JP7370121B2 - プラスミドの製造方法及びプラスミド - Google Patents
プラスミドの製造方法及びプラスミド Download PDFInfo
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- JP7370121B2 JP7370121B2 JP2023523494A JP2023523494A JP7370121B2 JP 7370121 B2 JP7370121 B2 JP 7370121B2 JP 2023523494 A JP2023523494 A JP 2023523494A JP 2023523494 A JP2023523494 A JP 2023523494A JP 7370121 B2 JP7370121 B2 JP 7370121B2
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- plasmid
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- biosynthetic enzyme
- dna
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Classifications
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
- C12N15/75—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora for Bacillus
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/52—Genes encoding for enzymes or proenzymes
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/70—Vectors or expression systems specially adapted for E. coli
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2820/00—Vectors comprising a special origin of replication system
- C12N2820/10—Vectors comprising a special origin of replication system multiple origins of replication
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- Medicinal Chemistry (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Enzymes And Modification Thereof (AREA)
Description
[1]
マルチモジュール型生合成酵素をコードする複数の遺伝子を含むプラスミドの製造方法であって、枯草菌を用いたDNAの集積方法により、前記複数の遺伝子を含む第一の遺伝子クラスターの調整と、枯草菌の複製起点、大腸菌の複製起点及び放線菌への接合開始配列を含む第二の遺伝子クラスターと前記第一の遺伝子クラスターとの連結と、を行うことを特徴とするプラスミドの製造方法。
[2]
前記枯草菌を用いたDNAの集積方法がOGAB法である[1]に記載のプラスミドの製造方法。
[3]
[1]又は[2]の方法で製造されたプラスミド。
[4]
[1]又は[2]の方法で製造されたプラスミドを有する放線菌。
[5]
[1]又は[2]の方法で製造されたプラスミドを有する宿主細胞にマルチモジュール型生合成酵素を生産させるマルチモジュール型生合成酵素の製造方法。
[6]
前記宿主細胞が放線菌である[5]に記載のマルチモジュール型生合成酵素の製造方法。
[7]
前記放線菌が大腸菌との接合伝達によりプラスミドを取得した放線菌である[6]に記載のマルチモジュール型生合成酵素の製造方法。
[8]
前記マルチモジュール型生合成酵素がI型ポリケチド合成酵素(PKS)である[5]~[7]に記載のマルチモジュール型生合成酵素の製造方法。
[9]
[5]~[8]の方法で製造されたマルチモジュール型生合成酵素。
[10]
少なくとも以下の全てを含むプラスミド。
(a)枯草菌の複製起点
(b)大腸菌の複製起点
[11]
配列番号2に記載のPKSをコードするDNA配列と80%以上の相同性を有するPKSをコードするDNA.。
[12]
配列番号23に記載のプラスミドに関するDNA配列と80%以上の相同性を有するプラスミド。
本明細書において、マルチモジュール型生合成酵素としては、I型ポリケチド合成酵素(PolyKetideSynthase ; PKS)と非リボソームペプチド合成酵素などが挙げられる。
I型ポリケチド合成酵素(PolyKetideSynthase ; PKS) のことであり、特に限定されないが、例えば、配列番号2で示されるDNA配列がコードするPKSが挙げられ、配列番号2と相同性が、80%以上、85%以上、90%以上、93%以上、95%以上、97%以上、99%以上であるものでも良い。
本明細書において枯草菌を用いたDNAの集積方法とは、枯草菌を用いたDNAの集積方法であれば特に限定されるものではなく、例えば、特開2004-129654号公報、特開2005-253462号公報、特開2007-135533号公報などに記載されているものが挙げれる。
本明細書においてOGAB法(Ordered Gene Assembly in Bacillus subtilis法)とは、枯草菌のプラスミド形質転換系を利用した多重DNA断片集積法である。具体的には、集積対象のDNA断片および集積プラスミドベクターを3~4塩基の特異的な突出を持つ様に準備し、この相補性を利用して連結するDNA断片の順序と向きを指定して連結する方法である。
DNAの制限酵素SfiIの消化により発生する3塩基の突出末端が任意の配列に指定できることを利用して、集積すべき構成要素のDNA断片と枯草菌菌体内で有効な複製機構を有する線状プラスミドベクター断片の各末端を、各断片が1つのDNA集積単位中で一回ずつ順序良く連結できるような末端を生成することによりSfiI切断部位を設計して調製し、これらのSfiIの断片を等モルとなるように濃度を合わせて混合した後、ポリエチレングリコールと塩存在下でライゲーション反応を行うことにより、このDNA連結単位が多重に繰り返した構造の直鎖の高分子DNAを生成させ、これを枯草菌コンピテント細胞に形質転換することで、枯草菌プラスミド中に望ましい順番と方向にDNAを連結することが可能である。また、該プラスミド中の配列と共通の配列をゲノムDNA中に挿入した枯草菌コンピテント細胞と上記で取得したDNA連結単位が多重に繰り返した構造の直鎖の高分子DNAとを共培養することにより、枯草菌ゲノムDNA中に望ましい順番と方向にDNAを連結することが可能である。
combi-OGAB法とは、国際公開番号WO2020/203496号公報に記載の方法であり、枯草菌のプラスミド形質転換系を利用した遺伝子集積法(OGAB法)において、コンビナトリアルライブラリーの集積に用いる全てのDNA断片のモル濃度の比率が可能な限り1に近づくようにする方法である。具体的には、コンビナトリアル化の対象となる選択肢遺伝子断片を一通り連結した種プラスミドを構築する。そして、別の選択肢遺伝子断片についても、別途種プラスミドを構築することで、選択肢の最大数に等しい数の種プラスミドを準備する。各種プラスミドを制限酵素で切断することで、一旦遺伝子断片が等モルに混合された溶液を得る。この溶液は、他の種プラスミドと混合しても等モル性が維持される。その後、これらの溶液が含む各種遺伝子断片を直線状に連結することにより、プラスミドベクター部分が周期的に出現する疑似タンデムリピート状態の高分子DNAを得て、これを用いて枯草菌を形質転換する。枯草菌体内でプラスミドベクター部分の相同性を利用して環状化することによりコンビナトリアルライブラリーを効率よく構築する。
この方法によると、コンビナトリアルライブラリーの構築に必要な等モル濃度の遺伝子断片を極めて簡便にかつ確実に準備でき、ライブラリーの構築規模を従来になく大規模にできるという特徴がある。
本発明の第一の遺伝子クラスターは、マルチモジュール型生合成酵素をコードする複数の遺伝子を含む遺伝子クラスターである。
本発明の第二の遺伝子クラスターは、枯草菌の複製起点、大腸菌の複製起点及び放線菌への接合開始配列を含む遺伝子クラスターである。
本発明の枯草菌の複製起点はその機能を発揮できるものであれば良く、特に限定されない。
本発明の大腸菌の複製起点はその機能を発揮できるものであれば良く、特に限定されないが、例えば、RepAなどが挙げられる。
本発明の放線菌への接合開始配列はその機能を発揮できるものであれば良く、特に限定されない。
本発明のプラスミドは、枯草菌の複製起点、大腸菌の複製起点及び放線菌への接合開始配列を含み、大腸菌でのシングルコピーメンテナンスのための原核生物のF因子分配システム、定義された場所でレシピエント宿主のゲノムにベクターを組み込むことを可能にする部位特異的組換えシステム、枯草菌、大腸菌、および放線菌発現宿主で機能する1つまたは複数の選択マーカーなどを含んでいても良い。
本発明のマルチモジュール型生合成酵素の製造方法は、マルチモジュール型生合成酵素をコードする複数の遺伝子を含むプラスミドの製造方法であって、枯草菌を用いたDNAの集積方法により、前記複数の遺伝子を含む第一の遺伝子クラスターの調整と、枯草菌の複製起点、大腸菌の複製起点及び放線菌への接合開始配列を含む第二の遺伝子クラスターと前記第一の遺伝子クラスターとの連結と、を行うことを特徴とするプラスミドの製造方法により製造されたプラスミドを用いることができる。
また、前記枯草菌を用いたDNAの集積方法が、OGAB法によるもので製造されたプラスミドを用いることができる。
コドン最適化前のGC含量(%):
LipPKS1: 74.2%
LipPKS2: 72.3%
LipPKS3: 71.3%
LipPKS4: 71.3%
LipNRPS: 75.2%
LipMT: 71.1%
LipTE: 74.5%
コドン最適化後のGC含量(%):
LipPKS1: 63.7%
LipPKS2: 63.7%
LipPKS3: 63.9%
LipPKS4: 63.9%
LipNRPS: 65.3%
LipMT: 59.6%
LipTE: 65.6%
Claims (9)
- マルチモジュール型生合成酵素をコードする複数の遺伝子を含むプラスミドの製造方法であって、枯草菌を用いたDNAの集積方法により、前記複数の遺伝子を含む第一の遺伝子クラスターの調整と、枯草菌の複製起点、大腸菌の複製起点及び放線菌への接合開始配列を含む第二の遺伝子クラスターと前記第一の遺伝子クラスターとの連結と、を行うことを特徴とするプラスミドの製造方法。
- 前記枯草菌を用いたDNAの集積方法がOGAB法である請求項1に記載のプラスミドの製造方法。
- 請求項1又は2の方法で製造されたプラスミド。
- 請求項1又は2の方法で製造されたプラスミドを有する放線菌。
- 請求項1の方法で製造されたプラスミドを有する宿主細胞にマルチモジュール型生合成酵素を生産させるマルチモジュール型生合成酵素の製造方法。
- 前記宿主細胞が放線菌である請求項5に記載のマルチモジュール型生合成酵素の製造方法。
- 前記放線菌が大腸菌との接合伝達によりプラスミドを取得した放線菌である請求項6に記載のマルチモジュール型生合成酵素の製造方法。
- 前記マルチモジュール型生合成酵素がI型ポリケチド合成酵素(PKS)である請求項5に記載のマルチモジュール型生合成酵素の製造方法。
- 請求項5~8のいずれか一項に記載の方法で製造されたマルチモジュール型生合成酵素。
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