L-精氨酸的微生物合成研究进展

doi:10.12211/2096-8280.2024-068

合成生物学

• 特约评述 •

L-精氨酸的微生物合成研究进展

王倩¹^,², 果士婷², 辛波¹, 钟成¹, 王钰²

^1.天津科技大学，生物工程学院，天津 300222
^2.中国科学院天津工业生物技术研究所，低碳合成工程生物学重点实验室，天津 300308

收稿日期:2024-08-28 修回日期:2024-10-31 出版日期:2024-10-04
通讯作者: 钟成,王钰
作者简介:王倩（1998—），女，硕士研究生。研究方向为甲醇合成氨基酸菌种选育和合成调控机制研究。E-mail：wangqian23@tib.cas.cn
钟成（1979—），男，教授，博士生导师，兼任中国生化与分子生物学会工业生化与分子生物学分会理事，中国造纸学会纳米纤维素与材料专业委员会委员，中国化工学会生物化工专业委员会委员，中国微生物学会会员，2014年至今担任国际期刊Frontiers in Microbiology副编辑，以及二十多种国际期刊同行评议人。在Biotechnology Advances等高水平期刊发表SCI论文100余篇（其中高被引论文3篇）。申请发明专利60余项（其中授权发明专利20项）。以第一完成人获2019年天津市科技进步二等奖1项，获天津市工程学位优秀教学成果奖1项（排名第一），获省部级教学成果一等奖4项。E-mail：czhong@tust.edu.cn
王钰（1987—），男，博士，研究员，博士生导师。研究方向为工业微生物的基因编辑育种和一碳原料的生物转化利用研究，以第一或通讯作者在Nat Commun、Trends Biotechnol、Nucleic Acids Res、Metab Eng等期刊发表论文40余篇，申请专利40余项。主持国家自然科学基金优秀青年基金、中国科学院关键核心技术攻坚先导专项等项目，
基金资助:
国家重点研发计划(2023YFD1300700)

Recent advances in biosynthesis of L-arginine using engineered microorganisms

Qian WANG¹^,², Shiting Guo², Bo XIN¹, Cheng ZHONG¹, Yu WANG²

^1.College of Biotechnology，Tianjin University of Science and Technology，Tianjin 300222，China
^2.Key Laboratory of Engineering Biology for Low-Carbon Manufacturing，Tianjin Institute of Industrial Biotechnology，Chinese Academy of Sciences，Tianjin 300308，China

Received:2024-08-28 Revised:2024-10-31 Online:2024-10-04
Contact: Cheng ZHONG, Yu WANG

摘要/Abstract

摘要：

L-精氨酸是一种碱性氨基酸，是护肤产品中常用的中和剂、保湿剂和抗氧化剂，此外，L-精氨酸还广泛应用于饲料、医药、食品等领域。以工程化的谷氨酸棒杆菌和大肠杆菌等微生物为催化剂，以可再生的淀粉糖为原料，通过微生物发酵的方法生产L-精氨酸是目前该产品最主要的生产方法。为创制高效的工程微生物菌种，早期研究者通常采用诱变筛选的方法，但由于突变的不确定性和非定向性，育种效率较低。随着合成生物技术的发展，人工设计L-精氨酸的合成途径和调控机制，并通过基因编辑理性创制工程微生物菌种成为研究的主流。本文综述了不同微生物中发现的L-精氨酸合成途径及调控机制，以谷氨酸棒杆菌和大肠杆菌为主，介绍了设计创制L-精氨酸高产菌种的合成生物学代谢改造策略，以及基于生物传感器的高通量筛选在L-精氨酸高产菌种筛选中的应用。最后，本文展望了进一步提高L-精氨酸生物合成水平的潜在策略，以及一碳原料等新型非粮碳资源在未来L-精氨酸生产中的应用前景。

关键词: L-精氨酸, 代谢工程, 合成生物学, 一碳原料, 谷氨酸棒杆菌, 大肠杆菌

Abstract:

L-Arginine is an alkaline amino acid that has been frequently used as a neutralizer, moisturizer and antioxidant in skin care products. In addition, L-arginine is also widely used in feed, medicine, and food industries. The wide range of applications for L-arginine has garnered significant attention for its production. L-Arginine can be produced through protein hydrolysis and microbial fermentation methods. However, protein hydrolysis has several drawbacks, including complicated operations, high purification costs, low recovery efficiency, and environmental pollution. In contrast, microbial fermentation can use renewable and cheap feedstocks. Besides, the production process can be conducted under milder reaction conditions and is considered more environmentally friendly. Therefore, microbial fermentation of renewable starch-derived sugars by engineered microorganisms such as Corynebacterium glutamicum and Escherichia coli is now the major production method of L-arginine. Design and construction of efficient microbial strains is the key for high-level L-arginine production through microbial fermentation. Random mutagenesis and screening strategies are used to develop L-arginine producing microbial strains. However, random mutagenesis suffers from uncertainty and non-directionality, resulting in a low-efficiency microbial breeding process. With the development of synthetic biotechnology, development of L-arginine producing strains is empowered by rational design of artificial synthetic pathways and regulatory machineries. The advanced genome editing technologies also accelerate the development of microbial strains. This paper reviews the synthetic pathways and regulatory mechanisms of L-arginine that have been discovered in different microorganisms. Synthetic biology-guided metabolic engineering strategies for improving L-arginine production in C. glutamicum and E. coli are summarized. Besides, application of the biosensor-based high-throughput screening strategy in selecting L-arginine producing strains is introduced. Finally, potential strategies to enhancing L-arginine production and the possibility of using new carbon resources such as non-food biomass and one-carbon feedstocks for L-arginine production are discussed. It is envisioned that synthetic biology-guided strain engineering will further enhance the production level of L-arginine and facilitate industrial and sustainable L-arginine production using non-food feedstocks in the near future.

Key words: L-arginine, metabolic engineering, synthetic biology, one-carbon feedstocks, Corynebacterium glutamicum, Escherichia coli

中图分类号:

Q816

王倩, 果士婷, 辛波, 钟成, 王钰. L-精氨酸的微生物合成研究进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-068.

Qian WANG, Shiting Guo, Bo XIN, Cheng ZHONG, Yu WANG. Recent advances in biosynthesis of L-arginine using engineered microorganisms[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-068.

图/表 3

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菌种	代谢改造策略	原料	产量（g/L）	转化率（g/g）	生产强度（g/L/h）	发酵方式	参考文献
谷氨酸棒杆菌	增强辅因子NADPH的供应：过表达pntAB和ppnk；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR和farR；阻断副产物合成途径：敲除ldh（编码乳酸脱氢酶）	葡萄糖	67.01	0.35	0.89	补料分批发酵	[38]
谷氨酸棒杆菌	诱变育种；增强辅因子NADPH的供应：下调pgi的表达，过表达tkt、tal、zwf、opcA、pgl；强化L-精氨酸合成途径：过表达argGH、carAB；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR和farR；增强前体物质L-谷氨酸的供应：敲除ncgl1221	葡萄糖；蔗糖	92.50	0.40	1.28	补料分批发酵	[39]
钝齿棒杆菌	解除终产物对L-精氨酸合成关键酶的反馈抑制：定点突变ArgB^{E19Y/I74V/F91H/K234T}	葡萄糖	61.20	0.43	0.64	补料分批发酵	[40]
大肠杆菌	解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR；解除终产物对L-精氨酸合成关键酶的反馈抑制：外源表达argJ；强化L-精氨酸合成途径：外源表达argCJBDF	葡萄糖	70.10	0.33	1.17	补料分批发酵	[41]
钝齿棒杆菌	增强前体物质L-谷氨酸的供应：过表达iolT1、ptsG、ppgk、pyc、gltA、gdh，下调odhA的表达；强化L-精氨酸合成途径：过表达argCJBDF、argGH；阻断副产物合成途径：敲除proB，下调lysC的表达；增强辅因子NADPH的供应：下调pgi的表达	葡萄糖	87.30	0.43	1.21	补料分批发酵	[42]
钝齿棒杆菌	增强辅因子ATP的供应：过表达pyk、pgk，敲除frd12、nox、amn	葡萄糖	57.30	0.33	0.58	补料分批发酵	[43]
钝齿棒杆菌	阻断副产物合成途径：敲除proB；解除终产物对L-精氨酸合成关键酶的反馈抑制：定点突变ArgB^{E19R,H26E,D311,D312R}	葡萄糖	16.50	0.39	0.15	摇瓶发酵	[44]
钝齿棒杆菌	增强前体物质L-谷氨酸的供应：敲除putP、pta、ncg12310、ncgl1221；增强L-精氨酸转运：过表达lysE	葡萄糖	24.85	0.57	0.23	摇瓶发酵	[45]
钝齿棒杆菌	增强氮源供应：过表达glnA、aspA、gdh	葡萄糖	53.20	0.32	0.55	补料分批发酵	[46]
钝齿棒杆菌	增强氮源供应：敲除amtR，过表达amtB2	葡萄糖	60.90	0.36	0.63	补料分批发酵	[47]
大肠杆菌	阻断L-精氨酸降解途径：敲除adiA、speC、speF；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR；解除终产物对L-精氨酸合成关键酶的反馈抑制：过表达ArgA^H15Y；增强L-精氨酸转运：过表达argO	葡萄糖	11.64	1.18	0.24	补料分批发酵	[48]
钝齿棒杆菌	增强L-精氨酸转运：过表达lysE	葡萄糖	35.91	—	0.37	摇瓶发酵	[49]
钝齿棒杆菌	解除终产物对L-精氨酸合成关键酶的反馈抑制：过表达glnK		49.98	0.34	0.52	补料分批发酵	[50]
大肠杆菌	解除终产物对L-精氨酸合成关键酶的反馈抑制：敲除argA；阻断副产物合成途径：敲除pflB（编码丙酮酸-甲酸裂解酶）、ldhA（编码乳酸脱氢酶）、poxB（编码丙酮酸氧化酶）、adhE（编码乙醇脱氢酶）、aceE（编码丙酮酸脱氢酶）、speF；阻断L-精氨酸降解途径：敲除speB、astA；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR；强化L-精氨酸合成途径：过表达argCBI、argD、argG、argH、carAB	葡萄糖；乙酰谷氨酸	4.00	—	—	摇瓶发酵	[51]

菌种	代谢改造策略	原料	产量（g/L）	转化率（g/g）	生产强度（g/L/h）	发酵方式	参考文献
谷氨酸棒杆菌	增强辅因子NADPH的供应：过表达pntAB和ppnk；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR和farR；阻断副产物合成途径：敲除ldh（编码乳酸脱氢酶）	葡萄糖	67.01	0.35	0.89	补料分批发酵	[38]
谷氨酸棒杆菌	诱变育种；增强辅因子NADPH的供应：下调pgi的表达，过表达tkt、tal、zwf、opcA、pgl；强化L-精氨酸合成途径：过表达argGH、carAB；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR和farR；增强前体物质L-谷氨酸的供应：敲除ncgl1221	葡萄糖；蔗糖	92.50	0.40	1.28	补料分批发酵	[39]
钝齿棒杆菌	解除终产物对L-精氨酸合成关键酶的反馈抑制：定点突变ArgB^{E19Y/I74V/F91H/K234T}	葡萄糖	61.20	0.43	0.64	补料分批发酵	[40]
大肠杆菌	解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR；解除终产物对L-精氨酸合成关键酶的反馈抑制：外源表达argJ；强化L-精氨酸合成途径：外源表达argCJBDF	葡萄糖	70.10	0.33	1.17	补料分批发酵	[41]
钝齿棒杆菌	增强前体物质L-谷氨酸的供应：过表达iolT1、ptsG、ppgk、pyc、gltA、gdh，下调odhA的表达；强化L-精氨酸合成途径：过表达argCJBDF、argGH；阻断副产物合成途径：敲除proB，下调lysC的表达；增强辅因子NADPH的供应：下调pgi的表达	葡萄糖	87.30	0.43	1.21	补料分批发酵	[42]
钝齿棒杆菌	增强辅因子ATP的供应：过表达pyk、pgk，敲除frd12、nox、amn	葡萄糖	57.30	0.33	0.58	补料分批发酵	[43]
钝齿棒杆菌	阻断副产物合成途径：敲除proB；解除终产物对L-精氨酸合成关键酶的反馈抑制：定点突变ArgB^{E19R,H26E,D311,D312R}	葡萄糖	16.50	0.39	0.15	摇瓶发酵	[44]
钝齿棒杆菌	增强前体物质L-谷氨酸的供应：敲除putP、pta、ncg12310、ncgl1221；增强L-精氨酸转运：过表达lysE	葡萄糖	24.85	0.57	0.23	摇瓶发酵	[45]
钝齿棒杆菌	增强氮源供应：过表达glnA、aspA、gdh	葡萄糖	53.20	0.32	0.55	补料分批发酵	[46]
钝齿棒杆菌	增强氮源供应：敲除amtR，过表达amtB2	葡萄糖	60.90	0.36	0.63	补料分批发酵	[47]
大肠杆菌	阻断L-精氨酸降解途径：敲除adiA、speC、speF；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR；解除终产物对L-精氨酸合成关键酶的反馈抑制：过表达ArgA^H15Y；增强L-精氨酸转运：过表达argO	葡萄糖	11.64	1.18	0.24	补料分批发酵	[48]
钝齿棒杆菌	增强L-精氨酸转运：过表达lysE	葡萄糖	35.91	—	0.37	摇瓶发酵	[49]
钝齿棒杆菌	解除终产物对L-精氨酸合成关键酶的反馈抑制：过表达glnK		49.98	0.34	0.52	补料分批发酵	[50]
大肠杆菌	解除终产物对L-精氨酸合成关键酶的反馈抑制：敲除argA；阻断副产物合成途径：敲除pflB（编码丙酮酸-甲酸裂解酶）、ldhA（编码乳酸脱氢酶）、poxB（编码丙酮酸氧化酶）、adhE（编码乙醇脱氢酶）、aceE（编码丙酮酸脱氢酶）、speF；阻断L-精氨酸降解途径：敲除speB、astA；解除阻遏蛋白对L-精氨酸操纵子的转录抑制：敲除argR；强化L-精氨酸合成途径：过表达argCBI、argD、argG、argH、carAB	葡萄糖；乙酰谷氨酸	4.00	—	—	摇瓶发酵	[51]

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L-精氨酸的微生物合成研究进展

Recent advances in biosynthesis of L-arginine using engineered microorganisms

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