 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Ser Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 10 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 10 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Arg Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Arg Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Thr Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Tyr Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 11 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 11 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Arg 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 12 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 12 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Arg 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala His Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 13 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 13 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Arg Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 14 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 14 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Thr Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Lys Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Thr Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 15 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 15 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Arg Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Ser Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Gly Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 16 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 16 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 His Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 17 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 17 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Arg Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Pro Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 18 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 18 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Asn Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 19 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 19 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 20 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 20 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Lys Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 21 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 21 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Ser Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Lys Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 22 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 22 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Arg Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ser 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 23 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 23 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Lys Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Arg Glu Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 24 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 24 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Lys Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 25 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 25 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Ala Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 26 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 26 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Glu Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Lys Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Lys Ile Tyr Leu His Gly Pro Glu Val Leu Ala Ser Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 27 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 27 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 28 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 28 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Lys Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 29 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 29 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Ala Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 30 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 30 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 31 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 31 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 32 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 32 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Asn Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 33 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 33 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Ala Ser Asn Val Lys Lys Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 His Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 34 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 34 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Arg Ile Tyr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Tyr Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 35 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 35 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Asn Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asn Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Ser Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 36 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 36 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Lys Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Lys Ile Tyr Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 37 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 37 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Leu Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 38 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 38 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Gly 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 39 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 39 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Ala Ser Asn Val Ala Lys Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Thr Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Lys Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Met Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val Arg 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 40 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 40 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Ala Ser Asn Val Ala Lys Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Glu Glu Asp Asn Asn Gly 180 185 190 Ser Ile Ser Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Lys Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Met Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 41 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 41 Glu Thr Thr Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Ala Ser Asn Val Ala Lys Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Val Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Thr Leu His Gly Pro Glu Val Leu Ala Asn Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asp Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Lys Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Met Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val Arg 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 42 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 42 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ala Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 43 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 43 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Gly Asn Val Lys Ala Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Lys Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Asp Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 44 <211> 409 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 44 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Arg Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp Leu Leu Tyr Val Ala 275 280 285 His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met Leu Gly Phe Thr Trp 290 295 300 Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro Pro Ala Gly Ser Leu 305 310 315 320 Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly Gln Arg Val Val Arg 325 330 335 Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile Arg Gly Leu Ala Ala 340 345 350 Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu Phe Ser Met Pro Asp 355 360 365 Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro Tyr Asp Ala Val Met 370 375 380 Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala Leu Leu Pro Val His 385 390 395 400 Tyr Thr Pro His His His His His His 405 <210> 45 <211> 414 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 45 Asp Thr Pro Ser Ala Ala Ala Pro Ser Ser Gly Trp Thr Leu Glu Lys 1 5 10 15 Val Val Glu Val Ser Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn 20 25 30 Val Lys Thr Ile Gln Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu 35 40 45 Thr Gln Tyr Gly Glu Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu 50 55 60 Lys Gly His Tyr Glu Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys 65 70 75 80 Gln Ala Cys Pro Ala Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu 85 90 95 Gln Arg Thr Arg Glu Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro 100 105 110 Gly Cys Gly Val Ala Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro 115 120 125 Leu Phe His Ala Glu Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val 130 135 140 Lys Ala Asp Leu Gln Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile 145 150 155 160 Gln Ala Gln Trp Gln Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys 165 170 175 Leu Pro Asp Lys Pro Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys 180 185 190 Glu Asp Asn Asn Gly Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala 195 200 205 Ile Ile Ala Glu Thr Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu 210 215 220 Ser Glu Val Ala Phe Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala 225 230 235 240 Leu Met Pro Leu Leu Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro 245 250 255 Tyr Val Ala Arg Arg Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu 260 265 270 Ala Leu Asn Thr Glu His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp 275 280 285 Leu Leu Tyr Val Ala His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met 290 295 300 Leu Gly Phe Thr Trp Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro 305 310 315 320 Pro Ala Gly Ser Leu Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly 325 330 335 Gln Arg Val Val Arg Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile 340 345 350 Arg Gly Leu Ala Ala Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu 355 360 365 Phe Ser Met Pro Asp Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro 370 375 380 Tyr Asp Ala Val Met Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala 385 390 395 400 Leu Leu Pro Val His Tyr Thr Pro His His His His His His 405 410 <210> 46 <211> 414 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 46 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Leu Ala Ile Ile Ala Glu Thr 195 200 205 Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu Ser Glu Val Ala Phe 210 215 220 Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala Leu Met Pro Leu Leu 225 230 235 240 Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro Tyr Val Ala Arg Arg 245 250 255 Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu Ala Leu Asn Thr Glu 260 265 270 His Gln Ala Ala Ala Ala Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp 275 280 285 Leu Leu Tyr Val Ala His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met 290 295 300 Leu Gly Phe Thr Trp Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro 305 310 315 320 Pro Ala Gly Ser Leu Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly 325 330 335 Gln Arg Val Val Arg Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile 340 345 350 Arg Gly Leu Ala Ala Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu 355 360 365 Phe Ser Met Pro Asp Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro 370 375 380 Tyr Asp Ala Val Met Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala 385 390 395 400 Leu Leu Pro Val His Tyr Thr Pro His His His His His His 405 410 <210> 47 <211> 414 <212> PRT <213> Artificial Sequence <220> <223> Variant of wt sequence (Seq2) <400> 47 Asp Thr Pro Ser Ser Gly Trp Thr Leu Glu Lys Val Val Glu Val Ser 1 5 10 15 Arg His Gly Val Arg Pro Pro Thr Glu Ser Asn Val Lys Thr Ile Gln 20 25 30 Glu Gly Thr Asp Arg Gln Trp Pro Thr Trp Leu Thr Gln Tyr Gly Glu 35 40 45 Leu Thr Gly His Gly Tyr Ala Ala Ala Glu Leu Lys Gly His Tyr Glu 50 55 60 Gly Gln Tyr Leu Arg Gln His Gly Leu Leu Cys Gln Ala Cys Pro Ala 65 70 75 80 Pro Gly Asp Val Phe Val Trp Ala Ser Pro Leu Gln Arg Thr Arg Glu 85 90 95 Thr Ala Met Ala Leu Met Asp Gly Val Phe Pro Gly Cys Gly Val Ala 100 105 110 Ile Gln Gly Pro Glu Asp Glu Asp Asn Asp Pro Leu Phe His Ala Glu 115 120 125 Thr Ala Gly Val Thr Leu Asp Gln Gln Gln Val Lys Ala Asp Leu Gln 130 135 140 Asn Ala Met Gln Asn Lys Ser Ala Ala Gln Ile Gln Ala Gln Trp Gln 145 150 155 160 Pro Ala Ile Asp Arg Leu Lys Gln Ala Val Cys Leu Pro Asp Lys Pro 165 170 175 Cys Pro Ala Phe Ser Thr Pro Trp Glu Val Lys Glu Asp Asn Asn Gly 180 185 190 Ser Ile Arg Leu His Gly Pro Glu Val Ala Ala Ala Glu Val Leu Ala 195 200 205 Ile Ile Ala Glu Thr Ile Gln Met Ser Tyr Ser Asn Asn Asn Pro Leu 210 215 220 Ser Glu Val Ala Phe Gly His Ala Lys Thr Ala Ala Glu Val Ala Ala 225 230 235 240 Leu Met Pro Leu Leu Thr Ala Asn Tyr Asp Phe Thr Asn Asp Leu Pro 245 250 255 Tyr Val Ala Arg Arg Gly Ala Ser Val Leu Met Asn Gln Ile Ala Leu 260 265 270 Ala Leu Asn Thr Glu His Gln Ala Asp Ala Pro Pro Asp Ala Lys Trp 275 280 285 Leu Leu Tyr Val Ala His Asp Thr Asn Ile Ala Lys Leu Arg Thr Met 290 295 300 Leu Gly Phe Thr Trp Gln Met Gly Asp Tyr Pro Arg Gly Asn Ile Pro 305 310 315 320 Pro Ala Gly Ser Leu Ile Phe Glu Arg Trp Arg Asn Gln Gln Ser Gly 325 330 335 Gln Arg Val Val Arg Ile Tyr Phe Gln Ala Gln Ser Leu Asp Gln Ile 340 345 350 Arg Gly Leu Ala Ala Leu Asp Asp Ser His Pro Pro Leu Arg Ser Glu 355 360 365 Phe Ser Met Pro Asp Cys Gln Lys Thr Asp Ile Gly Thr Leu Cys Pro 370 375 380 Tyr Asp Ala Val Met Lys Arg Leu Asn Asp Ala Val Asp Arg Thr Ala 385 390 395 400 Leu Leu Pro Val His Tyr Thr Pro His His His His His His 405 410

Claims (9)

  1. 서열번호 2에 대해 적어도 약 96.25%의 서열 동일성을 갖는 생물학적 효능이 있는 피타아제 돌연변이체로서, 상기 돌연변이체가 서열번호 2의 서열과, D149N, S189D, K190N, K191N, R210Q, L211E, L211M, K25E, K25A, G26N, G26S, N193H, N193K, N193S, N193R, D1E, P3T, G26K, K29A, T30S, T30A, T30K, D36N, Q45N, Q45R, V58E, S75C, Q76R, P107S, A112G, D120K, T129K, Q136R, Q144L, D149N, K187E, D189N, G192R, S195R, S195Y, S195T, S195N, N204I, N204T, N204S, S214A, N216D, A230T, M237L, N243K, N248K, R255H, G257S, F264Y, A275P, D276G, K295Y, K295M, Q332D, A352S, V383M, R393H, A395T 및 이들의 조합으로 이루어진 군으로부터 선택된 돌연변이를 포함하는 것인, 상기 생물학적 효능이 있는 피타아제 돌연변이체.
  2. 제1항에 있어서, 돌연변이 D149N, S189D, K190N 및 K191N을 포함하는 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  3. 제1항 또는 제2항에 있어서, 돌연변이 R210Q 및 L211M을 포함하는 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  4. 제1항 내지 제3항 중 어느 한 항에 있어서, 돌연변이 K25E 또는 K25A, 및 G26N 또는 G26S, 및 N193S 또는 N193R을 포함하는 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  5. 제1항 내지 제4항 중 어느 한 항에 있어서, 25, 26, 193, 210 및/또는 211번 위치에 돌연변이를 포함하는 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  6. 제1항 내지 제5항 중 어느 한 항에 있어서, D149N, S189D, K190N, K191N, K25E 또는 K25A, G26S 또는 G26N, N193S, N193R 또는 N193K, R210Q 및 L211M 위치에 돌연변이를 포함하는 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  7. 제1항 내지 제6항 중 어느 한 항에 있어서, 최대 90℃까지 활성 상태인 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  8. 제1항 내지 제7항 중 어느 한 항에 있어서, pH 3 내지 5.5에서 활성 상태인 것인, 생물학적 효능이 있는 피타아제 돌연변이체.
  9. 식품 또는 사료 제품의 제조에 사용하기 위한, 제1항 내지 제8항 중 어느 한 항에 따른 생물학적 효능이 있는 피타아제 돌연변이체의 용도.
KR1020217006844A 2018-08-08 2019-07-17 최적화된 3-피타아제, 및 식품 또는 사료에서의 이의 용도 KR20210041049A (ko)

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