JP7439142B2 - 含硫アミノ酸またはその誘導体の製造方法 - Google Patents
含硫アミノ酸またはその誘導体の製造方法 Download PDFInfo
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- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
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- 235000005822 corn Nutrition 0.000 description 1
- 239000013601 cosmid vector Substances 0.000 description 1
- 101150111114 cysE gene Proteins 0.000 description 1
- 101150041643 cysH gene Proteins 0.000 description 1
- 101150094831 cysK gene Proteins 0.000 description 1
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- 229960002433 cysteine Drugs 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 101150011371 dapA gene Proteins 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006326 desulfonation Effects 0.000 description 1
- 238000005869 desulfonation reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
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- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 101150097303 glyA gene Proteins 0.000 description 1
- 101150079604 glyA1 gene Proteins 0.000 description 1
- 108010014977 glycine cleavage system Proteins 0.000 description 1
- 101150077981 groEL gene Proteins 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 108010071598 homoserine kinase Proteins 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 101150005467 lifO gene Proteins 0.000 description 1
- 101150031897 lipB gene Proteins 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 229940099596 manganese sulfate Drugs 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 101150117293 metC gene Proteins 0.000 description 1
- 101150108178 metE gene Proteins 0.000 description 1
- 101150051471 metF gene Proteins 0.000 description 1
- 101150097685 metI gene Proteins 0.000 description 1
- 101150089110 metN gene Proteins 0.000 description 1
- 101150021603 metQ gene Proteins 0.000 description 1
- 101150115974 metX gene Proteins 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 150000004028 organic sulfates Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 102000030592 phosphoserine aminotransferase Human genes 0.000 description 1
- 101150000475 pntAB gene Proteins 0.000 description 1
- 229920001522 polyglycol ester Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 101150100525 pykA gene Proteins 0.000 description 1
- 101150053304 pykF gene Proteins 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 101150003830 serC gene Proteins 0.000 description 1
- 230000037432 silent mutation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 101150014006 thrA gene Proteins 0.000 description 1
- 101150072448 thrB gene Proteins 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000011426 transformation method Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 101150062776 yccA gene Proteins 0.000 description 1
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Description
また、任意の2個のポリヌクレオチドまたはポリペプチド配列が相同性、類似性または同一性を有するかどうかは、定義されたストリンジェントな条件下でサザンハイブリダイゼーション実験により配列を比較することにより確認することができ、定義される適切なハイブリダイゼーション条件は当該技術の範囲内であり、当業者によく知られている方法(例えば、J. Sambrook et al., Molecular Cloning, A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory press, Cold Spring Harbor, New York, 1989; F.M. Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York)で決定されてもよい。
1)上記ポリペプチドまたはタンパク質をコードする遺伝子またはポリヌクレオチドの細胞内コピー数の増加、
2)上記ポリペプチドまたはタンパク質をコードする染色体上の遺伝子発現調節領域を活性が強力な配列で交換する方法、
3)上記ポリペプチドまたはタンパク質の開始コドンまたは5'-UTR地域の塩基配列を変形させる方法、
4)上記ポリペプチドまたはタンパク質の活性が強化されるように染色体上のポリヌクレオチド配列を変形させる方法、
5)上記ポリペプチドまたはタンパク質の活性を示す外来ポリヌクレオチドまたは上記ポリヌクレオチドのコドン最適化された変異型ポリヌクレオチドの導入、または
6)上記方法の組合わせにより強化されるように変形する方法などにより行われてもよいが、これに制限されない。
1)上記タンパク質をコードする上記遺伝子の全体または一部を欠失させる方法、
2)上記タンパク質をコードする上記遺伝子の発現が減少するように発現調節領域(または発現調節配列)の変形、
3)上記タンパク質の活性が除去または弱化するようにタンパク質をコードする上記遺伝子配列の変形、
4)上記タンパク質をコードする上記遺伝子の転写体に相補的に結合するアンチセンスオリゴヌクレオチド(例えば、アンチセンスRNA)の導入、
5)上記タンパク質をコードする上記遺伝子のシャイン・ダルガノ(Shine-Dalgarno)配列の前段にシャイン・ダルガノ配列と相補的な配列を付加して2次構造物を形成させてリボソーム(ribosome)の付着を不可能にさせる方法、
6)上記タンパク質をコードする上記遺伝子のポリヌクレオチド配列のORF(open reading frame)の3'末端に反対方向に転写されるプロモーターを付加する方法(Reverse transcription engineering, RTE)などがあり、これらの組合わせでも達成できるが、これに特に制限されるのではない。
まず、代表的な含硫アミノ酸であるメチオニン生産菌株を製作するために、コリネバクテリウム・グルタミカムATCC13032菌株をもって既に公知となったメチオニンシステイン転写調節因子タンパク質をコードするmcbR (J. Biotechnol. 103:51-65, 2003)の不活性化のためにベクターを製作した。
上記実施例1で製作されたpDZ-ΔmcbRベクターを染色体上における相同組換えによりATCC13032菌株にそれぞれ電気穿孔法で形質転換させた(van der Rest et al., Appl Microbiol Biotechnol 52:541-545, 1999)。その後、スクロースを含んでいる固体培地で2次組換えを行った。2次組換えが完了した上記コリネバクテリウム・グルタミカム形質転換株を対象に配列番号6、7を用いてPCR法を通じてmcbR遺伝子が欠損した菌株を確認し、この組換え菌株をCM02-0618と命名した。
ブドウ糖20g、ペプトン10g、酵母抽出物5g、尿素1.5g、KH2PO4 4g、K2HPO4 8g、MgSO4・7H2O 0.5g、ビオチン100μg、チアミンHCl 1000μg、パントテン酸カルシウム2000μg、ニコチンアミド2000μg(蒸溜水1リットルを基準)
ブドウ糖50g、(NH4)2S2O3 12g、Yeast extract 5g、KH2PO4 1g、MgSO4・7H2O 1.2g、ビオチン100μg、チアミン塩酸塩1000μg、パントテン酸カルシウム2000μg、ニコチンアミド3000μg、CaCO3 30g、シアノコバラミン(Vitamin B12) 1μg (蒸溜水1リットルを基準)。
コリネバクテリウム菌株のチオスルフェートに特異的なタンパク質については知られていない。しかし、実施例2で確認した通り、CM02-0618菌株の場合、チオスルフェートを単独硫黄sourceとして用いた時、メチオニンを生産することを確認したところ、チオスルフェートの利用に関与するタンパク質を選別するための実験を行った。
実施例3においてチオスルフェートに特異的に反応するタンパク質として選別したSsuDの不活性化効果を確認するためにssuD遺伝子を欠損させようとベクターを製作した。
ssuD遺伝子をコリネバクテリウムATCC13032染色体上で欠損させるために、下記方法で組換えプラスミドベクターを製作した。
実施例4-1で製作したpDZ-ΔSsuD、ベクターを染色体上における相同組換えにより13032/ΔmcbR菌株にそれぞれ電気穿孔法で形質転換させた(van der Rest et al.、Appl Microbiol Biotechnol 52:541-545、1999)。その後、スクロースを含んでいる固体培地で2次組換えを行った。2次組換えが完了した上記コリネバクテリウム・グルタミカム形質転換株を対象に配列番号13、14を用いてPCR法を通じてssuD遺伝子が欠損した菌株を確認し、本組換え菌株をコリネバクテリウム・グルタミカムCM02-0618/ΔSsuDと命名した。
上記製作されたCM02-0618/ΔSsuD菌株のL-メチオニン生産能を分析するために、親株であるコリネバクテリウム・グルタミカムATCC13032菌株と共に下記のような方法で培養した。
ブドウ糖20g、ペプトン10g、酵母抽出物5g、尿素1.5g、KH2PO4 4 g、K2HPO4 8 g、MgSO4・7H2O 0.5g、ビオチン100μg、チアミンHCl 1000μg、パントテン酸カルシウム2000μg、ニコチンアミド2000μg (蒸溜水1リットルを基準)
ブドウ糖50g、(NH4)2S2O3 12g、Yeast extract 5g、KH2PO4 1g、MgSO4・7H2O 1.2g、ビオチン100μg、チアミン塩酸塩1000μg、パントテン酸カルシウム2000μg、ニコチンアミド3000μg、CaCO3 30 g (蒸溜水1リットルを基準)。
実施例3においてチオスルフェートに特異的に反応するタンパク質として選別したSsuDの活性強化のためにベクターを製作した。
ssuD遺伝子をコリネバクテリウムATCC13032染色体上に追加挿入させるために、下記方法で組換えプラスミドベクターを製作した。
実施例5-1で製作されたPDZ-ΔNcgl1464及びpDZ-ΔNcgl1464-PgapASsuD 、ベクターを染色体上における相同組換えによりCM02-0618菌株にそれぞれ電気穿孔法で形質転換させた(van der Rest et al.、Appl Microbiol Biotechnol 52:541-545、1999)。その後、スクロースを含んでいる固体培地で2次組換えを行った。2次組換えが完了した上記コリネバクテリウム・グルタミカム形質転換株を対象に配列番号24、25を用いてPCR法を通じてNcgl1464が欠損した菌株及びNcgl1164が欠損しながらssuD遺伝子が挿入された菌株を確認した。Ncgl1464が欠損した菌株はCM02-0618/ΔNcgl1464と命名し、Ncgl1164が欠損しながらssuD遺伝子が挿入された菌株はCM02-0736と命名した。
上記製作されたCM02-0618/ΔNcgl1464及びCM02-0736菌株のL-メチオニン生産能を分析するために、親株であるCM02-0618菌株と共に下記のような方法で培養した。
ブドウ糖20g、ペプトン10g、酵母抽出物5g、尿素1.5g、KH2PO4 4 g、K2HPO4 8 g、MgSO4・7H2O 0.5g、ビオチン100μg、チアミンHCl 1000μg、パントテン酸カルシウム2000μg、ニコチンアミド2000μg (蒸溜水1リットルを基準)
ブドウ糖50g、(NH4)2S2O3 12 g、Yeast extract 5g、KH2PO4 1g、MgSO4・7H2O 1.2g、ビオチン100μg、チアミン塩酸塩1000μg、パントテン酸カルシウム2000μg、ニコチンアミド3000μg、CaCO3 30g、コバラミン(Vitamin B12) 1μg (蒸溜水1リットルを基準)。
SsuDタンパク質は、本来、スルホネートの脱スルホン(desulfonation)に関与するタンパク質として知られている。スルホネート(sulfonate)はR-S03からなり、その時のRはOrganic groupであるが、チオスルフェートはS-S03からなるため、スルホネートとは異なる。
ブドウ糖20g、ペプトン10g、酵母抽出物5g、尿素1.5g、KH2PO4 4g、K2HPO4 8g、MgSO4・7H2O 0.5g、ビオチン100μg、チアミンHCl 1000μg、パントテン酸カルシウム2000μg、ニコチンアミド2000μg (蒸溜水1リットルを基準)
ブドウ糖50g、(NH4)2S2O3 12gまたはMethanesulfonate 12gまたはEthanesulfonate 12g(硫黄源に応じて)、Yeast extract 5g、KH2PO4 1 g、MgSO4・7H2O 1.2 g、ビオチン100μg、チアミン塩酸塩1000μg、パントテン酸カルシウム2000μg、ニコチンアミド3000μg、CaCO330g、コバラミン(Vitamin B12) 1 μg (蒸溜水1リットルを基準)。
実施例7-1:metH、cysIを同時に強化する組換えベクターの製作
本出願のSsuDタンパク質活性強化及びチオスルフェートを硫黄源として用いる場合、多様な含硫アミノ酸を製造できるかを確認するために、他のメチオニン生産菌株に上記構成を適用することにした。これについて、mcbRが欠損しないメチオニン生産菌株を製作するために、ATCC13032菌株に基づいて、既に公知となったメチオニン合成酵素をコードするmetH(Ncgl1450)、亜硫酸レダクターゼをコードするcysI(Ncgl2718)の発現を同時に強化するためにベクターを製作した。
実施例7-1で製作されたpDZ-ΔNcgl1021及びpDZ-ΔNcgl1021-Pcj7metH-Pspl1cysI ベクターを染色体上における相同組換えによりATCC13032菌株にそれぞれ電気穿孔法で形質転換させた(van der Rest et al.、Appl Microbiol Biotechnol 52:541-545、1999)。その後、スクロースを含んでいる固体培地で2次組換えを行った。2次組換えが完了した上記コリネバクテリウム・グルタミカム形質転換株を対象に配列番号41、42を用いてPcj7-metH-Pspl1cysI遺伝子の挿入を確認した。本組換え菌株は、それぞれコリネバクテリウム・グルタミカム13032/ΔNcgl1021(pDZ-ΔNcgl1021で形質転換した菌株)、 CM02-0753 (pDZ-ΔNcgl1021-Pcj7metH-Pspl1cysIで形質転換した菌株)と命名した。
ブドウ糖20g、ペプトン10g、酵母抽出物5g、尿素1.5g、KH2PO4 4g、K2HPO4 8g、MgSO4・7H2O 0.5g、ビオチン100μg、チアミンHCl 1000μg、パントテン酸カルシウム2000μg、ニコチンアミド2000μg (蒸溜水1リットルを基準)
ブドウ糖50g、(NH4)2S2O3 12 g、Yeast extract 5g、KH2PO4 1 g、MgSO4・7H2O 1.2 g、ビオチン100μg、チアミン塩酸塩1000μg、パントテン酸カルシウム2000μg、ニコチンアミド3000μg、CaCO3 30g、コバラミン(Vitamin B12) 1 μg (蒸溜水1リットルを基準)。
実施例7で製作したメチオニン生産菌株を基盤としてSsuDタンパク質活性を強化した菌株を製作した後、L-メチオニン生産能を確認した。
具体的には、実施例5で製作されたpDZ-ΔNcgl464-PgapASsuDベクターを染色体上における相同組換えにより実施例7のCM02-0753菌株に電気穿孔法で形質転換させた(van der Rest et al.、Appl Microbiol Biotechnol 52:541-545、1999)。その後、スクロースを含んでいる固体培地で2次組換えを行った。
実施例7のCM02-0753と実施例8-1で製作されたCM02-0756のL-メチオニン生産能を分析するために、下記のような方法で培養した。
ブドウ糖20g、ペプトン10g、酵母抽出物5g、尿素1.5g、KH2PO4 4g、K2HPO4 8g、MgSO4・7H2O 0.5g、ビオチン100μg、チアミンHCl 1000μg、パントテン酸カルシウム2000μg、ニコチンアミド2000μg (蒸溜水1リットルを基準)
ブドウ糖50g、(NH4)2S2O3 12 g、Yeast extract 5g、KH2PO4 1 g、MgSO4・7H2O 1.2 g、ビオチン100μg、チアミン塩酸塩1000μg、パントテン酸カルシウム2000μg、ニコチンアミド3000μg、CaCO3 30g、コバラミン(Vitamin B12) 1 μg (蒸溜水1リットルを基準)。
Claims (11)
- 遺伝的に変形された微生物を、チオスルフェートを含む培地で培養することを含む含硫アミノ酸または含硫アミノ酸誘導体の製造方法であって、上記微生物は、非変形微生物に比べてssuD遺伝子によりコーディングされるタンパク質の活性が増加する遺伝的変形を有するものであり、
上記微生物は、コリネバクテリウム属(Corynebacterium sp.)またはエシェリキア属(Escherichia sp.)微生物である、製造方法。 - 上記ssuD遺伝子によりコーディングされるタンパク質は、チオスルフェート還元酵素(thiosulfate reductase)の活性を有するものである、請求項1に記載の含硫アミノ酸または含硫アミノ酸誘導体の製造方法。
- 上記ssuD遺伝子によりコーディングされるタンパク質は、配列番号43のアミノ酸配列を含むものである、請求項1に記載の製造方法。
- 上記微生物は、コリネバクテリウム・グルタミカム(Corynebacterium glutamicum)、コリネバクテリウム・カルナエ(Corynebacterium callunae)、コリネバクテリウム・デセルティ(Corynebacterium deserti)、コリネバクテリウム・クレナタム(Corynebacterium crenatum)またはエシェリキア・コリ(Escherichia coli)である、請求項1に記載の製造方法。
- 上記方法は、上記微生物または培養培地から含硫アミノ酸または含硫アミノ酸誘導体を回収することを含む、請求項1に記載の製造方法。
- 上記タンパク質活性が増加する遺伝的変形は、i)上記タンパク質をコードするポリヌクレオチドの細胞内コピー数の増加、ii)上記タンパク質をコードするポリヌクレオチドの発現調節領域を活性が強力な配列で交換、iii)上記タンパク質をコードするポリヌクレオチドの開始コドンまたは5'-UTR変形、iv)上記タンパク質の活性が強化するように染色体上のポリヌクレオチド配列を変形、v)上記タンパク質の活性を示す外来ポリヌクレオチドまたは上記タンパク質をコードするポリヌクレオチドのコドン最適化された変異型ポリヌクレオチドの導入、またはvi)その組合わせである、請求項1に記載の製造方法。
- 上記含硫アミノ酸または含硫アミノ酸誘導体は、メチオニン(methionine)、システイン(cysteine)、シスチン(cystine)、ランチオニン(lanthionine)、ホモシステイン(homocysteine)、ホモシスチン(homocystine)、ホモランチオニン(homolanthionine)、タウリン(taurine)の中から選択されるいずれか一つ以上である、請求項1に記載の製造方法。
- 非変形微生物に比べてssuD遺伝子によりコーディングされるタンパク質活性が内在的増加する遺伝的変形を有する、コリネバクテリウム属(Corynebacterium sp.)またはエシェリキア属(Escherichia sp.)の微生物、またはその培養物;及びチオスルフェートを含む、含硫アミノ酸または含硫アミノ酸誘導体製造用組成物。
- コリネバクテリウム属(Corynebacterium sp.)またはエシェリキア属(Escherichia sp.)のssuD遺伝子によりコーディングされるタンパク質の、チオスルフェート還元酵素としての使用。
- 非変形微生物に比べてssuD遺伝子によりコーディングされ、チオスルフェート還元酵素活性を有するタンパク質活性が増加する遺伝的変形を有する、コリネバクテリウム属(Corynebacterium sp.)またはエシェリキア属(Escherichia sp.)の微生物の含硫アミノ酸または含硫アミノ酸誘導体製造のための使用。
- 培地中の微生物の培養物であって、前記培地においてチオスルフェートが前記微生物の唯一の硫黄源であり、前記微生物は、含硫アミノ酸または含硫アミノ酸誘導体を生産し、かつ、ssuD遺伝子によりコーディングされるチオスルフェート還元酵素活性を有するタンパク質の活性が非変形微生物に比べて増加する遺伝的変形を含み、
上記微生物は、コリネバクテリウム属(Corynebacterium sp.)またはエシェリキア属(Escherichia sp.)微生物である、培地中の微生物の培養物。
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