CN116640810A - 一种赖氨酸生产方法、突变体及重组微生物与应用 - Google Patents
一种赖氨酸生产方法、突变体及重组微生物与应用 Download PDFInfo
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- CN116640810A CN116640810A CN202210142069.2A CN202210142069A CN116640810A CN 116640810 A CN116640810 A CN 116640810A CN 202210142069 A CN202210142069 A CN 202210142069A CN 116640810 A CN116640810 A CN 116640810A
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Abstract
本发明涉及微生物工程技术领域,具体公开了一种赖氨酸生产方法、突变体及重组微生物与应用。本发明的赖氨酸生产方法,包括以重组微生物进行发酵培养的步骤,所述重组微生物相比于出发菌株,具有降低的天冬氨酸‑tRNA连接酶活性,优选还具有降低的异柠檬酸脱氢酶活性。本发明采用的重组微生物进行赖氨酸的制备,可提高赖氨酸的产量。
Description
技术领域
本发明涉及微生物工程技术领域,具体地说,涉及一种赖氨酸生产方法、突变体及重组微生物与应用。
背景技术
L-赖氨酸是碱性必需氨基酸,分子式为C6H14N2O2,外观为白色或近乎于白色结晶粉末。在210℃变暗,在224.5℃下分解,易溶于水,微溶于醇,不溶于醚。广泛应用于动物饲料、医药和食品工业,其中L-赖氨酸约90%用于饲料工业,10%用于食品和医药行业。用于动物饲料添加剂,L-赖氨酸可帮助机体吸收其他氨基酸,从而提高饲料质量。因此,生产赖氨酸具有广阔的前景。
目前,L-赖氨酸最常用的生产方法为微生物发酵法,微生物发酵法具有原料成本低、反应条件温和、容易实现大规模生产等优点。大肠杆菌(Escherichia coli)由于其生长速度快,遗传背景清晰,培养条件简单,代谢工程手段成熟等优点,广泛应用于工业发酵领域,可用于生产L-氨基酸、核苷酸及其他有机酸等。大肠杆菌合成L-赖氨酸,从L-天冬氨酸开始,经过多步酶催化反应得到L-赖氨酸。L-赖氨酸的产率与生物合成途径中的酶活性及代谢流的分布相关,通过增强末端合成途径的酶活性,或改变中央代谢流方向,以及增加还原力的供给,都利于大肠杆菌高产L-赖氨酸。
天冬氨酸-tRNA连接酶(argS)是氨酰-tRNA合成酶家族的成员,通过将氨基酸共价连接到特定的tRNA分子来进行翻译。在大肠杆菌中天冬氨酸-tRNA连接酶主要参与L-天冬氨酸与tRNA(Asp)的连接反应。此过程分为两步,首先L-天冬氨酸作为底物,被ATP激活后形成Asp-AMP,之后Asp-AMP转移到tRNA(Asp)的受体端形成L-天冬氨酸-tRNAasp,L-天冬氨酸是L-赖氨酸合成的前体。目前,关于天冬氨酸-tRNA连接酶活性的降低对大肠杆菌积累L-赖氨酸等天冬氨酸族氨基酸是否有影响未见报道。
发明内容
本发明的目的是提供一种提升赖氨酸产量的方法。
本发明的技术方案如下:
一种赖氨酸生产方法,其包括以重组微生物进行发酵培养的步骤,所述重组微生物相比于出发菌株,具有降低的天冬氨酸-tRNA连接酶活性。
本发明研究发现,降低天冬氨酸-tRNA连接酶的活性,可提升赖氨酸的产量。
降低方式可以采用代谢工程领域内常规技术手段,比如启动子调控区的改变,或起始密码子的替换,或氨基酸序列的改变。
优选,所述天冬氨酸-tRNA连接酶活性的降低通过启动子调控区的改变、起始密码子的替换或氨基酸序列的突变实现;更优选,所述天冬氨酸-tRNA连接酶活性的降低通过将天冬氨酸-tRNA连接酶的氨基酸序列第275位的丙氨酸突变为缬氨酸实现。
本发明经研究发现,对天冬氨酸-tRNA连接酶基因特定位置的氨基酸置换可以达到降低其酶活的效果,进而提高赖氨酸产量。
本发明的赖氨酸生产方法中,所述重组微生物表达突变的天冬氨酸-tRNA连接酶,其氨基酸序列如SEQ ID NO.21所示。
优选,本发明的赖氨酸生产方法中,所述重组微生物相比于出发菌株,还具有降低的异柠檬酸脱氢酶活性。
本发明还发现,天冬氨酸-tRNA连接酶的弱化与异柠檬酸脱氢酶的修饰改造具有组合提升的效果。
更优选,所述异柠檬酸脱氢酶活性的降低通过使异柠檬酸脱氢酶携带D398E和D410E突变实现。
即突变的异柠檬酸脱氢酶其氨基酸序列第398位和第410位氨基酸均由天冬氨酸突变为谷氨酸。
进一步优选,所述重组微生物表达突变的异柠檬酸脱氢酶,其氨基酸序列如SEQID NO.23所示。
本发明的赖氨酸生产方法中,所述出发菌株为大肠杆菌。
本发明还提供一种天冬氨酸-tRNA连接酶突变体,其以野生型天冬氨酸-tRNA连接酶的氨基酸序列为参考序列,所述天冬氨酸-tRNA连接酶突变体含有第275位丙氨酸被缬氨酸取代的突变;优选,天冬氨酸-tRNA连接酶突变体的氨基酸序列如SEQ ID NO.21所示。
本发明另提供一种重组微生物,所述重组微生物表达上述天冬氨酸-tRNA连接酶突变体;
优选,所述重组微生物还表达异柠檬酸脱氢酶突变体,所述异柠檬酸脱氢酶突变体含有D398E和D410E突变;
和/或,所述重组微生物的出发菌株为大肠杆菌。
本发明另提供一种上述重组微生物的如下任一种应用:
(1)在发酵生产赖氨酸中的应用;
(2)在用于生产赖氨酸的微生物遗传育种中的应用;
(3)在提高发酵生产赖氨酸产量上的应用。
本发明的有益效果至少在于:
本发明将突变的天冬氨酸-tRNA连接酶应用于大肠杆菌发酵,其赖氨酸产率得到显著提高。突变的异柠檬酸脱氢酶,其氨基酸序列第398位和第410位氨基酸均由天冬氨酸突变为谷氨酸,本身即可促进赖氨酸产率的提升,与突变的天冬氨酸-tRNA连接酶组合改造后,具有叠加的效果。该突变不仅可应用于赖氨酸,还适用于其他以天冬氨酸为前体的化合物。
具体实施方式
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的,并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下,可以对本发明进行各种修改和替换。下述实施例中所使用的实验方法如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。下述实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
本发明实施例中涉及的引物名称及序列如表1所示。
表1引物序列(SEQ ID No.1-19)
实施例1突变基因aspS(A275V)的重组菌株构建
aspS氨基酸序列如SEQ ID No.20所示,aspS(A275V)氨基酸序列如SEQ ID No.21所示。
(1)pTargetF-N20质粒及Donor DNA构建
步骤1:使用pTF-aspS-sgRNA-F/pTF-aspS-sgRNA-R为引物(所有引物序列见表1),以质粒pTargetF为模板(可参见Multigene Editing in the Escherichiacoli Genomevia the CRISPR-Cas9 System,Jiang Y,Chen B,et al.Appl.EnvironMicrobiol,2015),扩增出带有N20的pTF线性质粒,使用无缝组装ClonExpress试剂盒将此线性质粒37℃进行组装,随后转化Trans1-T1感受态细胞,获得质粒pTargetF-N20(aspS A275V),PCR鉴定及测序验证;
步骤2:以大肠杆菌MG1655基因组(NC_000913)为模板,选用aspS-UF/aspS-UR引物对,扩增出上游同源臂①,选用aspS-DF/aspS-DR引物对,扩增出下游同源臂②,以①、②为模板,选用aspS-UF/aspS-DR引物对,扩增出Donor DNA。
(2)感受态细胞制备及电转化
步骤1:将pCas质粒(可参见Multigene Editing in the EscherichiacoliGenome via the CRISPR-Cas9 System,Jiang Y,Chen B,etal.Appl.EnvironMicrobiol,2015)电转入CGMCC No.22648感受态细胞中(转化方法及感受态制备方法均参照《分子克隆III》);
出发菌株CGMCC No.22648是一株诱变获得的产赖氨酸的大肠杆菌MHZ-0914,该菌株已经于2021年6月1日保藏于中国微生物菌种保藏管理委员会普通微生物中心(简称CGMCC,地址:北京市朝阳区北辰西路1号院3号,中国科学院微生物研究所,邮编100101),保藏编号为CGMCC No.22648,分类命名为大肠埃希氏菌Escherichia coli。
步骤2:挑取单菌落于5mL含卡那霉素和终浓度为10mM阿拉伯糖的LB试管中,30℃,200r/min培养至OD 650为0.4后,制备电转感受态细胞(感受态制备方法参照《分子克隆III》);
步骤3:将(1)中构建得到的pTargetF-N20质粒和Donor DNA同时电转入带有pCas感受态细胞中(电转条件:2.5kV,200Ω,25μF),涂布于含壮观霉素和卡那霉素的LB平板上,30℃静置培养至单菌落可见。
(3)重组菌株验证
步骤1:使用引物对aspS-F1/aspS-R对上述单菌落进行菌落PCR验证;
步骤2:将PCR鉴定正确的菌株用引物对aspS-F/aspS-R扩增,扩增产物送测序。
(4)构建相关质粒丢失
步骤1:挑取测序验证正确的单菌落接种于5mL含卡那霉素及终浓度为0.5mM IPTG的LB试管中,30℃过夜培养后划线于含卡那霉素的LB平板上;
步骤2:挑取单菌落对点于含卡那霉素、壮观霉素LB平板和只含卡那霉素的LB平板上,30℃过夜培养,若在含卡那霉素、壮观霉素的LB平板上不能生长,在卡那霉素的LB平板上生长,表明pTargetF-N20质粒已丢失;
步骤3:挑取pTargetF-N20质粒丢失的阳性菌落,接种于无抗LB试管中,42℃培养8h后划线于LB平板上,37℃过夜培养;
步骤4:挑取单菌落对点于含卡那霉素LB平板和无抗LB平板上,若在含卡那霉素的LB平板上不能生长,在无抗LB平板上生长,表明pCas质粒丢失,得到菌株CGMCC No.22648-aspS(A275V)。
实施例2突变基因icd(D398E、D410E)的重组菌株构建
icd氨基酸序列如SEQ ID No.22所示,icd(D398E、D410E)氨基酸序列如SEQ ID No.23所示。
参照实施例1的方法,以CGMCC No.22648为出发菌,以pTF-icd-sgRNA-F、pTF-icd-sgRNA-R、icd-UF、icd-UR、icd-DF、icd-DR、icd-F1、icd-F2、icd-F、icd-R为引物,获得异柠檬酸脱氢酶其氨基酸序列第398位和第410位氨基酸均由天冬氨酸突变为谷氨酸的菌株,菌株命名为CGMCC No.22648-icd(D398E、D410E)。
实施例3包含突变基因icd(D398E、D410E)的重组菌株构建
参照实施例1的方法,以CGMCC No.22648-aspS(A275V)为出发菌,以pTF-icd-sgRNA-F、pTF-icd-sgRNA-R、icd-UF、icd-UR、icd-DF、icd-DR、icd-F1、icd-F2、icd-F、icd-R为引物,获得异柠檬酸脱氢酶其氨基酸序列第398位和第410位氨基酸均由天冬氨酸突变为谷氨酸的菌株,菌株命名为CGMCC No.22648-aspS(A275V)-icd(D398E、D410E)。
实施例4赖氨酸发酵实验
种子活化培养基:蛋白胨10g/L,NaCl 10g/L,酵母粉5g/L,18g/L琼脂粉,调节pH至7.0。
种子培养基:葡萄糖20g/L,硫酸铵4g/L,玉米浆2.0g/L,磷酸二氢钾3g/L,七水硫酸镁0.4g/L,硫酸铁0.01g/L,硫酸锰0.01g/L,调节pH至7.0。
发酵培养基:葡萄糖60g/L,糖蜜10g/L,硫酸铵40g/L,玉米浆10g/L,磷酸二氢钾1.6g/L,七水硫酸镁1.0g/L,硫酸铁0.03g/L,硫酸锰0.03g/L,碳酸钙25g/L,调节pH至7.0。
(1)种子活化:从冻存管中取待验证菌株,在种子活化培养基上划线活化,37℃培养12h;
(2)种子培养:挑取平板活化种子1环接至装有20mL种子培养基的500mL三角瓶中,33℃,220r/min振荡培养7h;
(3)发酵培养:将2mL种子液接种至装有30mL发酵培养基的500mL三角瓶中,37℃、220r/min振荡培养12h,每株菌做三个平行。
4、OD600测定:取100μl发酵液稀释适当倍数,使用分光光度计在波长600处检测OD,每株菌做三个平行,计算平均值,检测到的OD600如表2所示。
赖氨酸浓度测定:取2mL发酵液离心(12000rpm,2min),收集上清液,用HPLC检测重组菌与对照菌发酵液中的L-赖氨酸含量,每株菌做三个平行,计算平均值,检测到的赖氨酸浓度如表2所示。
表2重组菌株的赖氨酸产量和生长检测
发酵结果表明,本发明的3种重组菌株相比出发菌CGMCC No.22648,其赖氨酸产量及转化率均有不同程度的提高,且具有显著性差异(P<0.05),OD600基本不变,说明本发明的突变位点有正效果。
天冬氨酸-tRNA连接酶和异柠檬酸脱氢酶均有正效果,两者叠加改造具有比单独改造更突出的效果。叠加改造获得的重组菌株CGMCC No.22648-icd(D398E、D410E)-aspS(A275V)L-赖氨酸产量较出发菌株提高4.2g/L,转化率较出发菌株提高7.0%。从代谢的角度分析,天冬氨酸-tRNA连接酶活性的降低有利于天冬氨酸的积累,异柠檬酸脱氢酶的弱化使得进入TCA循环的碳流减少,更多的碳流进入天冬氨酸途径,有利于赖氨酸的积累。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
序列表
<110> 廊坊梅花生物技术开发有限公司
<120> 一种赖氨酸生产方法、突变体及重组微生物与应用
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Claims (10)
1.一种赖氨酸生产方法,其特征在于,包括以重组微生物进行发酵培养的步骤,所述重组微生物相比于出发菌株,具有降低的天冬氨酸-tRNA连接酶活性。
2.根据权利要求1所述的赖氨酸生产方法,其特征在于,所述天冬氨酸-tRNA连接酶活性的降低通过启动子调控区的改变、起始密码子的替换或氨基酸序列的突变实现;优选,所述天冬氨酸-tRNA连接酶活性的降低通过将天冬氨酸-tRNA连接酶的氨基酸序列第275位的丙氨酸突变为缬氨酸实现。
3.根据权利要求2所述的赖氨酸生产方法,其特征在于,所述重组微生物表达突变的天冬氨酸-tRNA连接酶,其氨基酸序列如SEQ ID NO.21所示。
4.根据权利要求1-3任一项所述的赖氨酸生产方法,其特征在于,所述重组微生物相比于出发菌株,还具有降低的异柠檬酸脱氢酶活性。
5.根据权利要求4所述的赖氨酸生产方法,其特征在于,所述异柠檬酸脱氢酶活性的降低通过使异柠檬酸脱氢酶携带D398E和D410E突变实现。
6.根据权利要求5所述的赖氨酸生产方法,其特征在于,所述重组微生物表达突变的异柠檬酸脱氢酶,其氨基酸序列如SEQ ID NO.23所示。
7.根据权利要求1-6任一项所述的赖氨酸生产方法,其特征在于,所述出发菌株为大肠杆菌。
8.一种天冬氨酸-tRNA连接酶突变体,其特征在于,以野生型天冬氨酸-tRNA连接酶的氨基酸序列为参考序列,所述天冬氨酸-tRNA连接酶突变体含有第275位丙氨酸被缬氨酸取代的突变;优选,天冬氨酸-tRNA连接酶突变体的氨基酸序列如SEQ ID NO.21所示。
9.一种重组微生物,其特征在于,所述重组微生物表达权利要求8所述的天冬氨酸-tRNA连接酶突变体;
优选,所述重组微生物还表达异柠檬酸脱氢酶突变体,所述异柠檬酸脱氢酶突变体含有D398E和D410E突变;
和/或,所述重组微生物的出发菌株为大肠杆菌。
10.权利要求9所述的重组微生物的如下任一种应用:
(1)在发酵生产赖氨酸中的应用;
(2)在用于生产赖氨酸的微生物遗传育种中的应用;
(3)在提高发酵生产赖氨酸产量上的应用。
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