CN106574237B - 生产o-乙酰高丝氨酸的微生物和使用其生产o-乙酰高丝氨酸的方法 - Google Patents
生产o-乙酰高丝氨酸的微生物和使用其生产o-乙酰高丝氨酸的方法 Download PDFInfo
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Abstract
本公开涉及以高效率生产O‑乙酰高丝氨酸的微生物和使用该微生物生产O‑乙酰高丝氨酸和L‑甲硫氨酸的方法。本公开提供了具有预期输出O‑乙酰高丝氨酸的蛋白质的增强活性的生产O‑乙酰高丝氨酸的微生物,和使用该微生物生产O‑乙酰高丝氨酸和L‑甲硫氨酸的方法。
Description
技术领域
本公开涉及以高产率生产O-乙酰高丝氨酸的微生物和使用该微生物生产O-乙酰高丝氨酸的方法。
背景技术
O-乙酰高丝氨酸充当作为一种体内必需氨基酸的甲硫氨酸的前体。甲硫氨酸不仅用作饲料和食品的添加剂,而且用作输液溶液和药物的原料。
甲硫氨酸是通过化学合成和生物合成生产的。最近,发表了通过酶转化从经发酵生产的L-甲硫氨酸前体中生产L-甲硫氨酸的两步法(国际公开号WO 2008/013432)。
两步法使用O-琥珀酰高丝氨酸和O-乙酰高丝氨酸作为前体,并且为了经济的大规模生产的目的,以高产率生产O-乙酰高丝氨酸是非常重要的。
公开内容
技术问题
在该情形下,本发明人已做出努力来提高O-乙酰高丝氨酸的产量,结果,他们已经找到一种能够输出O-乙酰高丝氨酸的蛋白质,从而完成本公开。
技术方案
本公开的目的是提供一种具有增强的O-乙酰高丝氨酸生产力的微生物。
本公开的另一目的是提供一种使用具有增强的O-乙酰高丝氨酸生产力的微生物有效生产O-乙酰高丝氨酸的方法。
发明的有利效果
具有YjeH(即,内膜蛋白质)的增强活性的本公开的微生物具有输出O-乙酰高丝氨酸的改进的能力,从而可以增加O-乙酰高丝氨酸生产的功效。因此,本公开的微生物能够广泛用于O-乙酰高丝氨酸的生产。
附图说明
图1显示了根据本公开的yjeH载体(pBAC-yjeH载体)的切割图。
最佳方式
本公开的方面提供了具有O-乙酰高丝氨酸生产力的微生物,其中与未经修饰的微生物相比,YjeH(即,内膜蛋白质)的活性增强。
如本文所使用的,术语“O-乙酰高丝氨酸”是指L-高丝氨酸的乙酰衍生物,其是微生物中甲硫氨酸的生物合成途径中的特定中间物质。已知O-乙酰高丝氨酸通过由高丝氨酸乙酰转移酶催化的高丝氨酸和乙酰辅酶A之间的反应产生。其化学式为C6H11NO4。
如本文所使用的,术语“具有O-乙酰高丝氨酸生产力的微生物”是指在培养基中培养时,能够在生物有机体内产生O-乙酰高丝氨酸并将其分泌到培养基中的微生物。可以通过物种的改进来提供或增强O-乙酰高丝氨酸生产力。具体地,具有O-乙酰高丝氨酸生产力的微生物可以是具有O-乙酰高丝氨酸生产力的埃希氏菌属的微生物,更具体地,大肠杆菌(E.coli)。例如,微生物可以是具有赖氨酸、苏氨酸、异亮氨酸或甲硫氨酸生产力的大肠杆菌,但并不限于此。如本文所使用的,术语“YjeH”被认为是存在于内膜中的蛋白质,其是氨基酸转运蛋白的氨基酸-多胺-有机阳离子(amino acid polyamine organocation)(APC)家族的成员。预期YjeH充当氨基酸转运蛋白,但其确切功能尚未知晓。因此,本发明人已经首先证实了YjeH特异性地输出O-乙酰高丝氨酸。
具体地,YjeH可以源自埃希氏菌属的微生物,更具体地源自大肠杆菌。具体而言,YjeH可以是具有SEQ ID NO:1的氨基酸序列的蛋白质,或者是与SEQ ID NO:1的氨基酸序列具有70%或更高、具体地80%或更高、或更具体地90%或更高的同源性的任何氨基酸序列。此外,明显的是,具有与SEQ ID NO:1相同的氨基酸序列的任何氨基酸序列、或者具有输出O-乙酰高丝氨酸活性的任何氨基酸序列都可以属于本公开的范围,即使该序列可能在其中具有部分缺失、修饰、取代或添加。此外,基于遗传密码子简并性,编码相同氨基酸的核苷酸序列及其变体属于本公开的范围,例如,由SEQ ID NO:2表示的核苷酸序列,但并不限于此。
如本文所使用的,术语“同源性”是指将两个序列与最大匹配序列(match)进行比对之后,在编码蛋白质的基因的核苷酸或氨基酸序列的特定比较区域中的两个不同的核苷酸或氨基酸残基序列之间的同一性程度。当同源性足够高时,对应基因的表达产物可具有相同或相似的活性。可以使用本领域已知的序列比较程序如BLAST(NCBI)、CLC MainWorkbench(CLC bio)、MegAlignTM(DNASTAR Inc.)等确定同源性。
如本文所使用的,术语“未经修饰的微生物”是指未引入有相应蛋白质的活性修饰的微生物,并且该微生物是指待引入有相应蛋白质的活性修饰的基础菌株(base strain),其可以是天然或经修饰的微生物。
如本文所使用的,术语蛋白质活性的“增强”是指提高微生物所具有的蛋白质活性状态。蛋白质活性的增强不受限制,只要与未经修饰的微生物相比,每种蛋白质的活性可以被增强,如同靶蛋白活性增强的情况一样。例如,可以通过选自以下的方法进行增强:i)增加编码每种蛋白质的多核苷酸的拷贝数,ii)对表达控制序列进行修饰以增加多核苷酸的表达,iii)对染色体上的多核苷酸序列进行修饰以增强每种蛋白质的活性;和iv)其组合。具体地,可以通过选自以下的方法进行蛋白质活性的增强:将编码每种蛋白质的核苷酸序列引入染色体的方法、在将核苷酸序列引入载体系统之后将其引入微生物的方法、将表现出改进活性的启动子引入编码每种蛋白质的核苷酸序列的上游或将对启动子的修饰引入每种蛋白质的方法、对5'-UTR区域的核苷酸序列进行修饰的方法、和引入编码每种蛋白质的核苷酸序列的变体的方法,但所述方法并不限于此。
在本公开的具体实施方式中,通过增加给定启动子的拷贝数或增强给定启动子的活性可以使YjeH活性与未经修饰的微生物相比得到增强。具体地,可以通过向YjeH(其为内膜)引入表现出改进活性的启动子来增强YjeH活性。在本公开的具体实施方案中,具有改进活性的启动子可包括但不限于与yjeH的自身启动子相比具有改进活性的任何启动子。这种启动子的实例可包括但不限于与yjeH的自身启动子相比具有更高的基因表达活性的基因的任何启动子,或者由于对yjeH的自身启动子中基因的修饰而具有改进活性的经修饰的启动子等等。具体地,表现出改进活性的本公开的启动子可选自icd启动子、pro启动子和cysk启动子。具体地,icd启动子可由SEQ ID NO:51的核苷酸序列组成;pro启动子可由SEQ IDNO:52的核苷酸序列组成;和cysk启动子可由SEQ ID NO:53的核苷酸序列组成,但每种启动子都可由与上述核苷酸序列中的每一种具有70%或更高、具体地80%或更高、更具体地90%或更高同源性的核苷酸序列组成。
在本公开的具体方面中,具有O-乙酰高丝氨酸生产力的埃希氏菌属微生物可以是其中胱硫醚合成酶活性进一步减弱或失活的微生物。具体地,微生物可以是其中胱硫醚合成酶活性与未经修饰的微生物活性相比减弱或失活,并且具体地,编码胱硫醚合成酶的基因(metB)缺失的微生物,但并不限于此。metB的氨基酸序列可以从已知数据库获得,并且可以包括但不限于具有胱硫醚合成酶活性的任何氨基酸序列,例如,其可以指具有SEQ IDNO:3的氨基酸序列的蛋白质。具有SEQ ID NO:3的氨基酸序列的蛋白质可以是由SEQ IDNO:4的核苷酸序列编码的蛋白质,但并不限于此。此外,在本公开的另一方面,埃希氏菌属微生物可以是其中高丝氨酸激酶活性进一步减弱或失活的微生物。具体地,微生物可以是其中高丝氨酸激酶活性与未经修饰的微生物的内源活性相比被减弱或失活的微生物,并且具体地,是其中编码高丝氨酸激酶的基因(thrB)缺失的微生物,但并不限于此。thrB的氨基酸序列可以从已知数据库获得,并且可以包括但不限于具有高丝氨酸激酶活性的任何氨基酸序列,例如,其可以是指具有SEQ ID NO:5的氨基酸序列的蛋白质。具有SEQ ID NO:5的氨基酸序列的蛋白质可以是由SEQ ID NO:6的核苷酸序列编码的蛋白质,但并不限于此。
在本公开中,蛋白质活性的“减弱”可以通过选自以下的方法进行:i)使编码每种蛋白质的基因的部分或全部缺失,ii)修饰表达控制序列以降低基因的表达,iii)修饰染色体上的基因序列以减弱蛋白质的活性;和iv)其组合,但并不限于此。
具体地,术语“蛋白质活性的减弱”是指与在其天然或基础菌株状态下的微生物所具有的酶的内源活性相比酶活性的降低。减弱是这样的概念,其包括由于对编码酶的基因等的修饰微生物中的酶活性与酶自身原始具有的活性相比下降时的情况、由于编码酶的基因的表达抑制或翻译抑制细胞中的总体酶活性水平低于野生型菌株时的情况、或其组合情况,但并不限于此。
“失活”是指与野生型菌株相比,微生物中的编码酶的基因完全不表达时的情况,和基因被表达但没有表现出活性时的情况。
酶的失活可以通过应用本领域已知的多种方法来实现。方法的实例可包括将染色体上的编码酶的基因用经突变以使酶活性降低(包括酶活性被消除时的情况)的基因取代的方法;将修饰引入到染色体上编码酶的基因的表达控制序列中的方法;将编码酶的基因的表达控制序列用具有弱活性或无活性的序列取代的方法;使染色体上的编码酶的基因的全部或部分缺失的方法;引入与染色体上基因的转录物互补结合的反义寡核苷酸(例如,反义RNA)从而抑制从mRNA翻译成酶的方法;将与SD序列互补的序列人工地并入编码酶的基因的SD序列上游,形成二级结构,从而使核糖体不能与其附接的方法;将启动子并入对应序列的开放阅读框(ORF)的3'末端以诱导逆转录(逆转录工程(RTE))的方法等,以及其组合,但并不限于此。
具体地,可以通过使用用于菌株内的染色体插入的载体将编码染色体中内源性靶蛋白质的多核苷酸用在核酸序列中具有部分缺失的多核苷酸或标记基因取代来进行使编码酶的基因的全部或部分缺失的方法。在使基因的部分或全部缺失的方法的示例性实施方式中,可以使用通过同源重组使基因缺失的方法,但并不限于此。
如本文所使用的,术语“部分”可以根据多核苷酸的种类而改变,并且其可以具体地指1至300,更具体地1至100,甚至更具体地1至50,但并不具体限于此。
如本文所使用的,术语“同源重组”是指通过具有相互同源性的基因链的基因座处的交换而发生的基因重组。
具体地,表达调控序列可以通过以下方式进行修饰:通过缺失、插入、非保守性或保守性取代、或其组合来诱导表达控制序列的修饰,以使表达控制序列的活性进一步减弱;或通过用具有非常弱活性的启动子取代。表达控制序列可包括启动子、操纵基因序列、编码核糖体结合区域的序列、和控制转录和翻译终止的序列,但并不限于此。
此外,染色体上的基因序列可以通过以下方式进行修饰:通过基因序列中的缺失、插入、非保守性或保守性取代、或其组合来诱导序列中的修饰以进一步使酶活性减弱;或通过用被改进以具有较弱活性的基因序列或被改进而以不具有活性的基因序列取代,但并不限于此。
在本公开的具体实施方式中,通过通过同源重组使编码胱硫醚合成酶的metB基因和/或thrB基因缺失来减弱每种蛋白质的活性。
此外,在本公开的具体实施方式中,埃希氏杆菌属微生物可以是其中高丝氨酸乙酰转移酶的活性与未经修饰的微生物相比另外地增强的微生物。具体地,微生物可以是其中高丝氨酸乙酰转移酶的活性与未经修饰的微生物相比增加的微生物,具体地,微生物可以是其中引入编码具有增强活性的高丝氨酸乙酰转移酶的经修饰的metA基因的微生物。经修饰的metA基因可以是编码高丝氨酸乙酰转移酶的基因,其中高丝氨酸乙酰转移酶的第111位氨基酸被谷氨酸取代并且第112位氨基酸被组氨酸取代,并且具体地,由SEQ ID NO:8的核苷酸序列组成的基因,但并不限于此。经修饰的metA基因可包括但不限于其中高丝氨酸乙酰转移酶的活性与野生型(例如,具有SEQ ID NO:7的氨基酸序列的蛋白质)相比增强的任何氨基酸。在韩国专利号10-1335841中公开了关于经修饰的metA基因的制备、使用的示例性实施方式、具有增强的高丝氨酸乙酰转移酶活性的菌株等,并且该韩国专利的全部内容可以被包括作为本申请的参考。
此外,在本公开的具体方面,埃希氏菌属微生物可以是其中天冬氨酸激酶(EC2.7.2.4)的活性与未经修饰的微生物相比增强的微生物。具体地,微生物可以是其中天冬氨酸激酶的活性与微生物的内源活性相比增加的微生物,但并不限于此。
在本公开的具体实施方式中,为了使O-乙酰高丝氨酸生产力最大化的目的而进一步增强生物合成途径。具体地,使用质粒引入天冬氨酸激酶和高丝氨酸O-乙酰转移酶,并在进一步增强具有增强的高丝氨酸生物合成途径的菌株中的YjeH之后,测量O-乙酰高丝氨酸生产力的变化。由于生物合成途径和yjeH的同时增强,证实了O-乙酰高丝氨酸生产力被进一步提高。具体地,证实了,当使用cysk启动子增强YjeH活性时,YjeH生产力增加约93%(2.8g/L->5.4g/L)(表5)。
此外,在本公开的具体实施方式中,检测了在具有高产量O-乙酰高丝氨酸生产力的现有菌株中YjeH活性的增强是否可以进一步提高其O-乙酰高丝氨酸生产力。更具体地,使用产生经NTG突变由具有苏氨酸生产力的菌株制备的O-乙酰高丝氨酸的菌株KCCM11146P(国际公开号WO2012/087039)检测O-乙酰高丝氨酸生产的量,所述菌株KCCM11146P是将内源性yjeH基因的启动子用具有高诱导表达活性的启动子取代后的野生型W3110衍生的菌株。结果,证实已经具有高产量O-乙酰高丝氨酸生产力的菌株可以通过增强YjeH活性——特别是通过使用cysk启动子增强YjeH活性——进一步增加生产O-乙酰高丝氨酸的活性约14%(14.2g/L->18.2g/L)(表7)。
关于本公开中所使用的基因、由该基因编码的蛋白质的序列、和启动子序列的信息可以从已知数据库如NCBI GenBank获得,但并不限于此。
本公开的编码每一种蛋白质的基因和启动子不仅包括由每个SEQ ID NO表示的核苷酸序列,还包括但不限于与这些序列具有80%或更高、具体地90%或更高、更具体地95%或更高、甚至更具体地98%或更高、最具体地99%或更高的同源性的任何基因序列,只要该基因序列编码表现出与上述每种酶基本相同或相当的作用的酶。此外,明显地是,具有上述序列同源性的任何核苷酸序列也必然属于本公开的范围,尽管氨基酸可在部分序列中具有缺失、修饰、取代或添加。
此外,明显的是,构成本公开的上述每一种蛋白质的任何氨基酸也必然属于本公开的范围,尽管氨基酸可在部分序列中具有缺失、修饰、取代或添加,只要该氨基酸序列具有由每一个SEQ ID NO表示的相同序列,或者与其具有同源性,同时与每一种蛋白质具有基本相同或相当的作用。
基于具有各种遗传背景和O-乙酰高丝氨酸生产力的微生物证实了通过增强YjeH活性均匀地增加O-乙酰高丝氨酸生产力的作用。这可通过在生物合成途径中促进由YjeH产生特定中间物质而发生。然而,考虑到为内膜和氨基酸转运蛋白家族中的一种的YjeH的特性,O-乙酰高丝氨酸生产力的增加被认为是通过增加输出O-乙酰高丝氨酸(其是最终产物并且是一种氨基酸)的能力,从而促进细胞内反应而实现的。
在本公开的又一方面,本公开提供了生产O-琥珀酰高丝氨酸的方法,包括培养本公开的生产O-乙酰高丝氨酸的埃希氏菌属微生物和回收培养基。
用于培养本公开的微生物的培养基和其它培养条件不受具体限制,但可以使用用于常规培养埃希氏菌属微生物的任何培养基。具体地,本公开的微生物可以在含有适当碳源、氮源、磷源、无机化合物、氨基酸和/或维生素等的常规培养基中、在需氧条件下同时调节温度、pH等进行培养。
在本公开中,碳源可包括碳水化合物(例如,葡萄糖、果糖、蔗糖、麦芽糖、甘露醇、山梨醇等);醇类(例如,糖醇、甘油、丙酮酸、乳酸、柠檬酸等);氨基酸(例如谷氨酸、甲硫氨酸、赖氨酸等);等,但并不限于此。此外,碳源可包括天然有机营养物,如淀粉水解物、糖蜜、黑糖蜜、米糠、木薯、甘蔗糖浆、玉米浆等。具体地,可以使用碳水化合物,如葡萄糖和无菌预处理的糖蜜(即,转化为还原糖的糖蜜),此外,可以使用但不限于适量的各种其它碳源。这些碳源可以单独使用或至少两种组合使用。
氮源的实例可包括无机氮源(例如,氨、硫酸铵、氯化铵、碳酸铵、磷酸铵、硝酸铵等);氨基酸(谷氨酸、甲硫氨酸、谷氨酰胺等);和有机氮源(例如,蛋白胨、N-Z胺、肉膏、酵母提取物、麦芽提取物、玉米浆、酪蛋白水解物、鱼肉或其分解产物、脱脂大豆饼或其分解产物等)。这些氮源可以单独使用或至少两种组合使用,但并不限于此。
磷源的实例可包括磷酸二氢钾、磷酸氢二钾及相应的含钠盐。所使用的无机化合物的实例可包括氯化钠、氯化钙、氯化铁、硫酸镁、硫酸铁、硫酸锰、碳酸钙等。此外,可包括氨基酸、维生素和/或合适的前体。可以将这些培养基或前体以分批培养法或连续培养法添加至培养物,但并不限于此。
在本公开中,可以以适当的方式在培养过程中通过向培养物添加化合物如氢氧化铵、氢氧化钾、氨、磷酸和硫酸来调节培养物的pH。在培养过程中,还可以添加消泡剂如脂肪酸聚乙二醇酯,以防止泡沫生成。此外,可以将氧气或含氧气体注入到培养物以维持培养物的需氧状态;或者可以在不注入气体的情况下注入氮气、氢气或二氧化碳气体,以便维持培养物的厌氧或微需氧状态。
培养温度通常可以在27℃至37℃、更具体地30℃至35℃的范围内,但并不限于此。可以持续进行培养直至获得期望量的有用物质,具体为10小时至100小时,但并不限于此。
本公开的生产O-乙酰高丝氨酸的方法可进一步包括从培养的微生物或培养基中回收O-乙酰高丝氨酸的方法。
具体地,O-乙酰高丝氨酸的回收可以通过培养本公开微生物的方法进行,例如,本领域已知的适当方法,如分批法、连续分批法或补料分批法。
回收可以包括纯化过程。
由此回收的O-乙酰高丝氨酸可用于通过由本发明人开发的两步法(韩国专利号10-0905381)(即,两步法)生产甲硫氨酸。
两步法包括通过利用由生产L-甲硫氨酸前体和甲硫醇的菌株产生的O-乙酰高丝氨酸作为底物通过使用具有O-乙酰高丝氨酸硫化氢解酶活性的酶或含有该酶的菌株的酶促反应生产L-甲硫氨酸和有机酸的方法。
更具体地,本公开提供了通过利用由上述方法积累的O-乙酰高丝氨酸作为底物通过使用酶如O-乙酰高丝氨酸硫化氢解酶的酶反应生产L-甲硫氨酸的方法。
在两步法中,当使用O-乙酰高丝氨酸作为L-甲硫氨酸的前体时,具体地,可以使用来源于属于钩端螺旋体属(genus Leptospira)、色杆菌属(genus Chromobacterium)和生丝单胞菌属(genus Hyphomonas)的微生物菌株,更具体地,来源于属于迈氏钩端螺旋体(Leptospira meyeri)、铜绿假单胞菌(Pseudomonas aurogenosa)、镎生丝单胞菌(Hyphomonas neptunium)和紫色色杆菌(Chromobacterium violaceum)的微生物菌株的O-乙酰高丝氨酸硫化氢解酶。
反应如下所示。
CH3SH+O-乙酰-L-高丝氨酸<=>乙酸酯+甲硫氨酸
在韩国专利号10-0905381中公开了这种额外的生产甲硫氨酸的方法,上述韩国专利的整个说明书可以被包括作为本公开的参考。
发明方式
在下文中,将参考以下实施例对本公开进行更加详细地描述。然而,这些实施例仅用于说明性目的,并且本公开并不旨在受这些实施例的限制。
实施例1:具有O-乙酰高丝氨酸生产力的菌株的制备
1-1.野生型大肠杆菌中的metB基因的缺失
为了制备生产O-乙酰高丝氨酸的菌株,使用大肠杆菌(埃希氏杆菌属的代表性微生物)。为此目的,从美国模式培养物收集中心(ATCC)获得野生型大肠杆菌(K12)W3110(ATCC27325)并使用。首先,为了阻断由O-琥珀酰-L-高丝氨酸生产胱硫醚的途径,使编码胱硫醚合成酶的metB基因(SEQ ID NO:4)缺失。
具体地,使用FRT一步PCR缺失法用于metB基因的缺失(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000)。在pKD3载体作为模板的基础上,使用SEQID NO:13和14的引物TKd,通过进行PCR来制备缺失盒(Wanner BL.,Proc.Natl.Acad.Sci.USA97:6640-6645,2000)。具体地,在下述条件下进行PCR,共30个循环:94℃变性30秒、55℃退火30秒和72℃延伸1分钟。
由此得到的PCR产物在1.0%琼脂糖凝胶上进行电泳,并纯化从1.2kb带获得的DNA。通过电穿孔将回收的DNA片段引入已经转化有pKD46载体的大肠杆菌(K12)W3110菌株(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000)。使用含有氨苄青霉素(100μg/L)和L-阿拉伯糖(5mM)的LB培养基培养转化有pKD46的W3110菌株,直到培养物在30℃达到OD 600=0.6,在用无菌蒸馏水冲洗两次并用10%甘油冲洗一次后使用。在2500V进行电穿孔。将回收的菌株涂布在含有氯霉素(25μg/L)的LB平板培养基上,37℃培养过夜,并选出抗性菌株。
使用由此选出的菌株作为模板和相同的引物(SEQ ID NO:13和14)进行PCR,并通过观察1.0%琼脂糖凝胶上的1.2kb基因带的存在来确认metB基因的缺失。用pCP20载体转化其中metB基因缺失被确认的菌株(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000),并在相同的LB培养基中培养。然后,在相同条件下进行PCR,随后在1.0%琼脂糖凝胶上进行电泳,以观察1.2kb基因带的存在,从而确认metB基因的缺失。在确认缺失后,用pCP20载体转化该菌株(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000),并在相同的LB培养基中培养。然后,在相同条件下进行PCR,随后在1.0%琼脂糖凝胶上进行电泳,以选出具有由缩小至150bp大小的基因带表示的metB基因缺失的最终菌株,从而确认氯霉素标记从该菌株中去除。
将由此制备和选出的、具有metB基因缺失、编码胱硫醚合成酶的菌株命名为“W3-B”。
1-2.thrB基因的缺失
为了增加来自实施例1-1中制备的W3-B菌株的O-琥珀酰高丝氨酸合成的量,从该菌株中将编码高丝氨酸激酶的thrB基因(SEQ ID NO:6)缺失。为使thrB基因缺失,使用用于实施例1-1中使metB基因缺失的相同的FRT一步PCR缺失法。
首先,为了制备thrB缺失盒,使用pKD4载体作为模板进行PCR(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000),从而制得缺失盒。具体地,在下述条件下使用SEQ ID NO:15和16的引物进行PCR共30个循环:94℃变性30秒、55℃退火30秒和72℃延伸1分钟。
由此得到的PCR产物在1.0%琼脂糖凝胶上进行电泳,并纯化从1.6kb带获得的DNA。通过电穿孔将回收的DNA片段引入已经转化有pKD46载体的W3-B菌株。将回收的菌株涂布在含有卡那霉素(50μg/L)的LB平板培养基上,37℃培养过夜,并选出抗性菌株。
使用通过上述方法选出的菌株作为模板和引物(SEQ ID NO:15和16)一起,在相同条件下进行PCR,并通过观察1.0%琼脂糖凝胶上的1.6kb基因的存在来确认thrB基因的缺失。用pCP20载体再次转化确认的菌株,并在LB培养基上进行培养,然后,在相同条件下进行PCR,随后在1.0%琼脂糖凝胶上进行电泳,以选出具有由缩小至150bp大小的基因带表示的thrB基因缺失的最终菌株,从而确认卡那霉素标记从该菌株中去除。将由此制备并选出的、具有thrB基因缺失、编码高丝氨酸激酶的菌株命名为“W3-BT”。
在韩国专利号10-0905381或国际公开号WO 2008/013432中公开了关于具有metB基因和thrB基因等缺失的菌株的示例性实施方式,并且韩国专利或国际专利公开的全部内容可以被包括在本文作为本公开的参考。
1-3.具有高丝氨酸乙酰转移酶活性的带有修饰metA基因的菌株的制备
为了增强实施例1-2制备的菌株中的高丝氨酸乙酰转移酶的活性,已做出尝试将编码具有增强活性的高丝氨酸乙酰转移酶的经修饰的metA基因(SEQ ID NO:8)引入菌株。
在这方面,为了制备具有增强活性的经修饰的metA基因,首先通过使用W3110菌株的染色体作为模板和引物(SEQ ID NO:17和18)的PCR扩增并得到metA基因。基于登记在NIHGenBank中的NC_000913的大肠杆菌染色体的核苷酸序列,制备用于PCR的引物(SEQ ID NO:17和18),以分别包括EcoRV限制性位点和HindIII限制性位点。
用EcoRV和HindIII处理由此得到的PCR产物和包括pcj1的pCL1920质粒并进行克隆。用克隆的质粒转化大肠杆菌DH5α,并在含有壮观霉素(50μg/L)的LB平板培养基中培养,选出转化的大肠杆菌DH5α,从而获得质粒。将由此得到的质粒命名为“pCL_Pcj1_metA”。
在上述获得的pCL_Pcj1_metA的基础上,使用定点突变试剂盒(Stratagene,USA)制备修饰的metA基因。具体地,将高丝氨酸乙酰转移酶的第111位氨基酸(Gly)取代为谷氨酸(Glu)(G111E)。将由此制备的质粒命名为“pCL_Pcj1_metA(EL)”。
此外,使用引物(SEQ ID NO:21和22),将高丝氨酸乙酰转移酶的第111位氨基酸(Gly)取代为谷氨酸(Glu),另外,将第112位氨基酸(Leu)取代为组氨酸(His)。因此,将包含metA基因的质粒——其中第111位氨基酸由甘氨酸变为谷氨酸和第112位氨基酸由亮氨酸变为组氨酸——命名为“pCL_Pcj1_metA(EH)”。
然后,为了制备在将其引入菌株后用修饰的metA基因取代的取代盒,使用pKD3载体作为模板和引物(SEQ ID NO:27和28),在下述条件下进行PCR共30个循环:94℃变性30秒、55℃退火30秒和72℃延伸2分钟。分别获得取代盒的metA(EH)部分,为使用pCL-Pcj1-metA(EH)作为模板和引物(SEQ ID NO:23和24)的PCR产物,和使用引物(SEQ ID NO:25和26)得到metA野生型的部分。使用引物(SEQ ID NO:23和26),将三种PCR产物用于制备包含有氯霉素标记的metA(EH)取代盒,并通过电穿孔将修饰的metA基因引入实施例1-2中制备的已经转化有pKD46载体的W3-BT菌株。用pCP20载体再次转化确认引入的菌株,在LB培养基中培养,并将其中去除氯霉素标记并将metA基因取代为metA(EH)的菌株命名为“W3-BTA”。
在韩国专利号10-1335841或国际公开号WO 2012/087039中公开了关于具有高丝氨酸乙酰转移酶等的增强活性的菌株的示例性实施方式,并且韩国专利或国际专利公开的整个说明书可以包括被包括在本文作为本公开的参考。
1-4.包括2个拷贝的ppc、aspC和asd基因的菌株的制备
为了增加实施例1-3中制备的W3-BTA的O-乙酰高丝氨酸生产力,引入用于增强生物合成途径的现有策略。已做出努力来制备这样的菌株,其中参与由磷酸烯醇丙酮酸酯生物合成草酰乙酸酯的磷酸烯醇丙酮酸羧化酶、参与由草酰乙酸酯生物合成天冬氨酸的天冬氨酸转氨酶和参与由天冬氨酸半醛脱氢酶生物合成高丝氨酸的天冬氨酸半醛脱氢酶被扩增为2个拷贝(即ppc基因、aspC基因和asd基因)。
因此,分别使用SEQ ID NO:29、30、31和32的引物将ppc基因扩增为2个拷贝;使用SEQ ID NO:33和34的引物将aspC基因扩增为2个拷贝;以及使用SEQ ID NO:35、36、37和38的引物将asd基因分别扩增为2个拷贝。
将通过上述方法基于W3-BTA菌株增强O-乙酰高丝氨酸的生物合成途径的菌株被命名为“W3-BTA2PCD(=WCJM)”。
在韩国专利号10-0905381或国际公开号WO 2008/013432中公开了关于具有高丝氨酸乙酰转移酶等的增强活性的菌株的示例性实施方式,并且韩国专利或国际专利公开的整个说明书可以被包括在本文作为本公开的参考。
1-5.摇瓶培养实验
对于通过实施例1-3和1-4中制备的菌株的O-乙酰高丝氨酸生产的量的实验,进行锥形瓶培养。将W3110、W3-BTA和WCJM菌株接种到LB培养基中,在33℃培养过夜。然后,将单菌落接种到LB培养基(3mL)中、33℃培养5小时、在含有25mL用于生产O-乙酰高丝氨酸的培养基的250mL锥形瓶中再次稀释200倍、在33℃以200rpm的速率培养30小时,并通过HPLC分析确认O-乙酰高丝氨酸产生的量。所用的培养基组成总结在下表1中。
[表1]用于产生O-乙酰高丝氨酸的摇瓶培养基的组成
将菌株在上述培养基中培养30小时,并通过HPLC分析确定O-乙酰高丝氨酸生产的量。结果显示在下表2中。
[表2]通过摇瓶培养的O-乙酰高丝氨酸产生
由表2可以确定,野生型W3110菌株完全不产生O-乙酰高丝氨酸,但是,W3-BTA菌株产生0.9g/L浓度的O-乙酰高丝氨酸,并且其中增强生物合成途径的WCJM菌株产生1.2g/L浓度的O-乙酰高丝氨酸。
实施例2:增加O-乙酰高丝氨酸生产力的膜蛋白质的鉴定
本发明人已经应用了与O-乙酰高丝氨酸输出和O-乙酰高丝氨酸生产力的关联从未被公开的yjeH(SEQ ID NO:1)。
使用存在于bac载体的HindIII限制性位点,通过将yjeH基因克隆到bac载体增强菌株的yjeH基因。对于bac载体,使用CopyControl BAC克隆试剂盒(目录号CCBAC1H-HindIII,Epicentre)。
首先,为了获得yjeH基因,在下述条件下,使用引物(SEQ ID NO:9和10)进行PCR共30个循环:94℃变性30秒、55℃退火30秒和68℃延伸1分钟。所得PCR产物在1.0%琼脂糖凝胶上进行电泳,纯化从1.2kb带获得的DNA。在37℃用HindIII处理纯化的DNA过夜,再次进行纯化,并使用T4连接酶克隆yjeH和BAC载体。用克隆的质粒转化大肠杆菌DH5α,并从含有氯霉素50μg/mL的LB平板培养基中选出转化的大肠杆菌DH5α。将由此制备的质粒引入产生O-乙酰高丝氨酸的W3-BTA和WCJM菌株,并对它们的O-乙酰高丝氨酸生产力进行摇瓶评估。
所得PCR产物在1.0%琼脂糖凝胶上进行电泳,纯化从1.2kb带获得的DNA。在37℃用HindIII处理纯化的DNA过夜,再次进行纯化,并使用T4连接酶克隆yjeH和BAC载体。用克隆的质粒转化大肠杆菌DH5α,并从含有氯霉素50μg/mL的LB平板培养基中选出转化的大肠杆菌DH5α,并从其中获得质粒。将由此制备的质粒引入产生O-乙酰高丝氨酸的W3-BTA和WCJM菌株中,并对其O-乙酰高丝氨酸生产力进行摇瓶评估。
具体地,将每种菌株涂布在固体LB培养基上,并在33℃培养箱中培养过夜。将在固体LB培养基上培养的每个菌株的单菌落接种到LB培养基(3mL),在33℃培养5小时。再次,将生成物在含有25mL用于生产O-乙酰高丝氨酸的培养基的250mL锥形瓶中稀释200倍,在33℃以200rpm的速率培养30小时,并通过HPLC分析确定O-乙酰高丝氨酸产生的量。结果总结在下表3中。
[表3]通过烧瓶培养对O-乙酰高丝氨酸产生的测量
由表3可以确定,与对照菌株相比,将yjeH质粒引入WCJM菌株导致更高的OD值,以及更高的葡萄糖消耗速率。WCJM/pBAC-yjeH菌株产生2.3g/L浓度的O-乙酰高丝氨酸,从而确认通过yjeH引入该菌株可以具有增加的O-乙酰高丝氨酸生产力。
实施例3:具有增强的yjeH启动子的质粒的制备和O-乙酰高丝氨酸生产力的评价
3-1.具有增强的yjeH启动子的质粒的制备
基于实施例2中制备的质粒,进行实验以将内源性yjeH启动子取代为与内源性yjeH启动子相比具有强表达诱导活性的3种不同的启动子。
具体地,使用pro、cysk或icd启动子制备具有增强活性的启动子的PCL载体。使用PCL载体的SmaI限制性位点制备PCL载体;使用SEQ ID NO:39和40的引物通过PCR扩增制备icd启动子(SEQ ID NO:51);使用SEQ ID NO:41和42的引物制备pro启动子(SEQ ID NO:52);和使用SEQ ID NO:43和44的引物制备cysk启动子(SEQ ID NO:53)。分别将由此制备的质粒引入WCJM菌株,并在摇瓶中评估它们的O-乙酰高丝氨酸生产力。
具体地,将每种菌株涂布在LB平板培养基上,并在33℃培养箱中培养过夜。将在LB平板培养基上培养过夜的每种菌株接种到25mL滴定培养基中,并在33℃培养箱中以200rpm培养过夜。结果显示在下表4中。
[表4]通过摇瓶培养的O-乙酰高丝氨酸产生的测量
由表4可以确定,与自身启动子相比,引入有pCL-Pcysk-yjeH质粒的菌株显示OD值降低,但是该菌株显示较高的葡萄糖消耗率和最高的O-乙酰高丝氨酸产生(4.4g/L)。
3-2.用于增强生物合成途径中的基因和启动子的质粒的制备
为了使O-乙酰高丝氨酸生产力最大化,制备用于增强生物合成途径直至高丝氨酸的质粒。为了将天冬氨酸激酶、高丝氨酸O-乙酰转移酶和yjeH克隆到PCL载体,使用已经制得的pCL-thrA-metX质粒。
具体地,为了得到yjeH基因,在下述条件下使用引物(SEQ ID NO:11和12)进行PCR共30个循环:94℃变性30秒、55℃退火30秒和68℃延伸1分钟。
所得PCR产物在1.0%琼脂糖凝胶上进行电泳,并纯化从1.2kb带获得的DNA。在37℃用KpnI处理纯化的DNA过夜,再一次纯化,并使用T4连接酶克隆yjeH和BAC载体。用克隆的质粒转化大肠杆菌DH5α,并从含有大观霉素50μg/mL的LB平板培养基中选出转化的大肠杆菌DH5α,并从其中获得质粒。将由此制备的质粒引入生产O-乙酰高丝氨酸的WCJM菌株中,并对其O-乙酰高丝氨酸生产力进行摇瓶评估。由此制备的质粒全部为3种,并使用实施例3-1中制备的3种不同启动子来制备它们。将3种不同的质粒引入WCJM菌株,并以与实施例3-1相同的方式进行摇瓶评估。结果显示在下表5中。
[表5]通过摇瓶培养的O-乙酰高丝氨酸产生的测量
由表5可以确定,当同时增强生物合成途径和yjeH时,O-乙酰高丝氨酸产生被进一步提高。O-乙酰高丝氨酸产生增加的顺序如下:以与上述相同的方式,与其中使用自身启动子的菌株相比,引入有pC2-Pcysk-yjeH质粒的菌株显示OD值降低,但是引入有pC2-Pcysk-yjeH质粒的菌株显示最高的葡萄糖消耗率以及最高的O-乙酰高丝氨酸产生(5.4g/L)。
实施例4:具有增强的内源性yjeH启动子的菌株的制备和O-乙酰高丝氨酸生产力
的评估
4-1.具有增强的内源性yjeH的菌株的制备及其评估
为了制备产生O-乙酰高丝氨酸、具有WCJM菌株的内源性yjeH基因的增强活性的菌株,进行了取代启动子的实验。本公开的WCJM菌株具有一个拷贝的yjeH基因,以及制得该菌株以通过增强启动子而不是增加yjeH基因的拷贝数来增加yjeH基因。
具体地,作为用于取代的启动子,使用实施例3中确认活性的icd、cysK和pro启动子(Picd、Pcysk和Ppro)和上面所述的FRT一步PCR缺失法(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000)。使用pKD4载体作为模板,连同用于icd启动子的SEQ ID NO:45和46的引物、用于cysk启动子的SEQ ID NO:47和48的引物以及用于pro启动子的SEQ ID NO:49和50的引物,制备插入盒。在下述条件下进行PCR共30个循环:94℃变性30秒、55℃退火30秒和72℃延伸1分钟。
由此得到的PCR产物在1.0%琼脂糖凝胶上进行电泳,并纯化从2.5kb带获得的DNA。通过电穿孔将回收的DNA片段引入已经转化有pKD46载体的WCJM菌株(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000)。使用含有氨苄青霉素100μg/L和L-阿拉伯糖5mM的LB培养基培养转化有pKD46的WCJM菌株,直到培养物在30℃下达到OD600=0.6,在用无菌蒸馏水冲洗两次并用10%甘油冲洗一次后使用。在2500V进行电穿孔。将回收的菌株涂布在含有氯霉素25μg/L的LB平板培养基上,37℃培养过夜,并选出抗性菌株。
在上述相同条件下,使用由此选出的菌株作为模板连同用于icd启动子的SEQ IDNO:45和46的引物、用于cysk启动子的SEQ ID NO:47和48的引物以及用于pro启动子的SEQID NO:49和50的引物一起,进行PCR,并通过观察1.0%琼脂糖凝胶上的2.5kb基因带的存在确认将yjeH基因的内源启动子取代为外源启动子的每一种。用pCP20载体转化确认启动子取代的菌株(Wanner BL.,Proc.Natl.Acad.Sci.USA 97:6640-6645,2000),并在LB培养基中培养。然后,在相同条件下进行PCR,随后在1.0%琼脂糖凝胶上进行电泳,以制备具有由缩小至1kb大小的基因带表示的启动子取代的最终菌株,从而确认卡那霉素标记从菌株中去除。根据它们各自的启动子命名由此制备的菌株:即“WCJM-PIY”(具有icd取代的icd启动子的菌株)、“WCJM-PCY”(具有cysk取代的启动子的菌株)和“WCJM-PCY”(具有pro取代的启动子的菌株)。通过进行摇瓶培养评估来测量其中取代yjeH基因启动子的菌株的O-乙酰高丝氨酸生产力,结果显示在下表6中。
[表6]通过摇瓶培养测量O-乙酰高丝氨酸产生
由表6可以确定,当通过将染色体内的yjeH基因的内源性启动子取代为具有强表达活性的启动子来增强WCJM菌株的yjeH基因表达时,与其中通过引入有质粒(5拷贝)转化菌株的实施例3的结果相比,O-乙酰高丝氨酸生产力没有快速变化,但每个菌株的O-乙酰高丝氨酸生产力与作为生产O-乙酰高丝氨酸的菌株的WCJM菌株相比显示增加。
4-2.具有O-乙酰高丝氨酸高产量的菌株中的yjeH基因的增强启动子的菌株的制
备和菌株的O-乙酰高丝氨酸生产力的评估
使用经NTG突变具有苏氨酸生产力的野生型W3110衍生的菌株来制备生产O-乙酰高丝氨酸的菌株的方法是已知的(国际公开号WO2012/087039)。具体地,将由此制备的以高产量生产O-乙酰高丝氨酸的菌株保藏于韩国微生物培养中心(KCCM),登录号为KCCM11146P。
登录号为KCCM11146P的菌株具有高产量O-乙酰高丝氨酸生产力,其在摇瓶培养期间消耗40g/L的葡萄糖并产生约15g/L至16g/LO-乙酰高丝氨酸。在这方面,本发明人检测了已经具有高O-乙酰高丝氨酸生产力的菌株是否可以通过增强菌株中的yjeH基因进一步提高其O-乙酰高丝氨酸生产力。
具体地,用具有高表达诱导活性的启动子取代yjeH基因的启动子,这以与实施例4-1相同的方式进行。分别将由此制备的菌株——其中KCCM11146P菌株的yjeH基因的启动子——命名为“KCCM11146P-PIY”(具有icd取代的启动子的菌株)、“KCCM11146P-PCY”(具有cysk取代的启动子的菌株)和“KCCM11146P-PPY”(具有pro取代的启动子菌株)。
通过摇瓶培养评估测量其中取代yjeH基因启动子的菌株的O-乙酰高丝氨酸生产力。具体地,将KCCM11146P、KCCM11146P-PIY、KCCM11146P-PCY和KCCM11146P-PPY菌株接种到LB培养基中并在33℃培养过夜。将所得单个菌落接种到3mL LB培养基中,在33℃培养5小时,在含有25mL用于生产O-乙酰高丝氨酸的培养基的250mL锥形瓶中稀释200倍,以200rpm的速率在33℃培养30小时,并通过HPLC分析O-乙酰高丝氨酸产生的量。结果显示在下表7中。
[表7]通过摇瓶培养测量O-乙酰高丝氨酸产生
由表7可以确认,KCCM11146P菌株产生14.2g/L的O-乙酰高丝氨酸,然而,在具有取代的启动子的菌株的情况下,与原始菌株相比,PCY菌株显示最高的产量(18.2g/L),PIY和PPY菌株显示增加的O-乙酰高丝氨酸产生。
本发明人已经证实,基于KCCM11146P菌株的其中yjeH基因活性被增强的菌株可以增加O-乙酰高丝氨酸产生。结果,发明人已将该菌株命名为“CA05-4008”,并根据布达佩斯条约于2013年11月22日将该菌株保藏于韩国微生物培养中心(KCCM),登录号为KCCM11484P。
由前述内容,本公开所属的本领域技术人员将能够理解,在不改变本公开的技术概念或本质特征的情况下,可以以其它具体形式体现本公开。在这方面,本文所公开的示例性实施方式仅用于说明性目的,并且不应被解释为限制本公开的范围。相反,本公开旨在不仅覆盖示例性实施方式,而且覆盖可以包括在由所附权利要求限定的本公开的精神和范围内的各种取代、修饰、等价物和其它实施方式。
<110> CJ第一制糖株式会社
<120> 生产O-乙酰高丝氨酸的微生物和使用其生产O-乙酰高丝氨酸的方法
<130> OPA15135-PCT
<150> KR10-2014-0068613
<151> 2014-06-05
<160> 53
<170> KopatentIn 2.0
<210> 1
<211> 418
<212> PRT
<213> 大肠杆菌 yjeH
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His Tyr Pro Ser Ala Gly Gly Val Ala His Phe Val Gly Met Ala Phe
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Pro Val Gly Leu Pro Ala Ala Leu Gln Ile Ala Ala Gly Phe Gly Gln
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Ala Met Phe Gly Trp His Ser Trp Gln Leu Leu Leu Ala Glu Leu Gly
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Thr Leu Ala Leu Val Trp Tyr Ile Gly Thr Arg Gly Ala Ser Ser Ser
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Ala Asn Leu Gln Thr Val Ile Ala Gly Leu Ile Val Ala Leu Ile Val
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Ala Ile Trp Trp Ala Gly Asp Ile Lys Pro Ala Asn Ile Pro Phe Pro
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Ala Pro Gly Asn Ile Glu Leu Thr Gly Leu Phe Ala Ala Leu Ser Val
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<210> 2
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<213> 大肠杆菌 yjeH
<400> 2
atgagtggac tcaaacaaga actggggctg gcccagggca ttggcctgct atcgacgtca 60
ttattaggca ctggcgtgtt tgccgttcct gcgttagctg cgctggtagc gggcaataac 120
agcctgtggg cgtggcccgt tttgattatc ttagtgttcc cgattgcgat tgtgtttgcg 180
attctgggtc gccactatcc cagcgcaggc ggcgtcgcgc acttcgtcgg tatggcgttt 240
ggttcgcggc ttgagcgagt caccggctgg ctgtttttat cggtcattcc cgtgggtttg 300
cctgccgcac tacaaattgc cgccgggttc ggccaggcga tgtttggctg gcatagctgg 360
caactgttgt tggcagaact cggtacgctg gcgctggtgt ggtatatcgg tactcgcggt 420
gccagttcca gtgctaatct acaaaccgtt attgccggac ttatcgtcgc gctgattgtc 480
gctatctggt gggcgggcga tatcaaacct gcgaatatcc cctttccggc acctggtaat 540
atcgaactta ccgggttatt tgctgcgtta tcagtgatgt tctggtgttt tgtcggtctg 600
gaggcatttg cccatctcgc ctcggaattt aaaaatccag agcgtgattt tcctcgtgct 660
ttgatgattg gtctgctgct ggcaggatta gtctactggg gctgtacggt agtcgtctta 720
cacttcgacg cctatggtga aaaaatggcg gcggcagcat cgcttccaaa aattgtagtg 780
cagttgttcg gtgtaggagc gttatggatt gcctgcgtga ttggctatct ggcctgcttt 840
gccagtctca acatttatat acagagcttc gcccgcctgg tctggtcgca ggcgcaacat 900
aatcctgacc actacctggc acgcctctct tctcgccata tcccgaataa tgccctcaat 960
gcggtgctcg gctgctgtgt ggtgagcact ttggtgattc atgctttaga gatcaatctg 1020
gacgctctta ttatttatgc caatggcatc tttattatga tttatctgtt atgcatgctg 1080
gcaggctgta aattattgca aggacgttat cgactactgg cggtggttgg cgggctgtta 1140
tgcgttctgt tactggcaat ggtcggctgg aaaagtctct atgcgctgat catgctggcg 1200
gggttatggc tgttgctgcc aaaacgaaaa acgccggaaa atggcataac cacataa 1257
<210> 3
<211> 386
<212> PRT
<213> 大肠杆菌 metB
<400> 3
Met Thr Arg Lys Gln Ala Thr Ile Ala Val Arg Ser Gly Leu Asn Asp
1 5 10 15
Asp Glu Gln Tyr Gly Cys Val Val Pro Pro Ile His Leu Ser Ser Thr
20 25 30
Tyr Asn Phe Thr Gly Phe Asn Glu Pro Arg Ala His Asp Tyr Ser Arg
35 40 45
Arg Gly Asn Pro Thr Arg Asp Val Val Gln Arg Ala Leu Ala Glu Leu
50 55 60
Glu Gly Gly Ala Gly Ala Val Leu Thr Asn Thr Gly Met Ser Ala Ile
65 70 75 80
His Leu Val Thr Thr Val Phe Leu Lys Pro Gly Asp Leu Leu Val Ala
85 90 95
Pro His Asp Cys Tyr Gly Gly Ser Tyr Arg Leu Phe Asp Ser Leu Ala
100 105 110
Lys Arg Gly Cys Tyr Arg Val Leu Phe Val Asp Gln Gly Asp Glu Gln
115 120 125
Ala Leu Arg Ala Ala Leu Ala Glu Lys Pro Lys Leu Val Leu Val Glu
130 135 140
Ser Pro Ser Asn Pro Leu Leu Arg Val Val Asp Ile Ala Lys Ile Cys
145 150 155 160
His Leu Ala Arg Glu Val Gly Ala Val Ser Val Val Asp Asn Thr Phe
165 170 175
Leu Ser Pro Ala Leu Gln Asn Pro Leu Ala Leu Gly Ala Asp Leu Val
180 185 190
Leu His Ser Cys Thr Lys Tyr Leu Asn Gly His Ser Asp Val Val Ala
195 200 205
Gly Val Val Ile Ala Lys Asp Pro Asp Val Val Thr Glu Leu Ala Trp
210 215 220
Trp Ala Asn Asn Ile Gly Val Thr Gly Gly Ala Phe Asp Ser Tyr Leu
225 230 235 240
Leu Leu Arg Gly Leu Arg Thr Leu Val Pro Arg Met Glu Leu Ala Gln
245 250 255
Arg Asn Ala Gln Ala Ile Val Lys Tyr Leu Gln Thr Gln Pro Leu Val
260 265 270
Lys Lys Leu Tyr His Pro Ser Leu Pro Glu Asn Gln Gly His Glu Ile
275 280 285
Ala Ala Arg Gln Gln Lys Gly Phe Gly Ala Met Leu Ser Phe Glu Leu
290 295 300
Asp Gly Asp Glu Gln Thr Leu Arg Arg Phe Leu Gly Gly Leu Ser Leu
305 310 315 320
Phe Thr Leu Ala Glu Ser Leu Gly Gly Val Glu Ser Leu Ile Ser His
325 330 335
Ala Ala Thr Met Thr His Ala Gly Met Ala Pro Glu Ala Arg Ala Ala
340 345 350
Ala Gly Ile Ser Glu Thr Leu Leu Arg Ile Ser Thr Gly Ile Glu Asp
355 360 365
Gly Glu Asp Leu Ile Ala Asp Leu Glu Asn Gly Phe Arg Ala Ala Asn
370 375 380
Lys Gly
385
<210> 4
<211> 1161
<212> DNA
<213> 大肠杆菌 metB
<400> 4
atgacgcgta aacaggccac catcgcagtg cgtagcgggt taaatgacga cgaacagtat 60
ggttgcgttg tcccaccgat ccatctttcc agcacctata actttaccgg atttaatgaa 120
ccgcgcgcgc atgattactc gcgtcgcggc aacccaacgc gcgatgtggt tcagcgtgcg 180
ctggcagaac tggaaggtgg tgctggtgca gtacttacta ataccggcat gtccgcgatt 240
cacctggtaa cgaccgtctt tttgaaacct ggcgatctgc tggttgcgcc gcacgactgc 300
tacggcggta gctatcgcct gttcgacagt ctggcgaaac gcggttgcta tcgcgtgttg 360
tttgttgatc aaggcgatga acaggcatta cgggcagcgc tggcagaaaa acccaaactg 420
gtactggtag aaagcccaag taatccattg ttacgcgtcg tggatattgc gaaaatctgc 480
catctggcaa gggaagtcgg ggcggtgagc gtggtggata acaccttctt aagcccggca 540
ttacaaaatc cgctggcatt aggtgccgat ctggtgttgc attcatgcac gaaatatctg 600
aacggtcact cagacgtagt ggccggcgtg gtgattgcta aagacccgga cgttgtcact 660
gaactggcct ggtgggcaaa caatattggc gtgacgggcg gcgcgtttga cagctatctg 720
ctgctacgtg ggttgcgaac gctggtgccg cgtatggagc tggcgcagcg caacgcgcag 780
gcgattgtga aatacctgca aacccagccg ttggtgaaaa aactgtatca cccgtcgttg 840
ccggaaaatc aggggcatga aattgccgcg cgccagcaaa aaggctttgg cgcaatgttg 900
agttttgaac tggatggcga tgagcagacg ctgcgtcgtt tcctgggcgg gctgtcgttg 960
tttacgctgg cggaatcatt agggggagtg gaaagtttaa tctctcacgc cgcaaccatg 1020
acacatgcag gcatggcacc agaagcgcgt gctgccgccg ggatctccga gacgctgctg 1080
cgtatctcca ccggtattga agatggcgaa gatttaattg ccgacctgga aaatggcttc 1140
cgggctgcaa acaaggggta a 1161
<210> 5
<211> 310
<212> PRT
<213> 大肠杆菌 thrB
<400> 5
Met Val Lys Val Tyr Ala Pro Ala Ser Ser Ala Asn Met Ser Val Gly
1 5 10 15
Phe Asp Val Leu Gly Ala Ala Val Thr Pro Val Asp Gly Ala Leu Leu
20 25 30
Gly Asp Val Val Thr Val Glu Ala Ala Glu Thr Phe Ser Leu Asn Asn
35 40 45
Leu Gly Arg Phe Ala Asp Lys Leu Pro Ser Glu Pro Arg Glu Asn Ile
50 55 60
Val Tyr Gln Cys Trp Glu Arg Phe Cys Gln Glu Leu Gly Lys Gln Ile
65 70 75 80
Pro Val Ala Met Thr Leu Glu Lys Asn Met Pro Ile Gly Ser Gly Leu
85 90 95
Gly Ser Ser Ala Cys Ser Val Val Ala Ala Leu Met Ala Met Asn Glu
100 105 110
His Cys Gly Lys Pro Leu Asn Asp Thr Arg Leu Leu Ala Leu Met Gly
115 120 125
Glu Leu Glu Gly Arg Ile Ser Gly Ser Ile His Tyr Asp Asn Val Ala
130 135 140
Pro Cys Phe Leu Gly Gly Met Gln Leu Met Ile Glu Glu Asn Asp Ile
145 150 155 160
Ile Ser Gln Gln Val Pro Gly Phe Asp Glu Trp Leu Trp Val Leu Ala
165 170 175
Tyr Pro Gly Ile Lys Val Ser Thr Ala Glu Ala Arg Ala Ile Leu Pro
180 185 190
Ala Gln Tyr Arg Arg Gln Asp Cys Ile Ala His Gly Arg His Leu Ala
195 200 205
Gly Phe Ile His Ala Cys Tyr Ser Arg Gln Pro Glu Leu Ala Ala Lys
210 215 220
Leu Met Lys Asp Val Ile Ala Glu Pro Tyr Arg Glu Arg Leu Leu Pro
225 230 235 240
Gly Phe Arg Gln Ala Arg Gln Ala Val Ala Glu Ile Gly Ala Val Ala
245 250 255
Ser Gly Ile Ser Gly Ser Gly Pro Thr Leu Phe Ala Leu Cys Asp Lys
260 265 270
Pro Glu Thr Ala Gln Arg Val Ala Asp Trp Leu Gly Lys Asn Tyr Leu
275 280 285
Gln Asn Gln Glu Gly Phe Val His Ile Cys Arg Leu Asp Thr Ala Gly
290 295 300
Ala Arg Val Leu Glu Asn
305 310
<210> 6
<211> 933
<212> DNA
<213> 大肠杆菌thrB
<400> 6
atggttaaag tttatgcccc ggcttccagt gccaatatga gcgtcgggtt tgatgtgctc 60
ggggcggcgg tgacacctgt tgatggtgca ttgctcggag atgtagtcac ggttgaggcg 120
gcagagacat tcagtctcaa caacctcgga cgctttgccg ataagctgcc gtcagaacca 180
cgggaaaata tcgtttatca gtgctgggag cgtttttgcc aggaactggg taagcaaatt 240
ccagtggcga tgaccctgga aaagaatatg ccgatcggtt cgggcttagg ctccagtgcc 300
tgttcggtgg tcgcggcgct gatggcgatg aatgaacact gcggcaagcc gcttaatgac 360
actcgtttgc tggctttgat gggcgagctg gaaggccgta tctccggcag cattcattac 420
gacaacgtgg caccgtgttt tctcggtggt atgcagttga tgatcgaaga aaacgacatc 480
atcagccagc aagtgccagg gtttgatgag tggctgtggg tgctggcgta tccggggatt 540
aaagtctcga cggcagaagc cagggctatt ttaccggcgc agtatcgccg ccaggattgc 600
attgcgcacg ggcgacatct ggcaggcttc attcacgcct gctattcccg tcagcctgag 660
cttgccgcga agctgatgaa agatgttatc gctgaaccct accgtgaacg gttactgcca 720
ggcttccggc aggcgcggca ggcggtcgcg gaaatcggcg cggtagcgag cggtatctcc 780
ggctccggcc cgaccttgtt cgctctgtgt gacaagccgg aaaccgccca gcgcgttgcc 840
gactggttgg gtaagaacta cctgcaaaat caggaaggtt ttgttcatat ttgccggctg 900
gatacggcgg gcgcacgagt actggaaaac taa 933
<210> 7
<211> 309
<212> PRT
<213> 人工序列
<220>
<223> metA
<400> 7
Met Pro Ile Arg Val Pro Asp Glu Leu Pro Ala Val Asn Phe Leu Arg
1 5 10 15
Glu Glu Asn Val Phe Val Met Thr Thr Ser Arg Ala Ser Gly Gln Glu
20 25 30
Ile Arg Pro Leu Lys Val Leu Ile Leu Asn Leu Met Pro Lys Lys Ile
35 40 45
Glu Thr Glu Asn Gln Phe Leu Arg Leu Leu Ser Asn Ser Pro Leu Gln
50 55 60
Val Asp Ile Gln Leu Leu Arg Ile Asp Ser Arg Glu Ser Arg Asn Thr
65 70 75 80
Pro Ala Glu His Leu Asn Asn Phe Tyr Cys Asn Phe Glu Asp Ile Gln
85 90 95
Asp Gln Asn Phe Asp Gly Leu Ile Val Thr Gly Ala Pro Leu Gly Leu
100 105 110
Val Glu Phe Asn Asp Val Ala Tyr Trp Pro Gln Ile Lys Gln Val Leu
115 120 125
Glu Trp Ser Lys Asp His Val Thr Ser Thr Leu Phe Val Cys Trp Ala
130 135 140
Val Gln Ala Ala Leu Asn Ile Leu Tyr Gly Ile Pro Lys Gln Thr Arg
145 150 155 160
Thr Glu Lys Leu Ser Gly Val Tyr Glu His His Ile Leu His Pro His
165 170 175
Ala Leu Leu Thr Arg Gly Phe Asp Asp Ser Phe Leu Ala Pro His Ser
180 185 190
Arg Tyr Ala Asp Phe Pro Ala Ala Leu Ile Arg Asp Tyr Thr Asp Leu
195 200 205
Glu Ile Leu Ala Glu Thr Glu Glu Gly Asp Ala Tyr Leu Phe Ala Ser
210 215 220
Lys Asp Lys Arg Ile Ala Phe Val Thr Gly His Pro Glu Tyr Asp Ala
225 230 235 240
Gln Thr Leu Ala Gln Glu Phe Phe Arg Asp Val Glu Ala Gly Leu Asp
245 250 255
Pro Asp Val Pro Tyr Asn Tyr Phe Pro His Asn Asp Pro Gln Asn Thr
260 265 270
Pro Arg Ala Ser Trp Arg Ser His Gly Asn Leu Leu Phe Thr Asn Trp
275 280 285
Leu Asn Tyr Tyr Val Tyr Gln Ile Thr Pro Tyr Asp Leu Arg His Met
290 295 300
Asn Pro Thr Leu Asp
305
<210> 8
<211> 933
<212> DNA
<213> 人工序列
<220>
<223> metA
<400> 8
atggttaaag tttatgcccc ggcttccagt gccaatatga gcgtcgggtt tgatgtgctc 60
ggggcggcgg tgacacctgt tgatggtgca ttgctcggag atgtagtcac ggttgaggcg 120
gcagagacat tcagtctcaa caacctcgga cgctttgccg ataagctgcc gtcagaacca 180
cgggaaaata tcgtttatca gtgctgggag cgtttttgcc aggaactggg taagcaaatt 240
ccagtggcga tgaccctgga aaagaatatg ccgatcggtt cgggcttagg ctccagtgcc 300
tgttcggtgg tcgcggcgct gatggcgatg aatgaacact gcggcaagcc gcttaatgac 360
actcgtttgc tggctttgat gggcgagctg gaaggccgta tctccggcag cattcattac 420
gacaacgtgg caccgtgttt tctcggtggt atgcagttga tgatcgaaga aaacgacatc 480
atcagccagc aagtgccagg gtttgatgag tggctgtggg tgctggcgta tccggggatt 540
aaagtctcga cggcagaagc cagggctatt ttaccggcgc agtatcgccg ccaggattgc 600
attgcgcacg ggcgacatct ggcaggcttc attcacgcct gctattcccg tcagcctgag 660
cttgccgcga agctgatgaa agatgttatc gctgaaccct accgtgaacg gttactgcca 720
ggcttccggc aggcgcggca ggcggtcgcg gaaatcggcg cggtagcgag cggtatctcc 780
ggctccggcc cgaccttgtt cgctctgtgt gacaagccgg aaaccgccca gcgcgttgcc 840
gactggttgg gtaagaacta cctgcaaaat caggaaggtt ttgttcatat ttgccggctg 900
gatacggcgg gcgcacgagt actggaaaac taa 933
<210> 9
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> yjeH 引物
<400> 9
aagctttgat aactctcctt tg 22
<210> 10
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> yjeH 引物
<400> 10
aagctttatg tggttatgcc at 22
<210> 11
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> yjeH 基因引物
<400> 11
ggtaccaggt cgactctaga ggatcccc 28
<210> 12
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> yjeH 基因引物
<400> 12
ggtaccttat gtggttatgc cat 23
<210> 13
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> MetB 引物
<400> 13
ttaccccttg tttgcagccc ggaagccatt ttccaggtcg gcaattaaat catatgaata 60
tcctccttag 70
<210> 14
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> metB 引物
<400> 14
ttactctggt gcctgacatt tcaccgacaa agcccaggga acttcatcac gtgtaggctg 60
gagctgcttc 70
<210> 15
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> thrB 引物
<400> 15
aaagaatatg ccgatcggtt cgggcttagg ctccagtgcc tgttcggtgg gtgtaggctg 60
gagctgcttc 70
<210> 16
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> thrB 引物
<400> 16
agacaaccga catcgctttc aacattggcg accggagccg ggaaggcaaa catatgaata 60
tcctccttag 70
<210> 17
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> metA 引物
<400> 17
aattgatatc atgccgattc gtgtgccgg 29
<210> 18
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> metA 引物
<400> 18
aattaagctt ttaatccagc gttggattca tgtg 34
<210> 19
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> metA G111E 突变引物
<400> 19
ttgtaactgg tgcgccgctg gaactggtgg ggtttaatga tgtc 44
<210> 20
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> metA G111E 突变引物
<400> 20
gacatcatta aaccccacca gttccagcgg cgcaccagtt acaa 44
<210> 21
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> metA EH 突变引物
<400> 21
tgtaactggt gcgccgctgg aacatgtggg gtttaatgat gtcg 44
<210> 22
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> metA EH 突变引物
<400> 22
cgacatcatt aaaccccaca tgttccagcg gcgcaccagt taca 44
<210> 23
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> metA EH 引物
<400> 23
aattgatatc atgccgattc gtgtgccgg 29
<210> 24
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> metA EH 引物
<400> 24
aattaagcct gctgaggtac gtttcgg 27
<210> 25
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> metA WT 引物
<400> 25
cagcaggtga ataaatttta ttc 23
<210> 26
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> metA WT 引物
<400> 26
cgcgaatgga agctgtttcc 20
<210> 27
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> pKD3 引物
<400> 27
tttccgaaac gtacctcagc aggtgtaggc tggagctgct tc 42
<210> 28
<211> 43
<212> DNA
<213> 人工序列
<220>
<223> pKD3 引物
<400> 28
gaataaaatt tattcacctg ctgcatatga atatcctcct tag 43
<210> 29
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> ppc 2 复制引物
<400> 29
gccggaattc tgtcggatgc gatacttgcg c 31
<210> 30
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> ppc 2 复制引物
<400> 30
gaaggagctc agaaaaccct cgcgcaaaag 30
<210> 31
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> ppc 2 复制引物
<400> 31
gccggagctc tgtcggatgc gatacttgcg c 31
<210> 32
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> ppc 2 复制引物
<400> 32
gaagggtacc agaaaaccct cgcgcaaaag 30
<210> 33
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> aspC 2 复制引物
<400> 33
tccgagctca taagcgtagc gcatcaggca 30
<210> 34
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> aspC 2 复制引物
<400> 34
tccgagctcg tccacctatg ttgactacat 30
<210> 35
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> asd 2 复制引物
<400> 35
ccggaattcc caggagagca ataagca 27
<210> 36
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> asd 2 复制引物
<400> 36
ctagtctaga tgctctattt aactcccg 28
<210> 37
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> asd 2 复制引物
<400> 37
ctagtctaga ccaggagagc aataagca 28
<210> 38
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> asd 2 复制引物
<400> 38
ccggaattct gctctattta actcccg 27
<210> 39
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> icd 启动子引物
<400> 39
cccggggtat tttcagagat tat 23
<210> 40
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> icd 启动子引物
<400> 40
cccgggatcc tccttcgagc gctactggtt 30
<210> 41
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> pro 启动子引物
<400> 41
cccggggatc ctctgtgtgg aattctcgga ca 32
<210> 42
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> pro 启动子引物
<400> 42
cccgggaatt cattaaagag gagaaaggat 30
<210> 43
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> cysk 启动子引物
<400> 43
cccgggagct tccagcctgt ttacgatga 29
<210> 44
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> cysk 启动子引物
<400> 44
cccgggtccc aatttcatac agttaagga 29
<210> 45
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> icd 启动子引物
<400> 45
gaaaaagaaa aaaaattctg gcgattgtgt aggctggagc tgct 44
<210> 46
<211> 48
<212> DNA
<213> 人工序列
<220>
<223> icd 启动子引物
<400> 46
cggcaattca taatctctga aaatacgcca tggtccatat gaatatcc 48
<210> 47
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> cysk 启动子引物
<400> 47
gaaaaagaaa aaaaattctg gcgattgtgt aggctggagc tgct 44
<210> 48
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> cysk 启动子引物
<400> 48
gcgggatcat cgtaaacagg ctgccatggt ccatatgaat atcc 44
<210> 49
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> pro 启动子引物
<400> 49
gaaaaagaaa aaaaattctg gcgattgtgt aggctggagc tgct 44
<210> 50
<211> 48
<212> DNA
<213> 人工序列
<220>
<223> pro 启动子引物
<400> 50
tgtccgagaa ttccacacag aggatcgcca tggtccatat gaatatcc 48
<210> 51
<211> 197
<212> DNA
<213> 人工序列
<220>
<223> icd 启动子
<400> 51
gtattttcag agattatgaa ttgccgcatt atagcctaat aacgcgcatc tttcatgacg 60
gcaaacaata gggtagtatt gacaagccaa ttacaaatca ttaacaaaaa attgctctaa 120
agcatccgta tcgcaggacg caaacgcata tgcaacgtgg tggcagacga gcaaaccagt 180
agcgctcgaa ggaggat 197
<210> 52
<211> 197
<212> DNA
<213> 人工序列
<220>
<223> pro 启动子
<400> 52
gtattttcag agattatgaa ttgccgcatt atagcctaat aacgcgcatc tttcatgacg 60
gcaaacaata gggtagtatt gacaagccaa ttacaaatca ttaacaaaaa attgctctaa 120
agcatccgta tcgcaggacg caaacgcata tgcaacgtgg tggcagacga gcaaaccagt 180
agcgctcgaa ggaggat 197
<210> 53
<211> 299
<212> DNA
<213> 人工序列
<220>
<223> cysk 启动子
<400> 53
agcttccagc ctgtttacga tgatcccgct gcttaatctg ttcatcatgc ccgttgccgt 60
ttgtggcgcg acggcgatgt gggtcgattg ctatcgcgat aaacacgcga tgtggcggta 120
acaatctacc ggttattttg taaaccgttt gtgtgaaaca ggggtggctt atgccgcccc 180
ttattccatc ttgcatgtca ttatttccct tctgtatata gatatgctaa atccttactt 240
ccgcatattc tctgagcggg tatgctacct gttgtatccc aatttcatac agttaagga 299
Claims (9)
1.生产O-乙酰高丝氨酸的埃希氏菌属的微生物,其中与未经修饰的微生物相比,包含SEQ ID NO:1氨基酸序列的蛋白质的活性增强;并且其中胱硫醚合成酶的活性与未经修饰的微生物相比被减弱或失活,
其中活性增强通过选自下列的方法进行:i)增加编码每种蛋白质的多核苷酸的拷贝数,ii)对表达控制序列进行修饰以增加所述多核苷酸的表达,iii)对染色体上的所述多核苷酸序列进行修饰以增强每种蛋白质的活性;和iv)其组合,并且
其中活性减弱通过选自下列的方法进行:i)使编码每种蛋白质的基因的部分或全部缺失,ii)修饰表达控制序列以降低所述基因的表达,iii)修饰染色体上的基因序列以减弱蛋白质的活性;和iv)其组合。
2.根据权利要求1所述的埃希氏菌属的微生物,其中所述微生物是大肠杆菌。
3.根据权利要求1所述的埃希氏菌属的微生物,其中高丝氨酸激酶的活性被进一步减弱或失活。
4.根据权利要求1所述的埃希氏菌属的微生物,其中与未经修饰的微生物相比,高丝氨酸乙酰转移酶的活性被进一步增强。
5.根据权利要求1所述的埃希氏菌属的微生物,其中选自磷酸烯醇丙酮酸羧化酶、天冬氨酸转氨酶和天冬氨酸半醛脱氢酶的至少一种酶的活性被进一步增强。
6.根据权利要求1所述的埃希氏菌属的微生物,其中与未经修饰的微生物相比,天冬氨酸激酶的活性增强。
7.生产O-乙酰高丝氨酸的方法,包括
培养权利要求1至6中任一项所述的生产O-乙酰高丝氨酸的埃希氏菌属的微生物,以获得培养的培养基。
8.根据权利要求7所述的方法,进一步包括从所述培养的微生物或所述培养的培养基中回收O-乙酰高丝氨酸。
9.生产L-甲硫氨酸的方法,包括:
培养权利要求1至6中任一项所述的生产O-乙酰高丝氨酸的埃希氏菌属的微生物,以积累O-乙酰高丝氨酸;和
通过利用酶反应,由积累的O-乙酰高丝氨酸生产L-甲硫氨酸。
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KR101915433B1 (ko) * | 2018-02-13 | 2018-11-05 | 씨제이제일제당 (주) | 시트레이트 신타아제 (Citrate synthase)의 활성이 약화된 변이형 폴리펩타이드 및 이를 이용한 L-아미노산 생산방법 |
BR112021011882A2 (pt) | 2018-12-27 | 2021-09-08 | Ajinomoto Co., Inc. | Método para produzir um l-aminoácido básico |
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