JP6204912B2 - グリセロールの有機酸発酵 - Google Patents
グリセロールの有機酸発酵 Download PDFInfo
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- JP6204912B2 JP6204912B2 JP2014521601A JP2014521601A JP6204912B2 JP 6204912 B2 JP6204912 B2 JP 6204912B2 JP 2014521601 A JP2014521601 A JP 2014521601A JP 2014521601 A JP2014521601 A JP 2014521601A JP 6204912 B2 JP6204912 B2 JP 6204912B2
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- Prior art keywords
- glycerol
- gene
- glpk
- coli
- strain
- Prior art date
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Description
本特許出願は、遺伝子改変微生物を使った発酵によるグリセロールからの有機酸の生産に関する。
脂肪酸のグリセロールエステル(グリセリド、モノグリセリド、ジグリセリド、およびトリグリセリドとも呼ばれている)をメタノール、エタノール、または他のアルコールのグリセロールエステルに転化するために、大規模プロセスが開発され、商業的に使用されている。その結果生じる脂肪酸エステル(脂肪酸メチルエステルについてはFAME、脂肪酸エチルエステルについてはFAEEとも呼ばれている)は、一般に「バイオディーゼル」として知られている。なぜなら、それらは、単独で、または従来の炭化水素と配合して、ディーゼルエンジン用の燃料として使用することができるからである。バイオディーゼルを合成するための原材料には、植物油、動物脂、および廃食用脂を含めることができる。バイオディーゼルプロセスの大量副産物は、グリセロール(グリセリン(glycerinまたはglycerine)とも呼ばれている)である。バイオディーゼルの生産量1キログラムにつき約0.1キログラムのグリセロール副産物が生成する。
本発明は、炭素源としてグリセロールを用いる生物学的発酵によって、商業上関心が持たれる1つ以上の化学品を生産するための微生物およびプロセスを提供する。炭素源としてのグリセロールと、本発明の微生物およびプロセスとを使って、商業上関心が持たれるさまざまな化学品、例えば限定するわけではないが、コハク酸、乳酸、リンゴ酸、フマル酸、1,2−プロパンジオール、1,3−プロパンジオール、1,4−ブタンジオール、エタノールおよび酢酸などを製造することができる。
本発明を使って、商業上関心が持たれる工業的に有用な化学品を数多く製造することができる。これら商業上関心が持たれる化学品の大半は微生物代謝における中間体である。本発明では、これらの微生物中間体の1つ以上が、有意な量かつ商業的に好都合な形で生産されるように、微生物ゲノムおよび増殖条件が適切に操作される。そのような化学品の例には、エタノール、ブタノール、ラクテート、スクシネート、フマレート、マレート、スレオニン、メチオニンおよびリジンなどがあるが、これらに限るわけではない。有機酸は遊離酸としても塩(例えば限定するわけではないがナトリウム、カリウム、マグネシウム、カルシウム、アンモニウムなどの塩)としても存在することができるので、コハク酸、フマル酸、リンゴ酸、アスパラギン酸、スレオニン、メチオニン、およびリジンなどの化学名は、遊離酸とその任意の塩との両方を包含するものとする。同様に、スクシネート、フマレート、マレート、アスパルテートなどの任意の塩も、遊離酸を包含するものとする。
KJ122株におけるグリセロール取り込みおよびグリセロール資化の負の調節の除去
細菌株の平板選択、試験管におけるスクシネート生産、またはpH制御発酵槽におけるスクシネート生産には、3つの異なる最少培地を使用することができる。最少培地を表1に列挙する。リッチなブロスまたはプレートは「LB」とも呼ばれるルリア(Luria)ブロスとした(10g/lトリプトン、5g/l酵母エキス、5g/l塩化ナトリウム)。以下の株をエール大学(コネチカット州ニューヘブン)のColi Genetic Stock Center(CGSC)から入手した:JW3386−1(ΔglpR::kan)およびJW3897−1(ΔglpK::kan)。P1virによる普遍ファージ形質導入を使って、JW3897−1からのΔglpK::kanアレルをKJ122に組み入れて、LB中の50mg/l硫酸カナマイシン+25mMクエン酸ナトリウムを使ってカナマイシン耐性について選択し、グリセロールを唯一の炭素源とする最少プレートでの増殖の欠如によってΔglpK::kanの正しい組み入れを確認した(図2)。結果として生じた株をRY812と名づけた。並行して、BB20−14株(イリノイ大学シャンペーン−アーバナ校(イリノイ州)のJohn Cronanから入手)中に存在する野生型ラムダプロファージを、選択用のN::kanを含む欠損ラムダプロファージを含有する供与株としてのTAP106株(ATCC47075としても知られている)からのP1vir形質導入によって取り除き、上述のようにカナマイシン耐性について選択することによってRY808株を得た。第2ステップでは、glpKi15アレルを含有するRY808からのglpK領域をRY812に形質導入し、最少SSグリセロールプレート(表1参照)での増殖について選択し、カナマイシン耐性の喪失について確認することにより、RY829C株を得た。第3ステップでは、JW3386−1のΔglpR::kanアレルをRY829Cに形質導入し、上述のようにカナマイシン耐性について選択することで、RY819J株を得た。これは、隣接するpck*アレルを保っていることが示される分離株であった(Zhangら 2009a;Zhang et al.,2009b)。
実施例2
試験管におけるグリセロールからのスクシネートの生産
KJ122株およびRY819J株をルリアブロス中で好気的に終夜増殖させた後、スクリューキャップ付き15mlポリプロピレン試験管中の、20g/lグリセロールを含有する12.5mlのNBS培地に、OD600が0.05になるように接種した。管に固く蓋をして、37℃、約60rpmで48時間、New Brunswick Scientificローラードラム上で転がした。Costarスピンフィルターによる遠心分離で細胞を除去することによって培養試料を調製し、必要に応じて0.008M硫酸に希釈し、BioRad Aminex HPX−87Hカラムを装備したAgilentモデル1200装置を用いる高速液体クロマトグラフィー(HPLC)で分析した。カラムを50℃で稼働し、0.008M硫酸を溶媒とし、検出は屈折率と210nmにおける吸収との両方によった。試料を、コハク酸、グリセロール、グルコース、アセテート、および他の副産物の濃度について分析した。各化学品の濃度は純粋な市販化合物で作成した標準曲線を使って算出した。KJ122は0.06g/lのスクシネートを生産したが、RY819Jは0.61g/lのスクシネートを生産し、出発株からの改良は明白だった。
RY819Jの代謝的進化
RY819J株を、10g/lグルコースおよび10g/lグリセロールを含有するNBS培地中で好気的に終夜増殖させてから、50g/lグリセロールおよび50g/lグルコースを含有する300mlのAM1培地(表1参照)が入っている作業容積500mlの有蓋発酵槽に、出発OD600が0.2になるように接種した。磁気撹拌子を使って発酵槽を150rpmで撹拌したが、意図的な通気は行わなかった。このように発酵槽は厳密な嫌気性ではなかった。試料採取中に、また塩基添加から、多少の空気は入ることができるからである。pHは3M炭酸カリウムの添加によって6.5に制御し、温度は40℃に維持した。スクシネートを約48時間生産した。グリセロールとグルコースは並行して消費されたが、48時間後は、グリセロールの一部が残っていた。最終細胞密度は約3.0のOD600であった。同じ培地を使用し、第1発酵槽からの試料を使って、出発OD600が0.2になるように第2発酵槽に接種し、増殖とスクしネート生産を再開した。この再接種手順を本明細書では「継代(transfer)」と呼ぶことにする。スクシネート生産が止まった後に、第3発酵槽への接種物の2回目の継代を上述のように行い、その後、さらに数回の継代を行った。最初の数回の継代中は、増殖を刺激するために、グルコースが培地中に存在した。一般に、最初の数回の継代では、ある程度のグルコースまたは硝酸カリウムが存在しない限り、増殖が遅かったので、後続の継代のために十分な増殖が得られるように、グルコースまたは硝酸塩をさまざまな時点で発酵槽に加えて、増殖を増強した。最初の4回の継代は50g/lグルコース+50g/lグリセロールで開始した。第5〜9継代は50g/lグリセロールだけで開始し、グルコースを含まなかったが、次の継代のために十分な増殖が得られるように、発酵中に10g/lグルコースを加えた。第10継代では、まず1g/l硝酸カリウムを補足し、後に10g/lグルコースを補足した。添加物および発酵槽への添加の時点を、表2に要約する。11回目の継代からは、グルコースも硝酸塩も培地に加えず、唯一の炭素源を50g/lグリセロールとした。それでも、ようやく、継代を行うのに十分な増殖が得られた。試料をさまざまな時点で、上述のようにHPLCで、分析した。第11継代では、384時間後に、グリセロールの全てが消費されており、スクシネート力価は425mMであった。これは、塩基による希釈後に、消費されたグリセロール1グラムあたり1.08グラムのスクシネートという収量を与えることになると計算された。さらに3回の継代を行ったが、コハク酸生産に関して株の性能のさらなる有意な改良は見られなかった。14回目の継代から単一コロニーを分離し、その分離株をRY819J−T14と名づけた(図2)
さまざまなglpKアレルのDNA配列決定
ここで使用した株の多くの元となった大腸菌C(ATCC8739)および大腸菌K−12のglpFKXオペロンの野生型DNA配列は、米国国立衛生研究所のGenBankデータベース、アクセッション番号NC_010468およびNC_000913に、それぞれ見出すことができる。
RY819J−T14からのカナマイシン耐性遺伝子の除去
RY819J−T14株は、「Keio Collection」のメンバーであるJW3386−1株(Baba et al., 2006)から形質導入されたΔglpR::kanアレルを含有している。したがって、ヘルパープラスミドpCP20をこの株に通すことによって、カナマイシン耐性遺伝子kanを除去して、短いDNA「痕(scar)」を残すことができる(Datsenko and Wanner, 2000)。このプロセスをRY819J−T14で行ったところ、カナマイシン感受性誘導体MH23株が生じた。
RY819Jおよび子孫のglpF遺伝子に見いだされる変異の矯正
BB20−14株のglpF遺伝子には点変異が見つかった。この変異はglpK遺伝子と密に連鎖しているので、RY819Jに組み入れられることになり、MH22株にも伝達された(実施例1および5参照)。Jantama et al.(2008a,2008b)に記載されているものと類似する2ステップ遺伝子置換法を使ってこの領域を野生型DNA配列で置き換えることにより、glpF中の変異を取り除いた。第1ステップでは、テンプレートとしてのpCA2(配列番号11)とプライマーBY71(配列番号6)およびBY72(配列番号7)とを用いるPCRによって、cat,sacBカセットを増幅した。その結果生じた3.2キロベースDNAフラグメントを、ヘルパープラスミドpKD46(Datsenko and Wanner,2000)を含有するMH23株に形質転換し、LB+30mg/lクロラムフェニコール上でクロラムフェニコール耐性について選択することで、MH27株(glpF::cat,sacB)を得た。第2ステップでは、テンプレートとしての大腸菌C(ATCC8739)DNAとプライマーBY73(配列番号8)およびBY74(配列番号9)とを用いるPCRによって、野生型glpF領域を増幅した。その結果生じた1.7キロベースDNAフラグメントをMH27に形質転換し、LB+6%スクロース上でスクロース耐性について選択し、LB+30mg/lクロラムフェニコール上でクロラムフェニコール感受性について確認した。その結果生じた株を、pKD46の除去後に、MH28と名づけた(図3)。MH28のglpFおよびglpK領域を配列決定することで、野生型glpFが組み入れられていること、およびglpK中のフィードバック耐性変異が、株構築の全ステップを通して保持されていることを確認した。
pH制御発酵槽におけるKJ122およびMH28によるグリセロールからのスクシネートの生産
出発株KJ122および派生株MH28を、7リットルNew Brunswick Scientific発酵槽におけるスクシネート生産について、接種物を含む3.15リットルの出発容積で評価した(図5および6)。20g/lグリセロールと0.1M MOPS緩衝液(pH7.0)とを含有するNBS培地(表1参照)を使って、150mlの接種物を、振とうフラスコ中で好気的に終夜増殖させた。その接種物を、名目上120g/lグリセロール(A.C.S.グレード、Mallinckrodt Chemicals、カタログ番号5092−02、CAS番号56−81−5)を唯一の炭素源として含む3リットルの発酵培地(表1参照)が入っている発酵槽に加えた。時刻0および発酵の終了時におけるグリセロール濃度の測定値については表4を参照されたい。温度は39℃に保ち、必要に応じて3M炭酸カリウムをポンプ注入することによってpHを7.0に保った。マイクロエアレーションは、空気を40ml/分の速度(この速度は、通気速度を体系的に変化させることによって、魅力的なスクシネート生産レベルにとって十分であることが示された)でポンプ注入することによって一定にした。インペラー速度は750rpmとした。
読者の便宜のために、参考文献を全てここに列挙する。各文献はそのまま本明細書に組み込まれる。
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Claims (9)
- 最少培地中の炭素源としてのグリセロールから少なくとも20g/Lの力価のコハク酸を48時間よりも少ない時間で生産するために遺伝子改変された大腸菌(Eschericha coli)であって、該大腸菌は、フィードバック耐性グリセロールキナーゼ、ならびに、glpFKXオペロン、glpABCオペロンおよびglpD遺伝子からなるグリセロール資化遺伝子の発現を負に調節するリプレッサーの活性の実質的な低下をもたらす、glpR遺伝子の変異を含み、50g/Lグリセロール含有培地での継代培養を経た、大腸菌。
- glpR遺伝子の変異が欠失である、請求項1に記載の大腸菌。
- glpK遺伝子によってコードされるフィードバック耐性グリセロールキナーゼが、フルクトース−1,6−二リン酸による阻害に対して実質的に耐性である、請求項1に記載の大腸菌。
- glpK遺伝子によってコードされるフィードバック耐性グリセロールキナーゼが、ホスホトランスフェラーゼ系の非リン酸化酵素IIAGlcによる阻害に対して実質的に耐性である、請求項1に記載の大腸菌。
- glpK遺伝子によってコードされるフィードバック耐性グリセロールキナーゼが、フルクトース−1,6−二リン酸による阻害およびホスホトランスフェラーゼ系の非リン酸化酵素IIAGlcによる阻害に対して実質的に耐性である、請求項1に記載の大腸菌。
- glpD、glpFKX、およびglpABCからなる群より選択される1つ以上の遺伝子またはオペロンのネイティブプロモーターを、構成的に活性なプロモーターで置き換える変異をさらに含む、請求項1に記載の大腸菌。
- 少なくとも20g/Lの力価のコハク酸を最少培地中のグリセロールから生産するための方法であって、グリセロールを炭素源とする発酵槽中で請求項1〜6のいずれか1項に記載の大腸菌を増殖させ、該発酵槽からコハク酸を収穫することを含む方法。
- 通気速度がブロス1リットルあたり毎分0.15リットル未満の酸素を供給する、請求項7に記載の方法。
- 通気速度がブロス1リットルあたり毎時20mgを上回る酸素を供給する、請求項7に記載の方法。
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WO2013015770A1 (en) | 2013-01-31 |
JP2014521318A (ja) | 2014-08-28 |
US20140234923A1 (en) | 2014-08-21 |
AU2011373671B2 (en) | 2016-04-28 |
CN103842495B (zh) | 2018-04-13 |
EP2734615B1 (en) | 2019-12-25 |
EP2734615A4 (en) | 2014-12-10 |
AU2011373671A1 (en) | 2014-01-30 |
CA2841461A1 (en) | 2013-01-31 |
KR20140083970A (ko) | 2014-07-04 |
US10041094B2 (en) | 2018-08-07 |
KR20160116352A (ko) | 2016-10-07 |
KR101928688B1 (ko) | 2018-12-13 |
CA2841461C (en) | 2020-05-26 |
CN103842495A (zh) | 2014-06-04 |
BR112014001371B1 (pt) | 2021-06-01 |
EP2734615A1 (en) | 2014-05-28 |
BR112014001371A2 (pt) | 2017-03-01 |
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