TW202307201A - 具有減弱之LacI家族DNA結合性轉錄調節子之活性之微生物及使用其之L-麩胺酸之生產方法 - Google Patents
具有減弱之LacI家族DNA結合性轉錄調節子之活性之微生物及使用其之L-麩胺酸之生產方法 Download PDFInfo
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Abstract
本申請案係關於一種具有減弱之LacI家族DNA結合性轉錄調節子蛋白之活性之微生物及一種使用其之L-麩胺酸之生產方法,且本申請案之具有減弱之LacI家族DNA結合性轉錄調節子蛋白之活性之棒狀桿菌屬物種(
Corynebacteriumsp.)微生物具有顯著增加的L-麩胺酸的生產率,且因此與習知微生物相比,使用此微生物有可能以更高產率生產L-麩胺酸。
Description
本申請案係關於一種具有減弱之LacI家族DNA結合性轉錄調節子之活性之微生物及一種使用其之L-麩胺酸之生產方法。
為了生產L-胺基酸及其他有用物質,進行各種研究以研發高效率生產微生物及醱酵製程技術。舉例而言,主要使用目標物質特異性方法,諸如增加編碼L-麩胺酸生物合成中所涉及之酶的基因之表現或移除生物合成所不必要之基因。
然而,根據對L-麩胺酸需求的增加,仍需要研究增加有效L-麩胺酸之生產率。
[專利文獻]
美國專利公開案第2011-0027840號
[技術難題]
本申請案之一個目的為提供一種具有減弱之LacI家族DNA結合性轉錄調節子之活性及增強的L-麩胺酸的生產率之棒狀桿菌屬物種(
Corynebacteriumsp.)微生物。
本申請案之另一目的為提供一種L-麩胺酸之生產方法,其包含在培養基中培養棒狀桿菌屬物種微生物。
[技術解決方案]
此將如下詳細描述。另一方面,本申請案中所揭示之各描述及具體實例可應用於其他描述及具體實例中之各者。換言之,本申請案中所揭示之各種要素的所有組合均屬於本申請案之範圍內。另外,可發現本申請案之範圍不受下文所描述的詳細描述限制。此外,貫穿本說明書引用數篇文章及專利文獻,且指示其等之引用。所引用文章及專利文獻之揭示內容以全文引用之方式併入本文中以更清楚地描述本發明所涉及之技術領域的水準及本發明之內容。
本申請案之一個態樣提供一種具有減弱之LacI家族DNA結合性轉錄調節子之活性之棒狀桿菌屬物種微生物(或菌株、重組細胞)。
在本申請案中,LacI家族DNA結合性轉錄調節子蛋白可為具有LacI家族轉錄調節子活性之蛋白質(例如LacI家族轉錄調節子),且例如可衍生自麩胺酸棒狀桿菌ATCC13869菌株或麩胺酸棒狀桿菌ATCC14067菌株,但不限於此。在一個具體實例中,LacI家族DNA結合性轉錄調節子蛋白可衍生自棒狀桿菌ATCC13869菌株(序列可獲自已知資料庫NCBI之GenBank,且例如其可為GenBank寄存編號第WP_060564415.1號)。在一個具體實例中,衍生自麩胺酸棒狀桿菌之LacI家族DNA結合性轉錄調節子蛋白可具有或包含SEQ ID NO: 3之胺基酸序列,或由該胺基酸序列組成,或基本上由該胺基酸序列組成。特定言之,蛋白質可由由SEQ ID NO: 3之胺基酸序列描述之多肽組成。
在一個具體實例中,LacI家族DNA結合性轉錄調節子蛋白可為具有LacI家族DNA結合性轉錄調節子活性之多肽,其由LacI家族DNA結合性轉錄調節子基因編碼,但不限於此。在一個具體實例中,LacI家族DNA結合性轉錄調節子基因可衍生自麩胺酸棒狀桿菌ATCC13869菌株,且特定言之,其可包含SEQ ID NO: 4之核酸序列(GenBank寄存編號序列ID:CP016335.1之核酸序列中的第1,421,016個至第1,422,125個的序列,例如BBD29_06680基因)。
在一個具體實例中,LacI家族DNA結合性轉錄調節子蛋白可包含與SEQ ID NO: 3所描述之胺基酸序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%、99.7%或99.9%或更高的同源性或一致性或由該序列組成的胺基酸序列。另外,只要其為具有此同源性或一致性且展示出與LacI家族DNA結合性轉錄調節子蛋白相對應之功效的胺基酸序列,具有缺失、修改、取代、保守取代或添加一些序列之胺基酸序列的變異體亦可包含在LacI家族DNA結合性轉錄調節子蛋白中。舉例而言,其為具有序列添加或缺失、天然存在之突變、靜默突變或保守取代的情況,其不改變本申請案之變異體在胺基酸序列N端、C端及/或內部之功能。
保守取代意謂將一個胺基酸用具有類似結構及/或化學特性之另一胺基酸進行取代。此胺基酸取代一般可基於殘基之極性、電荷、溶解性、疏水性、親水性及/或兩親性性質之類似性而發生。通常,保守取代幾乎不影響或不影響蛋白質或多肽的活性。
在本申請案中,多核苷酸或多肽「具有、包含特定核酸序列(核苷酸序列)或胺基酸序列、或由該序列組成、或基本上由該序列組成」可意謂該多核苷酸或多肽基本上包含該特定核酸序列(核苷酸序列)或胺基酸序列,且可解釋為包含「實質上等效的序列」,其中突變(缺失、取代、修改及/或添加)在維持多核苷酸或多肽之原始功能及/或所要功能之範圍內應用於特定核酸序列(核苷酸序列)或胺基酸序列中。在一個具體實例中,多核苷酸或多肽「具有或包含特定核酸序列(核苷酸序列)或胺基酸序列、或由該序列組成、或基本上由該序列組成」可意謂多核苷酸或多肽(i)基本上包含特定核酸序列(核苷酸序列)或胺基酸序列,或(ii)由與特定核酸序列或胺基酸序列具有70%或更高、80%或更高、85%或更高、90%或更高、91%或更高、92%或更高、93%或更高、94%或更高、95%或更高、96%或更高、97%或更高、98%或更高、98%或更高、99%或更高、99.5%或更高或99.9%或更高的同源性或一致性的核酸序列(核苷酸序列)或胺基酸序列組成,或基本上包含此且維持原始功能及/或所要功能。在一個具體實例中,所要功能可意謂微生物之增加(增強)或提供L-麩胺酸生產率之功能。
在本申請案中,「同源性」或「一致性」意謂兩個給定胺基酸序列或核苷酸序列之間的相關程度,且可以表示為百分比。術語、同源性及一致性通常可互換使用。
保守多核苷酸或多肽之序列同源性或一致性藉由標準排列算法確定,且由所用程式建立之預設間隙罰分可一起使用。實質上,同源或一致序列一般可與序列之全部或一部分在中度或高度嚴格條件下雜合。顯而易見的係,雜合亦包括與含有一般密碼子或考慮多核苷酸中之密碼子簡併之密碼子的多核苷酸進行雜合。
任何兩個多核苷酸或多肽序列是否具有同源性、類似性或一致性均可藉由使用已知電腦演算法,諸如使用如Pearson等人(1988)[Proc. Natl. Acad. Sci. USA 85]: 2444之預設參數之「FASTA」程式來確定。否則,其可藉由使用Needleman-Wunsch演算法(Needleman及Wunsch, 1970, J. Mol. Biol. 48: 443-453),如EMBOSS包裝之Needleman程式中所進行(EMBOSS:歐洲分子生物學開放軟體套,Rice等人, 2000, Trends Genet. 16: 276-277)(版本5.0.0或後續版本)(包括GCG程式包(Devereux, J., 等人, Nucleic Acids Research 12: 387 (1984))、BLASTP、BLASTN、FASTA(Atschul, [S.] [F.,] [ET AL, J MOLEC BIOL 215]: 403 (1990);Guide to Huge Computers, Martin J. Bishop, [ED.,] Academic Press, San Diego,1994,及[CARILLO ETA/.](1988) SIAM J Applied Math 48: 1073)。舉例而言,可藉由使用國家生物技術資訊資料庫中心之BLAST或ClustalW確定同源性、類似性或一致性。
多核苷酸或多肽之同源性、類似性或一致性可藉由比較序列資訊來確定,使用例如GAP電腦程式,諸如Needleman等人(1970), J Mol Biol. 48:443,已知於例如Smith及Waterman, Adv. Appl. Math (1981) 2:482。概言之,GAP程式可定義為以類似方式排列之符號(亦即,核苷酸或胺基酸)之數目除以兩個序列中之較短序列中之符號之總數的值。GAP程式之預設參數可包括:(1)二元比較矩陣(含有值1用於一致性及值0用於非一致性)及Gribskov等人(1986) Nucl. Acids Res. 14: 6745之加權比較矩陣,如Schwartz及Dayhoff編, Atlas Of Protein Sequence And Structure, National Biomedical Research Foundation, 第353-358頁(1979)所揭露(或EDNAFULL(NCBI NUC4.4之EMBOSS版本)替代矩陣);(2)各間隙之罰分為3.0及各間隙中之各符號為額外010罰分(或間隙開放罰分為10,及間隙延伸罰分為0.5);及(3)末端間隙無罰分。
在本申請案中,術語「微生物(或菌株)」包括所有野生型微生物或天然或人工基因修改微生物,且可為包含用於生產所要多肽、蛋白質或產物之基因修改的微生物,作為由於諸如插入外來基因或削弱內源性基因的活性等原因而使特定機制減弱或增強的微生物。
在本申請案中,術語多肽之「減弱」為包括全部降低活性或無活性之概念。減弱可與諸如失活、不足、下調、降低、減少、衰減及其類似者之術語一起使用。
減弱亦可包含以下情況:由於編碼多肽(或蛋白質,例如LacI家族DNA結合性轉錄調節子蛋白)的多核苷酸發生突變,多肽本身的活性與原微生物具有的多肽活性相比降低或消失,由於編碼多肽的多核苷酸基因的表現受到抑制或轉譯成多肽的過程受到抑制二導致多肽的總體活性水準及/或濃度(表現量)低於細胞中的天然菌株的情況,完全不表現多核苷酸的情況,及/或即使表現多核苷酸亦不存在多肽活性的情況。當性狀由於由天然或人工因素引起之基因突變而改變時,「內源性活性」意謂轉形前親本菌株或野生型或非經修改之微生物最初所具有的特異性多肽的活性。此可與「修改前的活性」互換使用。與內源性活性相比,多肽之活性為「失活、不足、降低、下調、減少或衰減」,意謂與轉形之前親本菌株或未經修改之微生物最初具有的特定多肽之活性相比,多肽之活性降低。
此多肽(或蛋白質,例如LacI家族DNA結合性轉錄調節子蛋白)之活性的減弱可藉由此項技術中已知之任何方法進行,但不限於此,且可藉由應用此項技術中熟知之各種方法來達成(例如Nakashima N等人, Bacterial cellular engineering by genome editing and gene silencing. Int J Mol Sci. 2014;15(2):2773-2793,Sambrook等人, Molecular Cloning 2012等)。
特定言之,多肽(或蛋白質,例如LacI家族DNA結合性轉錄調節子蛋白;下文中,描述為多肽)之減弱可為
1)缺失編碼多肽之基因的全部或一部分;
2)修改表現調節區(或表現調節序列),使得編碼多肽之基因的表現降低;
3)修改構成多肽之胺基酸序列,使得多肽之活性經移除或減弱(例如胺基酸序列中一或多個胺基酸之缺失/取代/添加);
4)修改編碼多肽之基因的序列,使得多肽之活性經移除或減弱(例如,多肽基因之核酸核苷酸序列中的核酸核苷酸中之一或多者的缺失/取代/添加,使得編碼經修改以移除或減弱多肽之活性的多肽);
5)修改編碼多肽之基因轉錄本的起始密碼子或5'-UTR區的核苷酸序列;
6)引入互補結合於編碼多肽之基因轉錄本的反義寡核苷酸(例如反義RNA);
7)在編碼多肽之基因的Shine-Dalgarno序列的前端添加一個與Shine-Dalgarno序列互補的序列,以形成其中不可能附接核糖體之二級結構;
8)在編碼多肽之基因序列的ORF(開放閱讀框架)的3'端添加一個反方向轉錄的啟動子(反轉錄工程,RTE);或
9)選自上文1)至8)中的兩種或更多種的組合,但不特別限於此。
例如,
1)缺失編碼多肽之基因的全部或一部分可為編碼染色體中之內源性目標多肽的整個多核苷酸缺失,取代成其中核苷酸之一部分缺失的多核苷酸或取代為標記基因。
另外,2)修改表現調節區(或表現調節序列)可為表現調節區(或表現調節序列)上藉由缺失、插入、非保守或保守取代或其等之組合發生突變,或取代為具有較弱活性的序列。表現調節區包括啟動子、操縱序列、編碼核糖體結合位點之序列及調節轉錄及轉譯終止之序列,但不限於此。
此外,3)修改編碼多肽之基因轉錄本的起始密碼子或5'-UTR區的核苷酸序列可例如用編碼另一起始密碼子之核苷酸序列取代,該另一起始密碼子與內源性起始密碼子相比具有較低多肽表現率,但不限於此。
此外,4)及5)之修改胺基酸序列或多核苷酸序列可為藉由多肽之胺基酸序列或編碼多肽之多核苷酸序列的缺失、插入、非保守或保守取代或其等之組合而在序列上發生突變以使多肽之活性變弱,或用經修改而具有較弱活性之胺基酸序列或多核苷酸序列或經修改而不具有活性之胺基酸序列或多核苷酸序列取代,但不限於此。舉例而言,藉由在多核苷酸序列中引入突變以形成終止密碼子,可抑制或衰減基因之表現,但不限於此。「終止密碼子」為充當指示不指代胺基酸之信號的密碼子且蛋白質合成過程在mRNA上之密碼子當中進行,且一般而言,3種UAA、UAG及UGA可用作終止密碼子。
根據一個實例之微生物可經其中在SEQ ID NO: 4之內源基因之ORF(開放閱讀框架)中之序列中引入突變以形成終止密碼子者置換(取代),且例如對應於LacI家族DNA結合性轉錄調節子蛋白之第310個胺基酸(例如麩醯胺酸、Gln、Q)的密碼子可經終止密碼子置換(取代)。舉例而言,在SEQ ID NO:4的核酸序列中,編碼第310個胺基酸麩醯胺酸的多核苷酸係「CAG」,且其可為其中分別引入用「TAA」、「TAG」、「TGA」置換(取代)「CAG」的突變以用終止密碼子取代該突變的多核苷酸。在一個具體實例中,引入突變以形成終止密碼子之核酸序列可為SEQ ID NO: 2之核酸序列(SEQ ID NO: 4之野生型多核苷酸的第928
個C經T取代;C928T)。
6)引入互補結合於編碼多肽之基因轉錄本的反義寡核苷酸(例如反義RNA)可指例如文獻[Weintraub, H.等人, Antisense-RNA as a molecular tool for genetic analysis, Reviews - Trends in Genetics, 第1(1)卷,1986]。
7)在編碼多肽之基因的Shine-Dalgarno序列的前端添加一個與Shine-Dalgarno序列互補的序列,以形成其中不可能附接核糖體之二級結構,使得mRNA轉譯不可能或降低其轉譯速率。
8)在編碼多肽之基因序列的ORF(開放閱讀框架)的3'端添加一個反方向轉錄的啟動子(反轉錄工程,RTE)可使與編碼多肽之基因轉錄本互補的反義核苷酸減弱活性。
在本申請案中,術語多肽活性之「增強」意謂多肽活性與內源性活性相比增加。該增強可與諸如活化、上調、過度表現、增加及其類似者之術語互換使用。本文中,活化、強化、上調、過度表現及增加可包括全部展現出其最初不具有的活性,或與內源性活性或修改之前的活性相比展現出改良的活性。當性狀藉由天然或人工因素之基因突變而改變時,「內源性活性」意謂轉形前親本菌株或非經修改之微生物最初所具有的特異性多肽的活性。此可與「修改前之活性」互換使用。與內源性活性相比,多肽之活性經「增強」、「上調」、「過度表現」或「增加」意謂其與轉形之前親本菌株或未經修改之微生物最初具有的特異性多肽之活性相比活性及/或濃度(表現量)得到改良。
增強可藉由引入外來多肽或增強內源性多肽之活性及/或濃度(表現量)來達成。多肽活性之增強可由相應多肽之活性之水準或表現量或自相應多肽排泄之產物之量的增加來證實。
此項技術中熟知之各種方法可應用於增強多肽之活性,且其不受限制,只要其在修改之前可強化目標多肽活性而非微生物。特定言之,其可使用熟習此項技術者熟知的基因工程改造及/或蛋白質工程改造,其為分子生物學之一般方法,但不限於此(例如Sitnicka等人, Functional Analysis of Genes. Advances in Cell Biology. 2010, 第2卷. 1-16,Sambrook等人, Molecular Cloning 2012等)。
特定言之,增強本申請案之多肽可為
1)增加編碼多肽之多核苷酸在細胞中的複本數;
2)用具有強活性之序列取代編碼多肽之染色體上的基因表現調節區;
3)修改編碼多肽之基因轉錄本的起始密碼子或5'-UTR區的核苷酸序列;
4)修改多肽之胺基酸序列以使得多肽活性增強;
5)修改編碼多肽之多核苷酸序列,使得多肽活性增強(例如,修改多肽基因的多核苷酸序列以編碼經修改以強化多肽的活性的多肽);
6)引入展示多肽或編碼此之外來多核苷酸之活性的外來多肽;
7)對編碼多肽的多核苷酸進行密碼子最佳化;
8)藉由分析多肽之三級結構選擇暴露位點進行變形或化學修改;或
9)選自1)至8)中的2種或更多種的組合,但不特別限於此。
更具體而言,
1)增加編碼多肽之多核苷酸在細胞中的複本數可藉由將載體引入至宿主細胞來達成,該載體可複製且起作用,而不考慮宿主,其中編碼對應多肽之多核苷酸可操作地連接。否則,編碼對應多肽之多核苷酸可藉由在宿主細胞中之染色體中引入1個複本或2個複本或更多個複本來達成。染色體中之引入可以藉由引入能夠將多核苷酸插入染色體中之載體來進行,該載體係引入宿主細胞中,但不限於此。
2)用具有強活性之序列取代編碼多肽之染色體上的基因表現調節區(或表現調節序列)可例如藉由缺失、插入、非保守或保守取代或其等之組合在序列上發生突變,或用具有強得多的活性之序列取代,以進一步強化表現調節區之活性。表現調節區不特別限於此,但可包含啟動子、操縱序列、編碼核糖體結合位點之序列及調節轉錄及轉譯終止之序列及其類似物。作為一個具體實例,其可用強啟動子取代原始啟動子,但不限於此。
已知強啟動子之實例包括CJ1至CJ7啟動子(美國專利US 7662943 B2)、lac啟動子、trp啟動子、trc啟動子、tac啟動子、λ噬菌體PR啟動子、PL啟動子、tet啟動子、gapA啟動子、SPL7啟動子、SPL13(sm3)啟動子(美國專利US 10584338 B2)、O2啟動子(美國專利US 10273491 B2)、tkt啟動子、yccA啟動子及其類似物,但不限於此。
3)修改編碼多肽之基因轉錄本的起始密碼子或5'-UTR區的核苷酸序列可例如用編碼另一起始密碼子之核苷酸序列取代,該另一起始密碼子與內源性起始密碼子相比具有高得多的多肽表現率,但不限於此。
4)及5)之修改胺基酸序列或多核苷酸序列可為藉由多肽之胺基酸序列或編碼多肽之多核苷酸序列的缺失、插入、非保守或保守取代或其等之組合而在序列上發生突變以強化多肽之活性,或用經修改以具有更強活性之胺基酸序列或多核苷酸序列或經修改以增加活性之胺基酸序列或多核苷酸序列取代,但不限於此。取代可特定地藉由將多核苷酸藉由同源重組而插入染色體中來進行,但不限於此。接著,待使用之載體可進一步包含用於確定染色體插入之選擇標記。
6)引入展示多肽活性之外來多肽可為將編碼展示與多肽相同/類似的活性的多肽之外來多核苷酸引入宿主細胞中。外源多核苷酸在其來源或序列上不受限制,只要其展現與多肽相同/類似的活性即可。用於引入之方法可藉由熟習此項技術者適當地選擇已知轉形方法來進行,且多肽由所引入之多核苷酸所表現來產生,且從而可增加其活性。
7)對編碼多肽的多核苷酸進行密碼子最佳化可能係針對內源性多核苷酸的密碼子最佳化以增加宿主細胞中的轉錄或轉譯,或針對外來多核苷酸使其密碼子最佳化以獲得宿主細胞中的最佳化轉錄及轉譯。
8)藉由分析多肽之三級結構選擇暴露位點進行變形或化學修改可例如藉由視待分析之多肽的序列資訊與資料庫(其中儲存鹼基蛋白之序列資訊)進行比較,確定視序列之相似性程度而定的模板蛋白候選物,且基於此來確認結構,且由此選擇待變形或化學修改之暴露位點來變形或修改。
此類增強多肽活性可為基於修改前野生型或微生物菌株中表現的多肽的活性或濃度,相應多肽活性或濃度的表現量增加,或者相應多肽產生的產物的量增加,但不限於此。
本申請案之微生物中之一部分或全部多核苷酸之修改(例如,對編碼前述蛋白質變異體進行修改)可藉由以下方式誘導:(a)使用用於在微生物中插入染色體之載體進行同源重組或使用基因剪刀(經工程改造之核酸酶,例如CRISPR-Cas9)進行基因體校正及/或(b)處理諸如紫外線及放射性射線之光及/或化學物質,但不限於此。修改一部分或全部基因之方法可包括藉由DNA重組技術之方法。舉例而言,藉由將核苷酸序列或包含與目標基因具有同源性之核苷酸序列的載體注射至微生物中以引起同源重組,可實現一部分或全部基因之缺失。待注射之核苷酸序列或載體可包含顯性選擇標記,但不限於此。
在一個具體實例中,多肽(或蛋白質,例如LacI家族DNA結合性轉錄調節子蛋白;下文中,描述為多肽)之衰減可由重組方法引起。重組方法可包括同源重組。當包含編碼多肽之基因序列之一部分的載體轉形至微生物中且在選擇標記產物存在下培養時,同源重組方法可引起基因序列之一部分與微生物中之內源性基因的同源重組。
本申請案之微生物可為LacI家族DNA結合性轉錄調節子蛋白或其編碼之多核苷酸失活或衰減的微生物;或由載體遺傳修改以使得LacI家族DNA結合性轉錄調節子蛋白或多核苷酸失活或衰減的微生物(例如重組微生物),但不限於此。
本申請案之微生物(或菌株,重組細胞)可為具有L-麩胺酸生產率或增強之L-麩胺酸生產率(或產率)之微生物。
本申請案之微生物可為天然具有L-麩胺酸生產率之微生物,或其中LacI家族DNA結合性轉錄調節子蛋白之活性減弱及/或使不具有L-麩胺酸生產率之親本菌株得到L-麩胺酸生產率或改良生產率的微生物,但不限於此。
微生物(或菌株,重組細胞)具有改良的L-麩胺酸生產率(或產量)或具有L-麩胺酸生產率可意謂,在微生物(或菌株,重組細胞)中,與未經修改之微生物、重組之前的細胞、親本菌株及/或野生型菌株相比L-麩胺酸生產率經改良,或得到的L-麩胺酸生產率與不具有L-麩胺酸生產率的未經修改之微生物、重組之前的細胞、親本菌株及/或野生型菌株的不同。
根據一個具體實例之具有衰減之LacI家族DNA結合性轉錄調節子蛋白之活性之微生物與同源未經修改之微生物相比可具有改良(增加)之L-麩胺酸生產率。在本申請案中,「未經修改之」微生物不排除包含可能天然存在於微生物中之突變的菌株,但其可為野生型菌株或天然菌株本身,或意謂由於自然或人工因素引起的基因突變而改變性狀之前的菌株。舉例而言,未經修改之微生物可意指根據一個具體實例,LacI家族DNA結合性轉錄調節子蛋白之活性未衰減的菌株或在其衰減之前的菌株(或誘導LacI家族DNA結合性轉錄調節子蛋白之活性衰減的突變未經引入或在引入之前的菌株)。「未經修改之微生物」可與「修改前菌株」、「修改前微生物」、「未經突變之菌株」、「未經修改之菌株」、「未經突變之微生物」、或「標準微生物」互換使用。LacI家族DNA結合性轉錄調節子蛋白之活性如前述衰減。在一個具體實例中,用於比較L-麩胺酸生產率是否增加之目標菌株、未經修改之微生物可為麩胺酸棒狀桿菌ATCC13032菌株、麩胺酸棒狀桿菌ATCC13869菌株、麩胺酸棒狀桿菌ATCC14067菌株、麩胺酸棒狀桿菌野生型中缺失odhA基因的菌株(例如ATCC13869△odhA菌株)或麩胺酸棒狀桿菌BL2菌株,被稱為生產L-麩胺酸的NTG突變型菌株(KFCC11074,韓國專利第10-0292299號),但不限於此。
微生物(或菌株,重組細胞)可進一步包含突變以增加L-麩胺酸之生產量,且只要其增加L-麩胺酸之生產量,突變之位置及/或待突變之基因及/或蛋白質之類型可不受限制被包括。可無限制地使用重組細胞,只要其為可轉形細胞即可。
作為一個具體實例,與突變型或未修改之微生物之前的親本菌株相比,在具有改良(增加)生產率(或產量)的微生物(或菌株,重組細胞)中,L-麩胺酸生產率可增加約1%或更多、約2.5%或更多、約5%或更多、約6%或更多、約7%或更多、約8%或更多、約9%或更多、約10%或更多、約10.5%或更多、約11%或更多、約11.5%或更多、約12%或更多、約12.5%或更多、約13%或更多、約13.5%或更多、約14%或更多、約14.5%或更多、約15%或更多、約15.5%或更多、約16%或更多、約16.5%或更多、約17%或更多、約17.4%或更多、約17.5%或更多、約18%或更多、約18.5%或更多、約19%或更多、約19.5%或更多、約20%或更多、約20.5%或更多、約21%或更多、約21.1%或更多、約21.5%或更多、約21.5%或更多、約22%或更多、約22.5%或更多、約23%或更多、約23.5%或更多、約24%或更多、約24.5%或更多、約25%或更多、約25.5%或更多、約26%或更多、約26.5%或更多、約27%或更多、約27.5%或更多、約28%或更多、約28.5%或更多、約29%或更多、約29.5%或更多、約30%或更多、約31%或更多、約32%或更多、約33%或更多、約34%或更多或35%或更多(上限不受特別限制,且舉例而言,其可為約200%或更少、約150%或更少、約100%或更少、約50%或更少、約45%或更少或約40%或更少或約35%更少),且在一個具體實例中,其可增加約17.2%或更多、約21.4%或更多或約21.6%或更多。在另一具體實例中,與突變型或未修改之微生物之前的親本菌株相比,在具有改良(增加)生產率(或產量)的微生物(或菌株,重組細胞)中,L-麩胺酸生產率可增加約1.1倍或更多、約1.12倍或更多、約1.13倍或更多、1.15倍或更多、1.16倍或更多、1.17倍或更多、1.18倍或更多、1.19倍或更多、約1.2倍或更多、約1.21倍或更多、約1.22倍或更多、1.25倍或更多或約1.3倍或更多(上限不受特別限制,且舉例而言,其可為約10倍或更少、約5倍或更少、約3倍或更少或約2倍更少),且在一個具體實例中,其可增加約1.172倍或更多、約1.214倍或更多或約1.216倍或更多。更特定言之,與突變型或未修改之微生物之前的親本菌株相比,在具有增加生產率(或產量)的重組菌株中,L-麩胺酸生產率可增加約17.2%、約21.4%或約21.6%(或約1.17倍、約1.21倍或約1.22倍),但不限於此。術語「約」為包括所有±0.5、±0.4、±0.3、±0.2、±0.1及其類似者的範圍,且包括等於或類似於術語約以下值的範圍內的所有值,但不限於此。
在一個具體實例中,棒狀桿菌屬物種微生物可能係麩胺酸棒狀桿菌、克魯迪拉克棒狀桿菌(
Corynebacterium crudilactis)、沙漠棒狀桿菌(
Corynebacterium deserti)、高效棒狀桿菌(
Corynebacterium efficiens)、帚石南棒狀桿菌(
Corynebacterium callunae)、停滯棒狀桿菌(
Corynebacterium stationis)、奇棒狀桿菌(
Corynebacterium singulare)、耐鹽棒狀桿菌(
Corynebacterium halotolerans)、紋帶棒狀桿菌(
Corynebacterium striatum)、產氨棒狀桿菌(
Corynebacterium ammoniagenes)、污染棒狀桿菌(
Corynebacterium pollutisoli)、亞胺棒狀桿菌(
Corynebacterium imitans)、龜板棒狀桿菌(
Corynebacterium testudinoris)及/或淡黃棒狀桿菌(
Corynebacterium flavescens)。
作為其他一個具體實例,本申請案之重組微生物可為如下微生物,其中L-麩胺酸之生物合成路徑中蛋白質之一部分的活性進一步增強,或L-麩胺酸之降解路徑中蛋白質之一部分的活性額外失活以強化L-麩胺酸生產率。
特定言之,本申請案之微生物可為如下微生物,其中OdhA蛋白進一步失活或odhA基因進一步缺失。更特定言之,本申請案之微生物可能係其中在麩胺酸棒狀桿菌ATCC13869中失活OdhA蛋白質的麩胺酸棒狀桿菌;或在麩胺酸棒狀桿菌ATCC13869中缺失odhA基因的微生物。OdhA蛋白可包含NCBI序列ID WP_060564343.1之胺基酸序列(例如,SEQ ID NO: 23之胺基酸序列)。OdhA蛋白質可為具有多官能酮戊二酸脫羧酶/酮戊二酸脫氫酶硫胺素焦磷酸結合次單元/二氫脂醯離胺酸-殘基丁二醯轉移酶次單元之活性的蛋白,該蛋白衍生自麩胺酸棒狀桿菌菌株。
odhA基因可衍生自麩胺酸棒狀桿菌ATCC13869菌株,且特定言之,其可包含SEQ ID NO: 24之核酸序列(GenBank寄存編號序列ID:CP016335.1之核酸序列中的第1,276,170個至第1,279,787個的序列,例如BBD29_06050基因)。
然而,OdhA蛋白失活或
odhA基因缺失為一類實例,且其不限於此,且本申請案之微生物可為各種已知的L-麩胺酸生物合成路徑之蛋白活性增強或降解路徑之蛋白活性失活或減弱的微生物。
本申請案之另一態樣提供一種L-胺基酸之生產方法,其包含在培養基中培養本申請案之微生物。
本申請案之L-胺基酸之生產方法可包含在培養基中培養本申請案之微生物。本申請案之微生物如前述。
此外,本申請案之L-胺基酸可為L-麩胺酸。
在本申請案中,「培養」意謂使本申請案之麩胺酸棒狀桿菌菌株在經適當調整的環境條件下生長。本申請案的培養過程可根據適當培養基及此項技術中已知的培養條件進行。此類培養方法可藉由熟習此項技術者根據待選擇之菌株容易地調整其而使用。特定言之,培養可為分批的、連續的及/或分批補料的,但不限於此。
在本申請案中,「培養基」意謂其中培養本申請案之麩胺酸棒狀桿菌菌株所需的養分經混合作為主要組分且供應養分及生長因子及其類似物的物質,包括存活及生長所必需的水。特定言之,可不受特定限制地使用用於培養本申請案之麩胺酸棒狀桿菌菌株的培養基及其他培養條件,只要其為用於培養常見微生物的培養基即可,但本申請案之麩胺酸棒狀桿菌菌株可在含有碳源、氮源、磷源、無機化合物、胺基酸及/或維生素等適合的普通培養基中,在好氧條件下,一邊調整溫度、pH值等一邊進行培養。
特定言之,棒狀桿菌屬物種菌株之培養基可在文獻[「《普通細菌學方法手冊(Manual of Methods for General Bacteriology)》」由美國細菌學協會編寫(美國華盛頓特區,1981年)]中發現。
在本申請案中,碳源可包括碳水化合物,諸如葡萄糖、蔗糖、乳糖、果糖、蔗糖、麥芽糖及其類似物;糖醇,諸如甘露糖醇、山梨糖醇及其類似物;有機酸,諸如丙酮酸、乳酸、檸檬酸及其類似物;及胺基酸,諸如麩胺酸、甲硫胺酸、離胺酸及其類似物。另外,可使用天然有機養分,諸如澱粉水解產物、糖蜜、黑糖蜜、米糠、木薯、甘蔗渣以及玉米浸漬液,且具體言之,可使用碳水化合物,諸如葡萄糖及滅菌經預處理之糖蜜(亦即轉化成還原糖之糖蜜)及其類似物,且可不受限制地使用其他適當量之碳源。此等碳源可單獨或以兩種或更多種類別之組合形式使用,但不限於此。
作為氮源,可使用無機氮源,諸如氨、硫酸銨、氯化銨、乙酸銨、磷酸銨、碳酸銨、硝酸銨及其類似物;及有機氮源,諸如胺基酸,包括麩胺酸、甲硫胺酸、麩醯胺酸及其類似物、蛋白腖、NZ-胺、肉萃取物、酵母萃取物、麥芽萃取物、玉米浸漬液、酪蛋白水合物、魚或其分解產物、經脫脂之大豆餅或其分解產物及其類似物。此等氮源可單獨或以兩種或更多種類別的組合使用,但不限於此。
磷源可包含磷酸一氫鉀、磷酸二氫鉀或與其對應之含鈉鹽或其類似物。可使用氯化鈉、氯化鈣、氯化鐵、硫酸鎂、硫酸鐵、硫酸錳、碳酸鈣以及類似物作為無機化合物,且可包括其他胺基酸、維生素及/或適當前驅物以及類似物。此等組分或前驅物可以分批或連續方式添加至培養基中。然而,其不限於此。
另外,在本申請案的棒狀桿菌屬物種菌株的培養期間,可以適當方式將化合物(諸如氫氧化銨、氫氧化鉀、氨、磷酸、硫酸以及類似物)添加至培養基中以調整培養基的pH。此外,在培養期間,諸如脂肪酸聚乙二醇酯之消泡劑可用於抑制氣泡產生。另外,為了維持培養基的好氧條件,將氧氣或含氧氣體注入培養基中,或為了維持厭氧及非好氧條件,可注入氣體、氮氣、氫氣或二氧化碳氣體,但不限於此。
在本申請案的培養中,培養溫度可維持在20至45℃,特定言之25至40℃,且培養可進行約10至160小時,但不限於此。
藉由本申請案的培養生產的L-胺基酸(例如,L-麩胺酸)可以分泌至培養基中或殘留在細胞中。
本申請案之L-胺基酸之生產方法可進一步包含例如在培養之前製備本申請案之微生物(菌株),製備用於培養微生物之培養基或其等之組合(以任何次序)。
本申請案之L-胺基酸之生產方法可進一步包含根據培養自培養基(其中進行培養之培養基)或微生物(棒狀桿菌屬物種菌株)回收L-胺基酸。回收可進一步包含在培養之後。
回收可藉由使用此項技術中已知之適當方法,根據本申請案之微生物的培養方法(例如分批、連續或分批補料培養方法及其類似方法)收集目標L-胺基酸。舉例而言,可使用離心、過濾、用結晶之蛋白質沈澱劑處理(鹽析方法)、萃取、超音波破壞、超過濾、透析、各種類型之層析(諸如分子篩層析(凝膠過濾)、吸附層析、離子交換層析、親和層析及類似層析)、HPLC或此等方法之組合,且目標L-胺基酸可藉由使用此項技術中已知之適當方法自培養基或微生物回收。
另外,本申請案之L-胺基酸之生產方法可另外包含純化。純化可藉由使用此項技術中已知之適合方法進行。在一個具體實例中,當本申請案之L-胺基酸之生產方法包含回收及純化兩者時,回收及純化可以任何順序連續或非連續地執行,或可同時執行或整合成一個步驟,但不限於此。
本申請案之其他一個態樣提供一種用於生產L-胺基酸(例如,L-麩胺酸)之組合物,其包含本申請案之微生物;培養其之培養基;或其中2個或更多個之組合。
本申請案之組合物可進一步包含用於生產胺基酸之組合物中常用的任何適當賦形劑,且此賦形劑可為例如防腐劑、潤濕劑、分散劑、懸浮劑、緩衝劑、穩定劑或張力劑或其類似物,但不限於此。
在本申請案之組合物中,微生物(菌株)、培養基及L-胺基酸及其類似者如上文其他態樣中所描述。
本申請案之其他一個態樣提供一種本申請案之微生物;培養其之培養基;或其中2個或更多個之組合用於產生L-胺基酸(例如L-麩胺酸)的用途。
本申請案之其他態樣提供一種本申請案之微生物;培養其之培養基;或其中2個或更多個之組合用於產生L-胺基酸(例如,L-麩胺酸)之組合物的用途。
[有利功效]
且本申請案之LacI家族DNA結合性轉錄調節子之活性減弱之棒狀桿菌屬物種微生物具有顯著增加的L-麩胺酸的生產率,且因此與習知微生物相比,使用此微生物有可能以更高產率生產L-麩胺酸。
[本發明的模式]
在下文中,將藉由實施例更詳細地描述本申請案。然而,以下實施例僅為說明本申請案之較佳具體實例,且因此並不意欲限制本申請案之範疇。另一方面,本說明書中未描述的技術事項可充分理解且容易地由熟習此項技術者或本申請案的類似技術領域實施。
實施例 1 : 生產用於在微生物中表現 LacI 家族 DNA 結合性 轉錄調節子蛋白變異體之載體
在本發明實施例中,為了證實其中對應於LacI家族DNA結合性轉錄調節子蛋白胺基酸序列(SEQ ID NO: 3之胺基酸序列)第310位的麩醯胺酸(Gln,Q)的密碼子被取代為終止密碼子(*)的變異體(Q310*;SEQ ID NO: 1,309序列)對L-麩胺酸生產的影響,按以下方法生產用於生產表現其之菌株的載體。
以野生型麩胺酸棒狀桿菌ATCC13869之gDNA(基因體DNA)為模板,藉由分別使用描述為SEQ ID NO: 5及6之序列的引子對及描述為SEQ ID NO: 7及8之序列的引子對分別進行PCR。使用上文獲得之兩個片段之混合物作為模板,再次使用SEQ ID NO: 5及SEQ ID NO: 8之序列之引子對進行重疊PCR以獲得片段。使用Solg
TMPfu-X DNA聚合酶作為聚合酶,且藉由在95℃下變性5分鐘,且接著重複在95℃下變性30秒,在55℃下黏合30秒且在72℃下聚合1分鐘30秒30次,且接著在72℃下聚合5分鐘進行PCR。
使用Gibson組裝(DG Gibson等人, NATURE METHODS, 第6卷,第5期,2009年5月, NEBuilder HiFi DNA Assembly Master Mix)方法選殖經擴增之基因片段及使用SmaI限制酶切割之用於染色體轉形的載體pDCM2(韓國專利公開案第10-2020-0136813號),且接著藉由按計算之莫耳數混合Gibson組裝試劑及各基因片段,且隨後將其在50℃下保存1小時來進行選殖。將菌株塗抹在包含康黴素(kanamycin)(25 mg/l)之LB固體培養基中。在選擇其中插入有目標基因之菌落之後,藉由使用通常已知的質體(載體)萃取方法獲得載體。該載體命名為pDCM2-BBD29_06680(Q310*)。本發明實施例中所用之引子序列描述於下表1中。
【表1】
實施例 2 : 生產衍生自 野生型 麩胺酸棒狀桿菌的產 L- 麩胺酸之 菌株且引入 LacI 家族 DNA 結合性 轉錄調節子蛋白變異體 實施例 2-1 : 生產具有 L- 麩胺酸 生產率之衍生自野生型麩胺酸棒狀桿菌的麩胺酸棒狀桿菌菌株
名稱 | 序列(5'->3') | SEQ ID NO |
1F | ATTCGAGCTCGGTACCCGAAAACCCAGAGCTGCTTG | SEQ ID NO: 5 |
2R | CATTGATCAGCTTCTaCAGAATCTCAAACGC | SEQ ID NO: 6 |
3F | GCGTTTGAGATTCTGtAGAAGCTGATCAATG | SEQ ID NO: 7 |
4R | CGACTCTAGAGGATCCCCCCTGTGCCTGCCTGCG | SEQ ID NO: 8 |
為了生產具有L-麩胺酸生產率的衍生自麩胺酸棒狀桿菌ATCC13869的菌株,基於先前技術(Appl Environ Microbiol. 2007年2月;73(4):1308-19. 電子出版2006年12月8日),生產了缺失
odhA基因(GenBank寄存編號第WP_060564343.1號,SEQ ID NO: 24)的麩胺酸棒狀桿菌ATCC13869△
odhA菌株。
特定言之,對於odhA缺失,使用麩胺酸棒狀桿菌ATCC13869染色體DNA作為模板,藉由分別使用SEQ ID NO: 17及18之引子對及SEQ ID NO: 19及20之引子對分別進行PCR,得到odhA基因之上游區及下游區。使用SolgTM Pfu-X DNA聚合酶作為聚合酶,且PCR擴增條件為在95℃下變性5分鐘,且接著重複在95℃下變性30秒,在58℃下黏合30秒,且在72℃下聚合60秒30次,且接著在72℃下聚合5分鐘。
藉由使用Gibson組裝方法選殖所擴增之
odhA上游及下游區及用SmaI限制酶切割之用於染色體轉形之載體pDCM2,從而獲得重組載體,且將其命名為pDCM2-△
odhA。藉由按計算之莫耳數混合Gibson組裝試劑及各基因片段,且隨後將其在50℃下保存1小時來進行選殖。
將所生產之pDCM2-△
odhA載體藉由電穿孔轉形至麩胺酸棒狀桿菌ATCC13869菌株中,然後進行二次雜交,由此得到染色體上缺失odhA基因的菌株。經由使用SEQ ID NO: 21及22之PCR及基因體定序確認
odhA基因的缺失,且將生產的菌株命名為ATCC13869△
odhA。用於本實施例中之引子之序列描述於下表2中。
【表2】
實施例 2-2 : 生產 LacI 家族 DNA 結合性 轉錄調節子蛋白變異體引入之菌株
名稱 | 序列(5'->3') | SEQ ID NO |
13F | TGAATTCGAGCTCGGTACCCTTGAACGGAATTGGGTGG | SEQ ID NO: 17 |
14R | CCCAGGTGGCATCGGTACCTTCACCCAGCGCCACGCAG | SEQ ID NO: 18 |
15R | CGCTGGGTGAAGGTACCGATGCCACCTGGGTTGGTCAAG | SEQ ID NO: 19 |
16R | GTCGACTCTAGAGGATCCCCGGACAAGGAATGGAGAGA | SEQ ID NO: 20 |
17F | CTTACCGTTGTTGCCCTT | SEQ ID NO: 21 |
18R | CTCCTTCACCCACATCATT | SEQ ID NO: 22 |
將上述實施例1中生產的載體pDCM2-BBD29_06680(Q310*)藉由電穿孔轉形至上述實施例2-1中生產的ATCC13869△
odhA中,然後進行二次雜交,由此得到在染色體上引入BBD29_06680(Q310*)突變的菌株。BBD29_06680(Q310*)突變引入之菌株藉由使用SEQ ID NO: 9及10之PCR及基因體定序得到確認,且將生產的菌株命名為CA02-1626。CA02-1626菌株被命名為麩胺酸棒狀桿菌CA02-1626,且在2021年1月18日寄存至韓國微生物保藏中心(KCCM),寄存編號為KCCM12930P。
用於本實施例中之引子之序列描述於下表3中。
【表3】
實施例 2-3 : 比較表現 LacI 家族 DNA 結合性 轉錄調節子蛋白變異體之菌株的 L- 麩胺酸 生產率
名稱 | 序列(5'->3') | SEQ ID NO |
5F | GCTGCTCGTGAAGCTGG | SEQ ID NO: 9 |
6R | GAACCCACCTGAGCATTC | SEQ ID NO: 10 |
使用2-2中生產之菌株ATCC13869△
odhA菌株作為對照組,證實L-麩胺酸生產率。對照組及CA02-1626菌株藉由如下方法培養。
各菌株接種於含有種子培養基25㎖之250㎖角擋板燒瓶(corner-baffled flask)中,且在以200 rpm振盪下,在30℃下培養20小時。此後,將1㎖之種細胞培養液接種於含有生產培養基25㎖之250㎖角擋板燒瓶中,且在以200 rpm振盪下,在30℃下培養40小時。完成培養之後,使用高效液相層析(HPLC)量測L-麩胺酸之產率,且量測結果展示於下表4中。
<種子培養基>
葡萄糖1%、牛肉萃取物0.5%、polypeptone 1%、氯化鈉0.25%、酵母萃取物0.5%、脲0.2%,pH 7.2
<生產培養基>
粗糖6%、碳酸鈣5%、硫酸銨2.25%、單磷酸鉀0.1%、硫酸鎂0.04%、硫酸鐵10 mg/L、鹽酸硫胺素0.2 mg/L、生物素50 μg/L
【表4】
菌株名稱 | L-麩胺酸濃度(g/L) | L-麩胺酸濃度增加率(%) |
ATCC13869△ odhA | 1.90 | - |
CA02-1626 | 2.31 | 21.6 |
如上表4中所展示,證實與對照組ATCC13869△
odhA菌株相比,在其中引入BBD29_06680(Q310*)突變之CA02-1626菌株中,L-麩胺酸的濃度增加約21.6%。
實施例 3 : 生產 LacI 家族 DNA 結合性 轉錄調節子蛋白缺失之菌株及量測 L- 麩胺酸 生產率 實施例 3-1 : 生產 LacI 家族 DNA 結合性 轉錄調節子蛋白基因缺失之載體
在該實施例中,證實了當與為LacI家族DNA結合性轉錄調節子蛋白的第310個胺基酸的麩醯胺酸(Gln,Q)相對應的密碼子經終止密碼子取代時,L-麩胺酸的生產率得到了提高。因此,在本實施例中,確認LacI家族DNA結合性轉錄調節子(BBD29_06680)基因缺失對L-麩胺酸之生產量的影響。
特定言之,對於BBD29_06680缺失,使用麩胺酸棒狀桿菌ATCC13869之gDNA(基因體DNA)作為模板,藉由使用SEQ ID NO: 11及12之引子對及描述為SEQ ID NO: 13及14之序列的引子對進行PCR,得到BBD29_06680基因之上游區及下游區。使用SolgTM Pfu-X DNA聚合酶作為聚合酶,且PCR擴增條件為在95℃下變性5分鐘,且接著重複在95℃下變性30秒,在58℃下黏合30秒且在72℃下聚合60秒30次,且接著在72℃下聚合5分鐘。藉由使用用SmaI限制酶切割之用於染色體轉形之載體pDCM2及Gibson組裝方法選殖所擴增之DNA片段,從而獲得重組載體,且將其命名為pDCM2-△BBD29_06680。藉由按計算之莫耳數混合Gibson組裝試劑及各基因片段,且隨後將其在50℃下保存1小時來進行選殖。
用於本實施例中之引子之序列描述於下表5中。
【表5】
實施例 3-2 :生產 LacI 家族 DNA 結合性 轉錄調節子蛋白缺失之菌株
名稱 | 序列(5'->3') | SEQ ID NO |
7F | attcgagctcggtacccCCAGTTCGGTCACAAGAC | SEQ ID NO: 11 |
8R | GCTTTTTGGGCTGCTTCGCTTCTTCGGGCTGG | SEQ ID NO: 12 |
9F | CCAGCCCGAAGAAGCGAAGCAGCCCAAAAAGC | SEQ ID NO: 13 |
10R | GACTCTAGAGGATCCCCGGACAACGCCTTGGCG | SEQ ID NO: 14 |
將上述實施例3-1中生產的載體pDCM2-△BBD29_06680藉由電穿孔轉形至上述實施例2-1中生產的ATCC13869△
odhA中,然後進行二次雜交,由此得到染色體上缺失BBD29_06680基因的菌株,且此藉由使用SEQ ID NO: 15及16之引子對進行PCR及基因體定序來確認。所選擇之菌株命名為CA02-1627。用於本實施例中之引子之序列描述於下表6中。
【表6】
實施例 3-3 : 量測 LacI 家族 DNA 結合性 轉錄調節子蛋白缺失之菌株的 L- 麩胺酸 生產率
名稱 | 序列(5'->3') | SEQ ID NO |
11F | GCAAGGCGATGGAACGTC | SEQ ID NO: 15 |
12R | CTCATCCAAGTGGTGCG | SEQ ID NO: 16 |
為了確認L-麩胺酸生產率,使用上述實施例2-1生產的ATCC13869△
odhA菌株為對照組,按照實施例2-3的醱酵滴度評價方法進行評價,且在完成培養後,用高效液相層析(HPLC)量測L-麩胺酸的產率,且經量測之結果如下表7所示。
【表7】
菌株名稱 | L-麩胺酸濃度(g/L) | L-麩胺酸濃度增加率(%) |
ATCC13869△ odhA | 1.92 | - |
CA02-1627 | 2.33 | 21.4 |
如上表7中所展示,證實與對照組ATCC13869△
odhA菌株相比,在其中缺失BBD29_06680基因之CA02-1627中,L-麩胺酸的濃度增加約21.4%。
實施例 4 : 生產 NTG 突變體衍生之 LacI 家族 DNA 結合性 轉錄調節子蛋白變異體引入之菌株及量測 L- 麩胺酸 生產率
為了證實BBD29_06680(Q310*)變體是否在衍生自NTG(N-甲基-N'-硝基-N-亞硝基胍)突變棒狀桿菌屬物種的L-麩胺酸生產率增加的菌株中亦顯示出相同效應,將該變異體引入至被稱為生產L-麩胺酸的NTG突變菌株的麩胺酸棒狀桿菌BL2菌株(KFCC11074,韓國專利第10-0292299號)中。
將實施例1中產生的載體pDCM2-BBD29_06680(Q310*)載體藉由電穿孔轉形至KFCC11074菌株中,然後進行二次雜交,由此選擇在染色體上引入BBD29_06680(Q310*)變異體的菌株。此藉由使用SEQ ID NO: 9及10之PCR及基因體定序進行確認,且所生產之菌株命名為CA02-1630。
對於所生產之CA02-1630及麩胺酸棒狀桿菌KFCC11074菌株,藉由下文所指定之方法進行醱酵滴定實驗。
各菌株接種於含有種子培養基25 ㎖之250 ㎖角擋板燒瓶中,且在以200 rpm振盪下,在30℃下培養20小時。此後,將1 ㎖之種細胞培養液接種於含有生產培養基25 ㎖之250 ㎖角擋板燒瓶中,且在以200 rpm振盪下,在30℃下培養40小時。完成培養之後,藉由使用HPLC方法量測L-麩胺酸之產率,且量測結果展示於下表8中。
<種子培養基>
葡萄糖1%、牛肉萃取物0.5%、polypeptone 1%、氯化鈉0.25%、酵母萃取物0.5%、脲0.2%,pH 7.2
<生產培養基>
粗糖6%、碳酸鈣5%、硫酸銨2.25%、單磷酸鉀0.1%、硫酸鎂0.04%、硫酸鐵10 mg/L、鹽酸硫胺素0.2 mg/L、生物素500 μg/L
【表8】
菌株名稱 | L-麩胺酸濃度(g/L) | L-麩胺酸濃度增加率(%) |
KFCC11074 | 6.91 | - |
CA02-1630 | 8.10 | 17.2 |
如上表8中所展示,證實與對照組KFCC11074菌株相比,在CA02-1630菌株中,L-麩胺酸的濃度增加約17.2%。
根據以上描述,本申請案所屬技術領域中具有通常知識者將能夠理解,本申請案可以其他特定形式進行而不改變其技術精神或基本特徵。就此而言,應理解,上文所描述之實施例在所有態樣中為例示性的而非限制性的。本申請案之範圍應解釋為包括由稍後將描述之申請專利範圍的含義及範圍衍生的所有變化或修改形式以及等效概念而非以上詳細描述。
[寄存編號]
保藏機構名稱:韓國微生物保藏中心(Korean Culture Center of Microorganisms)
寄存編號:KCCM12930P
寄存日期:20210118
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<![CDATA[<110> 南韓商CJ第一製糖股份有限公司(CJ CheilJedang Corporation)]]> <![CDATA[<120> 具有減弱之LacI家族DNA結合性轉錄調節子之活性之微生物及使用其之L-麩胺酸之生產方法]]> <![CDATA[<130> OPP20222192TW]]> <![CDATA[<140> TW 111127834]]> <![CDATA[<141> 2022-07-25]]> <![CDATA[<150> KR 10-2021-0098072]]> <![CDATA[<151> 2021-07-26]]> <![CDATA[<160> 24]]> <![CDATA[<170> koPatentIn 3.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 309]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_LacI家族DNA結合性轉錄調節子(Q310變異體)]]> <![CDATA[<400> 1]]> Met Ala Ser Glu Thr Ser Ser Pro Lys Lys Arg Ala Thr Thr Leu Lys 1 5 10 15 Asp Ile Ala Gln Ala Thr Gln Leu Ser Val Ser Thr Val Ser Arg Ala 20 25 30 Leu Ala Asn Asn Ala Ser Ile Pro Glu Ser Thr Arg Ile Arg Val Val 35 40 45 Glu Ala Ala Gln Lys Leu Asn Tyr Arg Pro Asn Ala Gln Ala Arg Ala 50 55 60 Leu Arg Lys Ser Arg Thr Asp Thr Ile Gly Val Ile Ile Pro Asn Ile 65 70 75 80 Glu Asn Pro Tyr Phe Ser Ser Leu Ala Ala Ser Ile Gln Lys Ala Ala 85 90 95 Arg Glu Ala Gly Val Ser Thr Ile Leu Ser Asn Ser Glu Glu Asn Pro 100 105 110 Glu Leu Leu Gly Gln Thr Leu Ala Ile Met Asp Asp Gln Arg Leu Asp 115 120 125 Gly Ile Ile Val Val Pro His Ile Gln Ser Glu Glu Gln Val Thr Asp 130 135 140 Leu Val Asp Arg Gly Val Pro Val Val Leu Ala Asp Arg Ser Phe Val 145 150 155 160 Asn Ser Ser Ile Pro Ser Val Thr Ser Asp Pro Val Pro Gly Met Thr 165 170 175 Glu Ala Val Asp Leu Leu Leu Ala Ala Asp Val Gln Leu Gly Tyr Leu 180 185 190 Ala Gly Pro Gln Asp Thr Ser Thr Gly Gln Leu Arg Leu Asn Thr Phe 195 200 205 Glu Lys Leu Cys Val Asp Arg Gly Ile Val Gly Ala Ser Val Tyr Tyr 210 215 220 Gly Gly Tyr Arg Gln Glu Ser Gly Tyr Asp Gly Ile Lys Val Leu Ile 225 230 235 240 Lys Gln Gly Ala Asn Ala Ile Ile Ala Gly Asp Ser Met Met Thr Ile 245 250 255 Gly Ala Leu Leu Ala Leu His Glu Met Asn Leu Lys Ile Gly Glu Asp 260 265 270 Val Gln Leu Ile Gly Phe Asp Asn Asn Pro Ile Phe Arg Leu Gln Asn 275 280 285 Pro Pro Leu Ser Ile Ile Asp Gln His Val Gln Glu Ile Gly Lys Arg 290 295 300 Ala Phe Glu Ile Leu 305 <![CDATA[<210> 2]]> <![CDATA[<211> 1110]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_編碼基因LacI家族DNA結合性轉錄調節子(Q310變異體)]]> <![CDATA[<400> 2]]> atggcttccg aaacctccag cccgaagaag cgggccacca cgctcaaaga catcgcgcaa 60 gcaacacagc tttcagtcag cacggtgtcc cgggcattgg ccaacaacgc gagcattccg 120 gaatccacac gcatccgagt ggttgaagcc gctcaaaagc tgaactaccg tcccaatgcc 180 caagctcgtg cattgcggaa gtcgaggaca gacaccatcg gtgtcatcat tccaaacatt 240 gagaacccat atttctcctc actagcagca tcgattcaaa aagctgctcg tgaagctggg 300 gtgtccacca ttttgtccaa ctctgaagaa aacccagagc tgcttggtca gactttggcg 360 atcatggatg accaacgcct cgatggaatc atcgtggtgc cacacattca gtcagaggaa 420 caagtcactg acttggttga caggggagtg ccagtagtgc tggcagaccg tagttttgtt 480 aactcgtcta ttccttcggt tacctcagat ccagttccgg gcatgactga agctgtggac 540 ttactcctgg cagctgacgt gcaattgggc taccttgccg gcccgcagga tacttccact 600 ggtcagctgc gtcttaacac ttttgaaaaa ctatgcgtgg accgcggcat cgtcggagca 660 tctgtctatt acggtggcta ccgccaagaa tctggatatg acggcatcaa ggtgctgatc 720 aagcagggag ccaatgcgat tatcgctggt gactccatga tgaccatcgg tgcgttgttg 780 gctcttcatg agatgaattt gaagatcggt gaggatgtgc agctcattgg gtttgataac 840 aacccaattt tccggctgca gaatccaccg ctgagcatca ttgaccagca cgtacaagag 900 atcggtaagc gtgcgtttga gattctgtag aagctgatca atggggacac cgcgcaaaaa 960 tctgtggtga ttccaacgca gctcagcatc aatggatcaa cggcggtttc ccaaaaggcc 1020 gccgcaaaag cagcaaaagc agcccaaaaa gcagccgcga aagccgcaca gaacacgcaa 1080 cacgaggtga gcctagatgg tgaactctga 1110 <![CDATA[<210> 3]]> <![CDATA[<211> 369]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_LacI家族DNA結合性轉錄調節子(野生)]]> <![CDATA[<400> 3]]> Met Ala Ser Glu Thr Ser Ser Pro Lys Lys Arg Ala Thr Thr Leu Lys 1 5 10 15 Asp Ile Ala Gln Ala Thr Gln Leu Ser Val Ser Thr Val Ser Arg Ala 20 25 30 Leu Ala Asn Asn Ala Ser Ile Pro Glu Ser Thr Arg Ile Arg Val Val 35 40 45 Glu Ala Ala Gln Lys Leu Asn Tyr Arg Pro Asn Ala Gln Ala Arg Ala 50 55 60 Leu Arg Lys Ser Arg Thr Asp Thr Ile Gly Val Ile Ile Pro Asn Ile 65 70 75 80 Glu Asn Pro Tyr Phe Ser Ser Leu Ala Ala Ser Ile Gln Lys Ala Ala 85 90 95 Arg Glu Ala Gly Val Ser Thr Ile Leu Ser Asn Ser Glu Glu Asn Pro 100 105 110 Glu Leu Leu Gly Gln Thr Leu Ala Ile Met Asp Asp Gln Arg Leu Asp 115 120 125 Gly Ile Ile Val Val Pro His Ile Gln Ser Glu Glu Gln Val Thr Asp 130 135 140 Leu Val Asp Arg Gly Val Pro Val Val Leu Ala Asp Arg Ser Phe Val 145 150 155 160 Asn Ser Ser Ile Pro Ser Val Thr Ser Asp Pro Val Pro Gly Met Thr 165 170 175 Glu Ala Val Asp Leu Leu Leu Ala Ala Asp Val Gln Leu Gly Tyr Leu 180 185 190 Ala Gly Pro Gln Asp Thr Ser Thr Gly Gln Leu Arg Leu Asn Thr Phe 195 200 205 Glu Lys Leu Cys Val Asp Arg Gly Ile Val Gly Ala Ser Val Tyr Tyr 210 215 220 Gly Gly Tyr Arg Gln Glu Ser Gly Tyr Asp Gly Ile Lys Val Leu Ile 225 230 235 240 Lys Gln Gly Ala Asn Ala Ile Ile Ala Gly Asp Ser Met Met Thr Ile 245 250 255 Gly Ala Leu Leu Ala Leu His Glu Met Asn Leu Lys Ile Gly Glu Asp 260 265 270 Val Gln Leu Ile Gly Phe Asp Asn Asn Pro Ile Phe Arg Leu Gln Asn 275 280 285 Pro Pro Leu Ser Ile Ile Asp Gln His Val Gln Glu Ile Gly Lys Arg 290 295 300 Ala Phe Glu Ile Leu Gln Lys Leu Ile Asn Gly Asp Thr Ala Gln Lys 305 310 315 320 Ser Val Val Ile Pro Thr Gln Leu Ser Ile Asn Gly Ser Thr Ala Val 325 330 335 Ser Gln Lys Ala Ala Ala Lys Ala Ala Lys Ala Ala Gln Lys Ala Ala 340 345 350 Ala Lys Ala Ala Gln Asn Thr Gln His Glu Val Ser Leu Asp Gly Glu 355 360 365 Leu <![CDATA[<210> ]]> 4 <![CDATA[<211> 1110]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_編碼LacII家族DNA結合性轉錄調節子(野生)之基因]]> <![CDATA[<400> 4]]> atggcttccg aaacctccag cccgaagaag cgggccacca cgctcaaaga catcgcgcaa 60 gcaacacagc tttcagtcag cacggtgtcc cgggcattgg ccaacaacgc gagcattccg 120 gaatccacac gcatccgagt ggttgaagcc gctcaaaagc tgaactaccg tcccaatgcc 180 caagctcgtg cattgcggaa gtcgaggaca gacaccatcg gtgtcatcat tccaaacatt 240 gagaacccat atttctcctc actagcagca tcgattcaaa aagctgctcg tgaagctggg 300 gtgtccacca ttttgtccaa ctctgaagaa aacccagagc tgcttggtca gactttggcg 360 atcatggatg accaacgcct cgatggaatc atcgtggtgc cacacattca gtcagaggaa 420 caagtcactg acttggttga caggggagtg ccagtagtgc tggcagaccg tagttttgtt 480 aactcgtcta ttccttcggt tacctcagat ccagttccgg gcatgactga agctgtggac 540 ttactcctgg cagctgacgt gcaattgggc taccttgccg gcccgcagga tacttccact 600 ggtcagctgc gtcttaacac ttttgaaaaa ctatgcgtgg accgcggcat cgtcggagca 660 tctgtctatt acggtggcta ccgccaagaa tctggatatg acggcatcaa ggtgctgatc 720 aagcagggag ccaatgcgat tatcgctggt gactccatga tgaccatcgg tgcgttgttg 780 gctcttcatg agatgaattt gaagatcggt gaggatgtgc agctcattgg gtttgataac 840 aacccaattt tccggctgca gaatccaccg ctgagcatca ttgaccagca cgtacaagag 900 atcggtaagc gtgcgtttga gattctgcag aagctgatca atggggacac cgcgcaaaaa 960 tctgtggtga ttccaacgca gctcagcatc aatggatcaa cggcggtttc ccaaaaggcc 1020 gccgcaaaag cagcaaaagc agcccaaaaa gcagccgcga aagccgcaca gaacacgcaa 1080 cacgaggtga gcctagatgg tgaactctga 1110 <![CDATA[<210> 5]]> <![CDATA[<211> 36]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_1F引子]]> <![CDATA[<400> 5]]> attcgagctc ggtacccgaa aacccagagc tgcttg 36 <![CDATA[<210> 6]]> <![CDATA[<211> 31]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_2R引子]]> <![CDATA[<400> 6]]> cattgatcag cttctacaga atctcaaacg c 31 <![CDATA[<210> 7]]> <![CDATA[<211> 31]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_3F引子]]> <![CDATA[<400> 7]]> gcgtttgaga ttctgtagaa gctgatcaat g 31 <![CDATA[<210> 8]]> <![CDATA[<211> 34]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_4R引子]]> <![CDATA[<400> 8]]> cgactctaga ggatcccccc tgtgcctgcc tgcg 34 <![CDATA[<210> 9]]> <![CDATA[<211> 17]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_5F引子]]> <![CDATA[<400> 9]]> gctgctcgtg aagctgg 17 <![CDATA[<210> 10]]> <![CDATA[<211> 18]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_6R引子]]> <![CDATA[<400> 10]]> gaacccacct gagcattc 18 <![CDATA[<210> 11]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_7F引子]]> <![CDATA[<400> 11]]> attcgagctc ggtaccccca gttcggtcac aagac 35 <![CDATA[<210> 12]]> <![CDATA[<211> 32]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_8R引子]]> <![CDATA[<400> 12]]> gctttttggg ctgcttcgct tcttcgggct gg 32 <![CDATA[<210> 13]]> <![CDATA[<211> 32]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_9F引子]]> <![CDATA[<400> 13]]> ccagcccgaa gaagcgaagc agcccaaaaa gc 32 <![CDATA[<210> 14]]> <![CDATA[<211> 33]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_10R引子]]> <![CDATA[<400> 14]]> gactctagag gatccccgga caacgccttg gcg 33 <![CDATA[<210> 15]]> <![CDATA[<211> 18]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_11F引子]]> <![CDATA[<400> 15]]> gcaaggcgat ggaacgtc 18 <![CDATA[<210> 16]]> <![CDATA[<211> 17]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_12R引子]]> <![CDATA[<400> 16]]> ctcatccaag tggtgcg 17 <![CDATA[<210> 17]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_13F引子]]> <![CDATA[<400> 17]]> tgaattcgag ctcggtaccc ttgaacggaa ttgggtgg 38 <![CDATA[<210> 18]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_14R引子]]> <![CDATA[<400> 18]]> cccaggtggc atcggtacct tcacccagcg ccacgcag 38 <![CDATA[<210> 19]]> <![CDATA[<211> 39]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_15F引子]]> <![CDATA[<400> 19]]> cgctgggtga aggtaccgat gccacctggg ttggtcaag 39 <![CDATA[<210> 20]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_16R引子]]> <![CDATA[<400> 20]]> gtcgactcta gaggatcccc ggacaaggaa tggagaga 38 <![CDATA[<210> 21]]> <![CDATA[<211> 18]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_17F引子]]> <![CDATA[<400> 21]]> cttaccgttg ttgccctt 18 <![CDATA[<210> 22]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_18R引子]]> <![CDATA[<400> 22]]> ctccttcacc cacatcatt 19 <![CDATA[<210> 23]]> <![CDATA[<211> 1205]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_odhA蛋白(野生)]]> <![CDATA[<400> 23]]> Met Phe Gln Gln Phe Gln Lys Asp Pro Lys Ser Val Asp Lys Glu Trp 1 5 10 15 Arg Glu Leu Phe Glu Ala Gln Gly Gly Pro Asn Ala Thr Pro Ala Thr 20 25 30 Thr Glu Ala Gln Pro Ser Ala Pro Lys Glu Ser Ala Lys Pro Ala Pro 35 40 45 Lys Ala Ala Pro Ala Ala Lys Ala Ala Pro Arg Val Glu Thr Lys Pro 50 55 60 Ala Ala Lys Thr Ala Pro Lys Ala Lys Glu Ser Ser Val Pro Gln Gln 65 70 75 80 Pro Lys Leu Pro Glu Pro Gly Gln Thr Pro Ile Arg Gly Ile Phe Lys 85 90 95 Ser Ile Ala Lys Asn Met Asp Ile Ser Leu Glu Ile Pro Thr Ala Thr 100 105 110 Ser Val Arg Asp Met Pro Ala Arg Leu Met Phe Glu Asn Arg Ala Met 115 120 125 Val Asn Asp Gln Leu Lys Arg Thr Arg Gly Gly Lys Ile Ser Phe Thr 130 135 140 His Ile Ile Gly Tyr Ala Met Val Lys Ala Val Met Ala His Pro Asp 145 150 155 160 Met Asn Asn Ser Tyr Asp Val Ile Asp Gly Lys Pro Thr Leu Ile Val 165 170 175 Pro Glu His Ile Asn Leu Gly Leu Ala Ile Asp Leu Pro Gln Lys Asp 180 185 190 Gly Ser Arg Ala Leu Val Val Ala Ala Ile Lys Glu Thr Glu Lys Met 195 200 205 Asn Phe Ser Glu Phe Leu Ala Ala Tyr Glu Asp Ile Val Thr Arg Ser 210 215 220 Arg Lys Gly Lys Leu Thr Met Asp Asp Tyr Gln Gly Val Thr Val Ser 225 230 235 240 Leu Thr Asn Pro Gly Gly Ile Gly Thr Arg His Ser Val Pro Arg Leu 245 250 255 Thr Lys Gly Gln Gly Thr Ile Ile Gly Val Gly Ser Met Asp Tyr Pro 260 265 270 Ala Glu Phe Gln Gly Ala Ser Glu Asp Arg Leu Ala Glu Leu Gly Val 275 280 285 Gly Lys Leu Val Thr Ile Thr Ser Thr Tyr Asp His Arg Val Ile Gln 290 295 300 Gly Ala Val Ser Gly Glu Phe Leu Arg Thr Met Ser Arg Leu Leu Thr 305 310 315 320 Asp Asp Ser Phe Trp Asp Glu Ile Phe Asp Ala Met Asn Val Pro Tyr 325 330 335 Thr Pro Met Arg Trp Ala Gln Asp Val Pro Asn Thr Gly Val Asp Lys 340 345 350 Asn Thr Arg Val Met Gln Leu Ile Glu Ala Tyr Arg Ser Arg Gly His 355 360 365 Leu Ile Ala Asp Thr Asn Pro Leu Ser Trp Val Gln Pro Gly Met Pro 370 375 380 Val Pro Asp His Arg Asp Leu Asp Ile Glu Thr His Ser Leu Thr Ile 385 390 395 400 Trp Asp Leu Asp Arg Thr Phe Ser Val Gly Gly Phe Gly Gly Lys Glu 405 410 415 Thr Met Thr Leu Arg Glu Val Leu Ser Arg Leu Arg Ala Ala Tyr Thr 420 425 430 Leu Lys Val Gly Ser Glu Tyr Thr His Ile Leu Asp Arg Asp Glu Arg 435 440 445 Thr Trp Leu Gln Asp Arg Leu Glu Ala Gly Met Pro Lys Pro Thr Gln 450 455 460 Ala Glu Gln Lys Tyr Ile Leu Gln Lys Leu Asn Ala Ala Glu Ala Phe 465 470 475 480 Glu Asn Phe Leu Gln Thr Lys Tyr Val Gly Gln Lys Arg Phe Ser Leu 485 490 495 Glu Gly Ala Glu Ala Leu Ile Pro Leu Met Asp Ser Ala Ile Asp Thr 500 505 510 Ala Ala Gly Gln Gly Leu Asp Glu Val Val Ile Gly Met Pro His Arg 515 520 525 Gly Arg Leu Asn Val Leu Phe Asn Ile Val Gly Lys Pro Leu Ala Ser 530 535 540 Ile Phe Asn Glu Phe Glu Gly Gln Met Glu Gln Gly Gln Ile Gly Gly 545 550 555 560 Ser Gly Asp Val Lys Tyr His Leu Gly Ser Glu Gly Gln His Leu Gln 565 570 575 Met Phe Gly Asp Gly Glu Ile Lys Val Ser Leu Thr Ala Asn Pro Ser 580 585 590 His Leu Glu Ala Val Asn Pro Val Met Glu Gly Ile Val Arg Ala Lys 595 600 605 Gln Asp Tyr Leu Asp Lys Gly Val Asp Gly Lys Thr Val Val Pro Leu 610 615 620 Leu Leu His Gly Asp Ala Ala Phe Ala Gly Leu Gly Ile Val Pro Glu 625 630 635 640 Thr Ile Asn Leu Ala Lys Leu Arg Gly Tyr Asp Val Gly Gly Thr Ile 645 650 655 His Ile Val Val Asn Asn Gln Ile Gly Phe Thr Thr Thr Pro Asp Ser 660 665 670 Ser Arg Ser Met His Tyr Ala Thr Asp Tyr Ala Lys Ala Phe Gly Cys 675 680 685 Pro Val Phe His Val Asn Gly Asp Asp Pro Glu Ala Val Val Trp Val 690 695 700 Gly Gln Leu Ala Thr Glu Tyr Arg Arg Arg Phe Gly Lys Asp Val Phe 705 710 715 720 Ile Asp Leu Val Cys Tyr Arg Leu Arg Gly His Asn Glu Ala Asp Asp 725 730 735 Pro Ser Met Thr Gln Pro Lys Met Tyr Glu Leu Ile Thr Gly Arg Glu 740 745 750 Thr Val Arg Ala Gln Tyr Thr Glu Asp Leu Leu Gly Arg Gly Asp Leu 755 760 765 Ser Asn Glu Asp Ala Glu Ala Val Val Arg Asp Phe His Asp Gln Met 770 775 780 Glu Ser Val Phe Asn Glu Val Lys Glu Gly Gly Lys Lys Gln Ala Glu 785 790 795 800 Ala Gln Thr Gly Ile Thr Gly Ser Gln Lys Leu Pro His Gly Leu Glu 805 810 815 Thr Asn Ile Ser Arg Glu Glu Leu Leu Glu Leu Gly Gln Ala Phe Ala 820 825 830 Asn Thr Pro Glu Gly Phe Asn Tyr His Pro Arg Val Ala Pro Val Ala 835 840 845 Lys Lys Arg Val Ser Ser Val Thr Glu Gly Gly Ile Asp Trp Ala Trp 850 855 860 Gly Glu Leu Leu Ala Phe Gly Ser Leu Ala Asn Ser Gly Arg Leu Val 865 870 875 880 Arg Leu Ala Gly Glu Asp Ser Arg Arg Gly Thr Phe Thr Gln Arg His 885 890 895 Ala Val Ala Ile Asp Pro Ala Thr Ala Glu Glu Phe Asn Pro Leu His 900 905 910 Glu Leu Ala Gln Ser Lys Gly Asn Asn Gly Lys Phe Leu Val Tyr Asn 915 920 925 Ser Ala Leu Thr Glu Tyr Ala Gly Met Gly Phe Glu Tyr Gly Tyr Ser 930 935 940 Val Gly Asn Glu Asp Ser Val Val Ala Trp Glu Ala Gln Phe Gly Asp 945 950 955 960 Phe Ala Asn Gly Ala Gln Thr Ile Ile Asp Glu Tyr Val Ser Ser Gly 965 970 975 Glu Ala Lys Trp Gly Gln Thr Ser Lys Leu Ile Leu Leu Leu Pro His 980 985 990 Gly Tyr Glu Gly Gln Gly Pro Asp His Ser Ser Ala Arg Ile Glu Arg 995 1000 1005 Phe Leu Gln Leu Cys Ala Glu Gly Ser Met Thr Val Ala Gln Pro Ser 1010 1015 1020 Thr Pro Ala Asn His Phe His Leu Leu Arg Arg His Ala Leu Ser Asp 1025 1030 1035 1040 Leu Lys Arg Pro Leu Val Ile Phe Thr Pro Lys Ser Met Leu Arg Asn 1045 1050 1055 Lys Ala Ala Ala Ser Ala Pro Glu Asp Phe Thr Glu Val Thr Lys Phe 1060 1065 1070 Gln Ser Val Ile Asp Asp Pro Asn Val Ala Asp Ala Ala Lys Val Lys 1075 1080 1085 Lys Val Met Leu Val Ser Gly Lys Leu Tyr Tyr Glu Leu Ala Lys Arg 1090 1095 1100 Lys Glu Lys Asp Gly Arg Asp Asp Ile Ala Ile Val Arg Ile Glu Met 1105 1110 1115 1120 Leu His Pro Ile Pro Phe Asn Arg Ile Ser Glu Ala Leu Ala Gly Tyr 1125 1130 1135 Pro Asn Ala Glu Glu Val Leu Phe Val Gln Asp Glu Pro Ala Asn Gln 1140 1145 1150 Gly Pro Trp Pro Phe Tyr Gln Glu His Leu Pro Glu Leu Ile Pro Asn 1155 1160 1165 Met Pro Lys Met Arg Arg Val Ser Arg Arg Ala Gln Ser Ser Thr Ala 1170 1175 1180 Thr Gly Val Ala Lys Val His Gln Leu Glu Glu Lys Gln Leu Ile Asp 1185 1190 1195 1200 Glu Ala Phe Glu Ala 1205 <![CDATA[<210> 24]]> <![CDATA[<211> 3618]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成_編碼odhA蛋白(野生)之基因]]> <![CDATA[<400> 24]]> atgttccagc agttccagaa ggaccccaag tccgtggaca aggaatggag agaactcttt 60 gaggcgcagg ggggaccaaa tgctaccccc gctacaacag aagcacagcc ttcagcgccc 120 aaggagtctg cgaaaccagc accaaaggct gcccctgcag ccaaggcagc accgcgcgta 180 gaaaccaagc cggccgccaa gaccgcccct aaggccaagg agtcctcagt gccacagcaa 240 cctaagcttc cggagccagg acaaacccca atcaggggta ttttcaagtc catcgcgaag 300 aacatggata tctccctgga aatcccaacc gcaacctcgg ttcgcgatat gccagctcgc 360 ctcatgttcg aaaaccgcgc gatggtcaac gatcagctca agcgcacccg cggtggcaag 420 atctccttca cccacatcat tggctacgcc atggtgaagg cagtcatggc tcacccggac 480 atgaacaact cctacgacgt catcgacggc aagccaaccc tgatcgtgcc tgagcacatc 540 aacctgggcc ttgccatcga ccttcctcag aaggacggct cccgcgcact tgtcgtagca 600 gccatcaagg aaaccgagaa gatgaacttc tccgagttcc tcgcagcata cgaagacatc 660 gtgacacgct cccgcaaggg caagctcacc atggatgact accagggcgt taccgtttcc 720 ttgaccaacc caggtggcat cggtacccgc cactctgtcc cacgtctgac caagggccag 780 ggcaccatca tcggtgtcgg ttccatggat tacccagcag agttccaggg cgcttccgaa 840 gaccgccttg cagagctcgg cgttggcaag cttgtcacca tcacctccac ctacgatcac 900 cgcgtgatcc agggtgctgt gtccggtgaa ttcctgcgta ccatgtctcg cctgctcacc 960 gatgattcct tctgggatga gatcttcgac gcaatgaacg ttccttacac cccaatgcgt 1020 tgggcacagg acgttccaaa caccggtgtt gataagaaca cccgcgtcat gcagctcatt 1080 gaggcatacc gctcccgtgg acacctcatc gctgacacca acccactttc atgggttcag 1140 cctggcatgc cagttccaga ccaccgcgac ctcgacatcg agacccacag cctgaccatc 1200 tgggatctgg accgtacctt cagcgtcggt ggcttcggcg gcaaggagac catgaccctg 1260 cgcgaggtac tgtcccgcct gcgcgctgcc tacaccttga aggtcggctc cgaatacacc 1320 cacatcctgg accgcgacga gcgcacctgg ctgcaggacc gcctcgaagc cggaatgcca 1380 aagccaaccc aggcagagca gaagtacatc ctgcagaagc tgaacgccgc agaggctttc 1440 gagaacttcc tgcagaccaa gtacgtcggc cagaagcgct tctccctcga aggtgcagaa 1500 gctctcatcc cactgatgga ctccgccatc gacaccgccg caggccaggg cctcgacgaa 1560 gttgtcatcg gtatgccaca ccgtggtcgc ctcaacgtgc tgttcaacat cgtgggcaag 1620 ccactggcat ccatcttcaa cgagtttgaa ggccaaatgg agcagggcca gatcggtggc 1680 tccggtgacg tgaagtacca cctcggttcc gaaggccagc acctgcagat gttcggcgac 1740 ggcgagatca aggtctccct gactgctaac ccgtcccacc tggaagctgt taacccagtg 1800 atggaaggta tcgtccgcgc aaagcaggac tacctggaca agggcgtaga cggcaagact 1860 gttgtgccac tgctgctcca cggtgacgct gcattcgcag gcctgggcat cgtgccagaa 1920 accatcaacc tggctaagct gcgtggctac gacgtcggag gcaccatcca catcgtggtg 1980 aacaaccaga tcggcttcac caccacccca gactccagcc gctccatgca ctacgcaacc 2040 gactacgcca aggcattcgg ctgcccagtc ttccacgtca atggtgatga cccagaggca 2100 gttgtctggg ttggccagct ggcaaccgag taccgtcgtc gcttcggcaa ggacgtcttc 2160 atcgacctcg tttgctaccg cctccgcggc cacaacgaag ctgatgatcc ttccatgacc 2220 cagccaaaga tgtatgagct catcaccggc cgcgagaccg ttcgtgctca gtacaccgaa 2280 gacctgctcg gacgtggaga cctctccaac gaagatgcag aagcagtcgt ccgcgacttc 2340 cacgaccaga tggaatctgt gttcaacgaa gtcaaggaag gcggcaagaa gcaggctgag 2400 gcacagaccg gcatcaccgg ctcccagaag cttccacacg gccttgagac caacatctcc 2460 cgtgaagagc tcctggaact gggacaggct ttcgccaaca ccccagaagg cttcaactac 2520 cacccacgtg tggctccagt tgctaagaag cgcgtctcct ctgtcaccga aggtggcatc 2580 gactgggcat ggggcgagct cctcgccttc ggttccctgg ctaactccgg ccgcttggtt 2640 cgccttgcag gtgaagattc ccgccgcggt accttcaccc agcgccacgc agttgccatc 2700 gacccagcga ccgctgaaga gttcaaccca ctccacgagc ttgcacagtc caagggcaac 2760 aacggtaagt tcctggtcta caactccgca ctgaccgagt acgcaggcat gggcttcgag 2820 tacggctact ccgtaggaaa cgaagactcc gtcgttgcat gggaagcaca gttcggcgac 2880 ttcgccaacg gcgctcagac catcatcgat gagtacgtct cctcaggcga agctaagtgg 2940 ggccagacct ccaagctgat ccttctgctg cctcacggct acgaaggcca gggcccagac 3000 cactcttccg cacgtatcga gcgcttcctg cagctgtgcg ctgagggttc catgactgtt 3060 gctcagccat ccaccccagc aaaccacttc cacctgctgc gtcgtcacgc tctgtccgac 3120 ctgaagcgtc cactggttat cttcaccccg aagtccatgc tgcgtaacaa ggctgctgcc 3180 tccgcaccag aagacttcac tgaggtcacc aagttccaat ccgtgatcga cgatccaaac 3240 gttgcagatg cagccaaggt gaagaaggtc atgctggtct ccggcaagct gtactacgaa 3300 ttggcaaagc gcaaggagaa ggacggacgc gacgacatcg cgatcgttcg tatcgaaatg 3360 ctccacccaa ttccgttcaa ccgcatctcc gaggctcttg ccggctaccc taacgctgag 3420 gaagtcctct tcgttcagga tgagccagca aaccagggcc catggccgtt ctaccaggag 3480 cacctcccag agctgatccc gaacatgcca aagatgcgcc gcgtttcccg ccgcgctcag 3540 tcctccaccg caactggtgt tgctaaggtg caccagctgg aggagaagca gcttatcgac 3600 gaggctttcg aggcttaa 3618
Claims (13)
- 一種具有減弱之LacI家族DNA結合性轉錄調節子蛋白之活性之棒狀桿菌屬物種( Corynebacteriumsp.)微生物。
- 如請求項1之微生物,其中該LacI家族DNA結合性轉錄調節子蛋白衍生自棒狀桿菌屬。
- 如請求項1之微生物,其中該LacI家族DNA結合性轉錄調節子蛋白由描述為SEQ ID NO: 3之胺基酸序列的多肽組成。
- 如請求項1之微生物,其中該LacI家族DNA結合性轉錄調節子蛋白由描述為SEQ ID NO: 4之核苷酸序列的多肽編碼。
- 如請求項1之微生物,其中該棒狀桿菌屬物種微生物為麩胺酸棒狀桿菌( Corynebacterium glutamicum)。
- 如請求項1之微生物,其中與其中LacI家族DNA結合性轉錄調節子蛋白之活性未經減弱的親本菌株或野生型相比,該棒狀桿菌屬物種微生物具有增加之L-麩胺酸生產率。
- 一種L-麩胺酸之生產方法,其包含在培養基中培養具有減弱之LacI家族DNA結合性轉錄調節子蛋白之活性之棒狀桿菌屬物種微生物。
- 如請求項7之L-麩胺酸之生產方法,其進一步包含根據該培養自該培養基或微生物回收L-麩胺酸。
- 如請求項7之L-麩胺酸之生產方法,其中該LacI家族DNA結合性轉錄調節子蛋白衍生自棒狀桿菌屬。
- 如請求項7之L-麩胺酸之生產方法,其中該LacI家族DNA結合性轉錄調節子蛋白由描述為SEQ ID NO: 3之胺基酸序列的多肽組成。
- 如請求項7之L-麩胺酸之生產方法,其中該LacI家族DNA結合性轉錄調節子蛋白由描述為SEQ ID NO: 4之核苷酸序列的多肽編碼。
- 如請求項7之L-麩胺酸之生產方法,其中該棒狀桿菌屬物種微生物為麩胺酸棒狀桿菌。
- 如請求項7之L-麩胺酸之生產方法,其中與其中LacI家族DNA結合性轉錄調節子蛋白之活性未經減弱的親本菌株或野生型相比,該棒狀桿菌屬物種微生物具有增加之L-麩胺酸生產率。
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KR1020210098072A KR20230016505A (ko) | 2021-07-26 | 2021-07-26 | LacI 계열 DNA 결합 전사 조절자의 활성이 약화된 미생물 및 이를 이용한 L-글루탐산의 생산방법 |
KR10-2021-0098072 | 2021-07-26 |
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EP (1) | EP4379056A1 (zh) |
KR (1) | KR20230016505A (zh) |
CN (1) | CN117730152A (zh) |
AR (1) | AR126567A1 (zh) |
AU (1) | AU2022319462A1 (zh) |
CA (1) | CA3224713A1 (zh) |
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KR100292299B1 (ko) | 1999-03-22 | 2001-06-01 | 손경식 | 글루탐산 생산 미생물 및 이를 이용한 글루탐산 생산방법 |
US6838267B2 (en) * | 2000-08-26 | 2005-01-04 | Degussa Ag | Nucleotide sequences coding for the ccpA1 gene |
WO2002018429A1 (en) * | 2000-08-26 | 2002-03-07 | Degussa Ag | Nucleotide sequences which code for the ccpa2 gene |
KR100620092B1 (ko) | 2004-12-16 | 2006-09-08 | 씨제이 주식회사 | 코리네박테리움 속 세포로부터 유래된 신규한 프로모터서열, 그를 포함하는 발현 카세트 및 벡터, 상기 벡터를포함하는 숙주 세포 및 그를 이용하여 유전자를 발현하는방법 |
KR100824457B1 (ko) | 2006-10-16 | 2008-04-22 | 씨제이제일제당 (주) | 고농도의 글루탐산을 생산하는 미생물 및 이를 이용한글루탐산의 제조 방법 |
KR101632642B1 (ko) | 2015-01-29 | 2016-06-22 | 씨제이제일제당 주식회사 | 신규한 프로모터 및 그의 용도 |
CN110283823B (zh) | 2016-08-31 | 2023-05-12 | Cj第一制糖株式会社 | 新型启动子及其应用 |
KR102278000B1 (ko) | 2020-03-17 | 2021-07-15 | 씨제이제일제당 주식회사 | 프리페네이트 디하이드라타아제 활성 강화를 통한 l-트립토판을 생산하는 방법 |
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- 2022-07-25 CN CN202280052622.1A patent/CN117730152A/zh active Pending
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AR126567A1 (es) | 2023-10-25 |
KR20230016505A (ko) | 2023-02-02 |
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