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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