JP6646075B2 - L−リジンを生産する微生物及びそれを用いたl−リジン生産方法 - Google Patents
L−リジンを生産する微生物及びそれを用いたl−リジン生産方法 Download PDFInfo
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- JP6646075B2 JP6646075B2 JP2017568121A JP2017568121A JP6646075B2 JP 6646075 B2 JP6646075 B2 JP 6646075B2 JP 2017568121 A JP2017568121 A JP 2017568121A JP 2017568121 A JP2017568121 A JP 2017568121A JP 6646075 B2 JP6646075 B2 JP 6646075B2
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Description
リジン生産能を増加させる遺伝子を獲得するための目的で、下記の方法によりベクターライブラリーを製作した。まず、EZ-Tn5TM<R6Kγori/KAN-2>Tnp TransposomeTM Kit(Epicentre)を用いて得られたプラスミドをKCCM11016P(前記微生物はKFCC10881として公開された後、ブダペスト条約下の国際寄託機関に再寄託されてKCCM11016Pと寄託番号を付与される、特許文献1)菌株を親菌株とし、形質転換してカナマイシン(25mg/l)が含まれた複合平板培地に塗抹し、約20,000個のコロニーを確保した。
ブドウ糖10g、ペプトン 10g、肉抽出物 5g、酵母抽出物 5g、脳心臓浸出液 18.5g、NaCl 2.5g、尿素 2g、ソルビトール 91g、寒天 20g(蒸留水1リットル基準)
前記実施例1で確保した約20,000個のコロニーをそれそれ300μlの選別培地に接種して96ディープウェルプレートで32℃、1000rpmで約24時間培養した。培養液で生産されたL-リジンの生産量を分析するためにニンヒドリン法を利用した(非特許文献3)。培養が完了した後、培養上清液10μlとニンヒドリン反応溶液190μlとを65℃で30分間反応させた後、波長570nmで分光光度計で吸光度を測定し、対照区であるKCCM11016Pと比較して高い吸光度を示す変異菌株として約60種余りのコロニーを選別した。その他のコロニーは対照区として用いられたKCCM11016P菌株と類似するかまたは減少した吸光度を示した。
ブドウ糖10g、硫酸アンモニウム 5.5g、MgSO4・7H2O 1.2g、KH2PO4 0.8g、K2HPO4 16.4g、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 2000μg(蒸留水1リットル基準)
前記実施例2で選抜された10種の菌株を対象にL‐リジン生産能が増加された菌株を最終選別するため、下記の培地を用いてフラスコにおける再現性テストを行った。前記10種の菌株と対照群とを下記の種培地25mlを含有する250mlコーナーバッフルフラスコに接種し、30℃で20時間、200rpmで振とう培養した。その後、1mlの種培養液を下記の生産培地24mlを含有する250mlコーナーバッフルフラスコに接種して、37℃で96時間、200rpmで振とう培養した。前記種培地と生産培地との組成はそれぞれ下記のとおりである。培養が完了した後、HPLCを用いて培養液内のL‐リジン濃度を分析し、各突然変異株のL‐リジン生産濃度を下記表1に示した。
ブドウ糖20g、ペプトン 10g、酵母抽出物 5g、尿素 1.5g、KH2PO44g、K2HPO4 8g、MgSO4・7H2O 0.5g 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 2000μg(蒸留水1リットル基準)
ブドウ糖100g、(NH4)2SO4 40g、大豆タンパク質 2.5g、トウモロコシ浸漬固形分(Corn Steep Solids) 5g、尿素 3g、KH2PO4 1g、MgSO4・7H2O 0.5g 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(蒸留水1リットル基準)
本実施例では、前記実施例3で最終選別された菌株を対象にトランスポゾンのランダム挿入により欠損された遺伝子を同定しようとした。KCCM11016P/mt‐1とKCCM11016P/mt‐8とのゲノムDNAを抽出して溶解した後、ライゲーションして大腸菌DH5αで形質転換し、カナマイシン(25mg/l)が含まれたLB固体培地に塗抹した。形質転換されたコロニー20種をそれぞれ選別した後、未知の遺伝子一部が含まれたプラスミドを獲得し、EZ-Tn5TM<R6Kγori/KAN-2>Tnp TransposomeTM Kitに含まれている配列番号9及び配列番号10の配列を用いて塩基配列を分析した結果(表2)、突然変異株でそれぞれNCgl2108、NCgl2986遺伝子が不活性化されていたことが分かった。
本実験例では、NCgl1480、NCgl2107、NCgl2108及びNCgl2986遺伝子の不活性化とL‐リジン生産能との影響を確認するために、前記実施例4で選別されたNCgl1480、NCgl2107、NCgl2108及びNCgl2986遺伝子をコリネバクテリウムL‐リジン生産菌株の染色体上から欠損させるための組換えプラスミドを製作した。
代表的なL‐リジン生産コリネバクテリウム属菌株であるKCCM11016P菌株を基盤に、前記で選別した細胞壁加水分解関連タンパク質遺伝子の不活性化菌株を製作して、そのリジン生産能を評価しようとした。
ブドウ糖20g、(NH4)2SO4 10g、ペプトン 10g、酵母抽出物 5g、尿素 1.5g、KH2PO44g、K2HPO4 8g、MgSO4・H2O 0.5g 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 2000μg(蒸留水1リットル基準)
ブドウ糖100g、(NH4)2SO4 40g、大豆タンパク質 2.5g、トウモロコシ浸漬固形分(Corn Steep Solids) 5g、尿素 3g、KH2PO4 1g、MgSO4・H2O 0.5g 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(蒸留水1リットル基準)
リジン生合成経路が強化されたL‐リジン生産菌株であるコリネバクテリウム・グルタミカムKCCM10770P(特許文献2)で細胞壁加水分解に関連するタンパク質の不活性化効果が前記実施例6の実験結果と類似であるかを比較するため、4種の細胞壁加水分解に関連するタンパク質が不活性化された菌株を前記実施例6と同様の方法で製造して、KCCM10770P::ΔNCgl1480、KCCM10770P::ΔNCgl2107、 KCCM10770P::ΔNCgl2108、KCCM10770P::ΔNCgl2986と命名し、L‐リジン生産能を比較した。
人工変異法により製作されたコリネバクテリウム・グルタミカムL‐リジン生産菌株であるKCCM11347P(前記微生物はKFCC10750として公開された後、ブダペスト条約下の国際寄託機関に再寄託されて、KCCM11347Pを付与された、特許文献3)でも細胞壁加水分解に関連するタンパク質の不活性化の効果を確認するために、4種の細胞壁加水分解に関連するタンパク質が不活性化された菌株を前記実施例6と同様の方法で製造して、KCCM11347P::ΔNCgl1480、KCCM11347P::ΔNCgl2107、 KCCM11347P::ΔNCgl2108、KCCM11347P::ΔNCgl2986と命名し、L‐リジン生産能を比較した。
コリネバクテリウム・グルタミカム野生株に3種の変異[pyc(P458S)、hom(V59A)、lysC(T311I)]を導入して、L‐リジン生産能を有することになったコリネバクテリウム・グルタミカムCJ3P(非特許文献4)においても前記実施例6,7,8と同様に細胞壁加水分解に関連するタンパク質の不活性化効果を調べるために、4種の細胞壁加水分解に関連するタンパク質が不活性化された菌株を前記実施例6と同様の方法で製造して、CJ3P::ΔNCgl1480、CJ3P::ΔNCgl2107、CJ3P::ΔNCgl2108、CJ3P::ΔNCgl2986と命名し、L‐リジン生産能を比較した。
前記実施例からL‐リジン生産菌株であるコリネバクテリウム属において細胞壁加水分解関連タンパク質をそれぞれ不活性化させた場合、L‐リジン生産能が増加されること確認した後、関連タンパク質を2種以上同時に不活性化させる場合もL‐リジン生産能が増加されるかを確認しようとした。
Claims (3)
- 細胞壁加水分解関連タンパク質の活性が内在的活性に比べて不活性化されるように変異された、L−リジン生産能を有するコリネバクテリウム属微生物であって、細胞壁加水分解関連タンパク質が、細胞壁関連加水分解酵素またはN‐アセチルムラモイル‐L‐アラニンアミダーゼであり、前記細胞壁加水分解関連タンパク質が、配列番号1〜4で表示されるアミノ酸配列を有するタンパク質からなる群から選択された1種以上のタンパク質である、微生物。
- 前記コリネバクテリウム属微生物が、コリネバクテリウム・グルタミカム(Corynebacterium glutamicum)である、請求項1に記載のL−リジン生産能を有するコリネバクテリウム属微生物。
- (i)請求項1または2に記載のコリネバクテリウム属微生物を培地で培養する段階;及び
(ii)前記培養による培地または前記微生物からL−リジンを回収する段階を含む、L−リジンの製造方法。
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PCT/KR2016/006833 WO2017007159A1 (ko) | 2015-07-03 | 2016-06-27 | L-라이신 생산능을 갖는 미생물 및 이를 이용한 l-라이신 생산 방법 |
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HUE048882T2 (hu) | 2020-08-28 |
JP2018518977A (ja) | 2018-07-19 |
MY171648A (en) | 2019-10-22 |
CN107922954B (zh) | 2022-01-11 |
EP3318637B1 (en) | 2020-04-01 |
ES2790382T3 (es) | 2020-10-27 |
EP3318637A4 (en) | 2018-12-12 |
EP3318637A1 (en) | 2018-05-09 |
US20180195097A1 (en) | 2018-07-12 |
PL3318637T3 (pl) | 2020-08-24 |
KR20170005350A (ko) | 2017-01-12 |
CN107922954A (zh) | 2018-04-17 |
BR112018000074B1 (pt) | 2024-03-05 |
US11104925B2 (en) | 2021-08-31 |
KR101793328B1 (ko) | 2017-11-03 |
RU2683551C1 (ru) | 2019-03-28 |
WO2017007159A1 (ko) | 2017-01-12 |
BR112018000074A2 (pt) | 2018-09-11 |
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