JP4511517B2 - CoQ10の微生物による生成 - Google Patents
CoQ10の微生物による生成 Download PDFInfo
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- JP4511517B2 JP4511517B2 JP2006501840A JP2006501840A JP4511517B2 JP 4511517 B2 JP4511517 B2 JP 4511517B2 JP 2006501840 A JP2006501840 A JP 2006501840A JP 2006501840 A JP2006501840 A JP 2006501840A JP 4511517 B2 JP4511517 B2 JP 4511517B2
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Description
DPP合成酵素をコードするヌクレオチド配列は
(a)配列番号16で特定されるDNA配列またはその相補鎖、
(b)(a)に定義のDNA配列またはその断片と標準的な条件下でハイブリッド形成し、DPP合成酵素の活性を有するポリペプチドをコードするDNA配列、
(c)配列番号17で表されるポリペプチドをコードするDNAと少なくとも80%、好ましくは少なくとも90%同一であり、DPP合成酵素の活性を有するポリペプチドをコードするDNA配列、および
(d)配列番号17で表されるアミノ酸配列と少なくとも80%同一であるポリペプチドをコードし、DPP合成酵素の活性を有するポリペプチドをコードするDNA配列
からなる群から選択され、
4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼをコードするヌクレオチド配列は
(a’)配列番号23で特定されるDNA配列またはその相補鎖、
(b’)(a’)に定義のDNA配列またはその断片と標準的な条件下でハイブリッド形成し、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼの活性を有するポリペプチドをコードするDNA配列、
(c’)配列番号24で表されるポリペプチドをコードするDNAと少なくとも80%、好ましくは少なくとも90%同一であり、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼの活性を有するポリペプチドをコードするDNA配列、および
(d’)配列番号24で表されるアミノ酸配列と少なくとも80%同一であるポリペプチドをコードし、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼの活性を有するポリペプチドをコードするDNA配列
からなる群から選択される
単離されたDNAを対象とする。
(a)DPP合成酵素を有するタンパク質をコードする遺伝子および/または4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼを有するタンパク質をコードする遺伝子の発現を増加させて、前記タンパク質の活性を高めるステップ、
(b)補酵素Q−10が生成される培地および条件下で、微生物または宿主細胞を培養するステップ
を含む、微生物における補酵素Q−10の生成の方法またはプロセスを提供する。DPP合成酵素をコードする遺伝子はddsAとして知られ、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼをコードする遺伝子はubiAとして知られている。一態様において、さらに本方法は、前記微生物のcrtE遺伝子を突然変異させることにより、ゲラニルゲラニル二リン酸(GGPP)合成酵素の活性を除去するステップを含む。
(a)配列番号16で特定されるDNA配列またはその相補鎖、
(b)(a)に定義されるDNA配列と相補的なDNA配列またはその断片と標準的な条件下でハイブリット形成し、デカプレニル二リン酸(DPP)合成酵素の活性を有するポリペプチドをコードするDNA配列、
(c)(a)または(b)のDNA配列によってコードされるアミノ酸配列を有するポリペプチドをコードするDNA配列、
(d)配列番号17のアミノ酸配列を含むポリペプチドをコードするDNAと少なくとも80%の程度まで同一であり、デカプレニル二リン酸(DPP)合成酵素の活性を有するポリペプチドをコードするDNA配列、および
(e)配列番号17のアミノ酸配列と少なくとも80%の程度まで同一なアミノ酸配列を含むポリペプチドをコードし、デカプレニル二リン酸(DPP)合成酵素の活性を有するポリペプチドをコードするDNA配列
からなる群から選択されるデカプレニル二リン酸(DPP)合成酵素をコードするヌクレオチド配列を含むDNAと、
(a’)配列番号23で特定されるDNA配列またはその相補鎖、
(b’)(a’)に定義されるDNA配列と相補的なDNA配列またはその断片と標準的な条件下でハイブリット形成し、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼの活性を有するポリペプチドをコードするDNA配列、
(c’)(a’)または(b’)のDNA配列によってコードされるアミノ酸配列を有するポリペプチドをコードするDNA配列、
(d’)配列番号24のアミノ酸配列を含むポリペプチドをコードするDNAと少なくとも80%の程度まで同一であり、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼの活性を有するポリペプチドをコードするDNA配列、および
(e’)配列番号24のアミノ酸配列と少なくとも80%の程度まで同一なアミノ酸配列を含むポリペプチドをコードし、4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼの活性を有するポリペプチドをコードするDNA配列
からなる群から選択される4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼをコードするヌクレオチド配列と
を含むDNA
から選択された単離DNAを提供することである。
大腸菌株は、37℃でLB培地(Becton Dickinson、米国メリーランド州スパークス)で増殖させた。組換え菌株でのプラスミドの維持のために、アンピシリン(100μg/mL)および/またはカナマイシン(実験によって25〜50μg/mL)を培地に添加した。寒天(最終濃度1.5%)を固形培地に添加した。液体培地は、200rpmで、回転振盪機で増殖させた。
すべての培養は、凍結した細胞懸濁液(−80℃で15〜20%グルセロース保存)から開始された。流加発酵の前培養は、2組のそれぞれ200mLの362F/2培地の入った2Lのバッフル付き振盪フラスコで調製した。各フラスコに対して解凍した細胞懸濁液1mLを接種物として使用した。前培養の初期のpHは7.2であった。前培養は、660nmでの光学密度(OD660)が14〜22吸光度(使用される菌株による)となったあと、28℃、250rpmで、28時間振盪培養した。この培養物は、Biostat EDバイオリアクター(B.Braun Biotech International、ドイツ メルスンゲン)で培養し、この中には以下の組成を有する培地を含んだ(蒸留水1Lあたり):D−グルコース・H2O 25g、酵母エキス(Tastone900)17g、NaCl 4.0g、MgSO4・7H2O 6.25g、(NH4)2Fe(SO4)2・6H2O 0.5g、ZnSO4・7H2O 0.038g、MnSO4・H2O 0.013g、NiSO4・5H2O 0.001g、CaCl2・2H2O 0.47g、FeCl3・6H2O 0.062g、ナイアシン0.01g、NH4Cl 0.5g、泡止め剤0.1mL、KP溶液3.5mL。KP溶液の組成は、K2HPO4 250g、NaH2PO4・2H2O 200g、(NH4)2HPO4 100gである(蒸留水1Lあたり)。カナマイシン(最終濃度50mg/L)をプラスミド保有株の培地に添加した。すべての方法で使用した供給溶液は、D−グルコース・H2O 550g、KP溶液18.25mLの組成を有した(蒸留水1Lあたり)。バイオリアクターの初期体積(接種後)は8Lであった。前培養は、例えば、初期OD660値を0.5にするためバイオリアクターに滅菌水50mL加えるというように、必要に応じて希釈した。発酵条件は自動的に、28℃、pH7.2(pHは28%NH4OHの添加で制御)、最低撹拌速度300rpm、および通気速度1v.v.m.(最終体積に対して)に制御され、溶存酸素は最低相対値40%に制御された(カスケードで撹拌しながら)。これらの条件下で、培養は約20時間、供給溶液の添加なしに進めた(回分期)。これ以降、撹拌速度の減速、基礎的消費の急激な減少、CO2生成の減少が見られ、このことは初期のグルコースが消費され、供給が開始されたことを示していた。標準的な供給プロフィールは(供給の開始時点から)、17時間は50g/hから80g/hへ増加し、7時間は80g/hで持続し、次に、11時間は55g/hへ減少し、残りの発酵期間は55g/hで維持すると定義した。本培養の最終体積は、約10mLであった。
ガードカラム:Pelliguard LC−18カートリッジ、20mm(SUPELCO、特許番号59654)
移動相:アセトニトリル、メタノール、TBMEの混合液(比率58%、10%、32%)、均一濃度溶離
実行時間:25分
通常カラム圧:開始時48bar
流速:1.0mL/分
検出:紫外部280nm
注入量:20μL
カラム温度:15℃
Claims (2)
- (1)デカプレニル二リン酸(DPP)合成酵素をコードするヌクレオチド配列であって、配列番号16で特定されるDNA配列またはその相補鎖と、
(2)4−ヒドロキシ安息香酸ポリプレニルトランスフェラーゼをコードするヌクレオチド配列であって、配列番号23で特定されるDNA配列またはその相補鎖と、
を含む単離されたDNA。 - 請求項1に記載のDNAが挿入された発現ベクターまたはプラスミドを含む微生物。
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KR100738681B1 (ko) * | 2007-04-11 | 2007-07-12 | 대상 주식회사 | 코엔자임 q10의 생산성이 우수한 변이주 및 코엔자임q10의 생산방법 |
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