Applications and advances in the research of biosynthesis of amino acid derivatives as key ingredients in cosmetics

doi:10.12211/2096-8280.2024-060

Abstract

Abstract:

The development of synthetic biology has witnessed rapid advancements, which has significantly promoted production innovations across multiple domains. In the cosmetics industry, the production methods of amino acid derivatives, which is a kind of pivotal raw materials in cosmetics, are experiencing groundbreaking innovations. The traditional methods for the production of amino acid derivatives have the problem of high production costs, and usually bring heavy burdens to the environment. Besides, the production stabilities of the target products are often unsatisfactory. The application of synthetic biology technology in the design and engineering of microbial cell factories for the bioproduction of amino acid derivatives, can greatly enhance the production efficiency and reduce the production costs of the target products. This innovative approach not only enhances the development of green biological manufacturing, but also benefits the demand of market for natural, safe, and functional cosmetic ingredients. In this review, an overall introduction to the utilization of amino acid derivatives in cosmetics industry was first provided. Subsequently, the strategies for the construction of high-producing strains for the bioproduction of amino acid derivatives were comprehensively summarized. The strategies have been broadly categorized into two groups, including enzyme conversion and microbial fermentation. The application of enzyme engineering, rational metabolic engineering, and non-rational screening in the construction of microbial cell factories for the production of amino acid derivatives were systematically introduced. Moreover, the current research advancements and the future anticipated trends in the biosynthesis of amino acid derivatives within the realm of cosmetic raw materials were outlined. With the support of the cutting-edge technologies such as artificial intelligence, synthetic biology will further promote the production innovation process, enabling efficient and eco-friendly biological manufacturing of a wider array of cosmetic raw materials. This ongoing evolution holds immense promise for the cosmetics industry, promising a future filled with sustainable and innovative products.

Key words: Synthetic biology, cosmetic raw materials, enzymatic conversion, microbial fermentation

摘要：

随着合成生物学的快速发展，氨基酸衍生物作为一类重要的化妆品原料，其生产方式正发生历史性革新。传统生产方法存在生产成本高、环境负担重、产品稳定性差等问题。运用合成生物技术设计构建微生物细胞工厂，不仅能有效提升目标产品生产效率、降低成本，还能实现绿色生物制造，满足市场对天然、安全、功能性强化妆品原料的供应需求。本文介绍了氨基酸衍生物在化妆品中的应用；并对其生物合成策略进行了总结，从酶转化和微生物发酵两种主要的生物合成工艺入手，探讨了酶工程、理性代谢工程以及非理性筛选等策略在化妆品原料氨基酸衍生物细胞工厂构建中的应用；进一步对化妆品原料氨基酸衍生物的生物合成研究进展与发展趋势进行了系统综述。在人工智能等前沿技术的赋能助力下，合成生物技术必将进一步推动化妆品原料高效绿色生物制造的革新进程。

关键词: 合成生物学, 化妆品原料, 酶转化, 微生物发酵

CLC Number:

Q816

Jinhang YI, Yulin TANG, Chunyu LI, Heyun WU, Qian MA, Xixian XIE. Applications and advances in the research of biosynthesis of amino acid derivatives as key ingredients in cosmetics[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-060.

伊进行, 唐宇琳, 李春雨, 吴鹤云, 马倩, 谢希贤. 氨基酸衍生物在化妆品中的应用及其生物合成研究进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-060.

Figures/Tables 6

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氨基酸及衍生物	底盘菌株	生产方法	主要策略	发酵规模	产量	生产强度	参考文献
精氨酸	钝齿棒杆菌	微生物发酵	argB定向突变，解除精氨酸抑制	5 L发酵罐	45.6 g/L	0.475 g/L/h	[68]
	谷氨酸棒杆菌	微生物发酵	解除精氨酸反馈抑制；增加胞内NADPH水平；优化精氨酸代谢通量	5 L发酵罐	92.5 g/L	1.29 g/L/h	[70]
	大肠杆菌	微生物发酵	多层次合理代谢工程改造；构建生物传感器辅助的高通量筛选平台BHTS；全基因组测序和逆向工程鉴定和优化有益的突变基因	5 L发酵罐	132 g/L	2.75 g/L/h	[80]
瓜氨酸	粪链球菌	全细胞催化	优化ADI固定化条件和催化反应条件	改进型填充床反应器	—	95.6 g/L/d	[54]
	大肠杆菌	全细胞催化	大肠杆菌中表达乳酸乳球菌来源的ADI并通过易错PCR对酶进行突变；反应条件优化	30 L生物反应器	176.9 g/L	22.1 g/L/h	[39]
	谷氨酸棒杆菌	微生物发酵	阻断瓜氨酸降解；质粒过表达argJ基因，提高瓜氨酸的代谢通量	摇瓶	8.51 g/L	0.12 g/L/h	[92]
	大肠杆菌	微生物发酵	系统代谢工程对合成途径多模块耦合；Esa QS系统动态控制argG基因的表达	5 L发酵罐	82.1 g/L	1.71 g/L/h	[65]
γ-聚谷氨酸	地衣芽孢杆菌	微生物发酵	⁶⁰Co-γ射线辐照和ARTP诱变协同复合诱变技术；发酵培养基组分及条件优化	摇瓶	32.53 g/L	0.45 g/L/h	[81]
	地衣芽孢杆菌	微生物发酵	代谢工程改善ATP供应	1 L发酵罐	43.81 g/L	1.37 g/L/h	[102]
	特基拉芽胞杆菌	微生物发酵	过表达外源ppc、aceE、pyk、icdh、gltA和gdhA基因；对关键酶Ppc、Pyk和AceE进行组装；低成本糖蜜作为发酵碳源	5 L发酵罐	25.73 g/L	0.48 g/L/h	[118]
	谷氨酸棒杆菌	微生物发酵	异源pgsBCA基因表达强度组合；优化发酵溶氧水平	5 L发酵罐	50.2 g/L	1.05 g/L/h	[96]
γ-氨基丁酸	大肠杆菌	全细胞催化	过表达乳球菌来源gadB基因；敲除gabA和gabB基因阻断竞争通路；发酵条件优化	200 L生物反应器	614.15 g/L	40.94 g/L/h	[103]
	大肠杆菌	全细胞催化	定向进化和高通量筛选；过表达GadE；建立PLP自供系统	5 L生物反应器	307.5 g/L	61.49 g/L/h	[104]
	谷氨酸棒杆菌	微生物发酵	胞外分泌表达大肠杆菌来源突变体GadBmut；阻断GABA降解	3 L发酵罐	77.6 g/L	1.21 g/L/h	[110]
	谷氨酸棒杆菌	微生物发酵	强化甘油利用途径；敲除GABA降解途径并引入外源GABA合成途径；构建GABS动态调控GABA合成途径的基因表达	7.5 L发酵罐	45.6 g/L	0.63 g/L/h	[111]
	谷氨酸棒杆菌	微生物发酵	敲除ldhA、pqo和ack基因；过表达ppc、gltA、acn、icd、gdh和pdxST基因；P_{CP_2836}odhA	5 L发酵罐	81.31 g/L	1.36 g/L/h	[87]
	短乳杆菌	全细胞催化	pH自动维持系统	10 L发酵罐	321.9 g/L	6.71 g/L/h	[107]
反式-4-羟基-L-脯氨酸	大肠杆菌	微生物发酵	将地中海交替单胞菌来源PHP引入脯氨酸途径	5 L发酵罐	45.83 g/L	1.27 g/L/h	[114]
	大肠杆菌	微生物发酵	建立木糖诱导表达体系；强化脯氨酸合成途径；引入小单孢菌属来源P4H	5 L发酵罐	48.6 g/L	1.22 g/L/h	[67]
	大肠杆菌	微生物发酵	增加前体物脯氨酸合成；引入指孢囊菌来源P4H；引入NOG途径；发酵工艺优化	5 L发酵罐	89.4 g/L	2.03 g/L/h	[73]
亚精胺	解淀粉芽孢杆菌	微生物发酵	同源重组共表达异源speD和speE基因；发酵介质优化	摇瓶	227.4 mg/L	3 mg/L/h	[115]
	酿酒酵母	微生物发酵	优化前体物供应；解除反馈抑制；强化转运途径	孔板	2.3 g/L	20 mg/L/h	[116]
	大肠杆菌	全细胞催化	高亚精胺合成酶双重突变	摇瓶	933.5 mg/L	155.6 mg/L/h	[47]
	大肠杆菌	全细胞催化	双酶级联催化系统；优化酶表达条件和反应条件	摇瓶	3.7 g/L	463 mg/L/h	[117]

氨基酸及衍生物	底盘菌株	生产方法	主要策略	发酵规模	产量	生产强度	参考文献
精氨酸	钝齿棒杆菌	微生物发酵	argB定向突变，解除精氨酸抑制	5 L发酵罐	45.6 g/L	0.475 g/L/h	[68]
	谷氨酸棒杆菌	微生物发酵	解除精氨酸反馈抑制；增加胞内NADPH水平；优化精氨酸代谢通量	5 L发酵罐	92.5 g/L	1.29 g/L/h	[70]
	大肠杆菌	微生物发酵	多层次合理代谢工程改造；构建生物传感器辅助的高通量筛选平台BHTS；全基因组测序和逆向工程鉴定和优化有益的突变基因	5 L发酵罐	132 g/L	2.75 g/L/h	[80]
瓜氨酸	粪链球菌	全细胞催化	优化ADI固定化条件和催化反应条件	改进型填充床反应器	—	95.6 g/L/d	[54]
	大肠杆菌	全细胞催化	大肠杆菌中表达乳酸乳球菌来源的ADI并通过易错PCR对酶进行突变；反应条件优化	30 L生物反应器	176.9 g/L	22.1 g/L/h	[39]
	谷氨酸棒杆菌	微生物发酵	阻断瓜氨酸降解；质粒过表达argJ基因，提高瓜氨酸的代谢通量	摇瓶	8.51 g/L	0.12 g/L/h	[92]
	大肠杆菌	微生物发酵	系统代谢工程对合成途径多模块耦合；Esa QS系统动态控制argG基因的表达	5 L发酵罐	82.1 g/L	1.71 g/L/h	[65]
γ-聚谷氨酸	地衣芽孢杆菌	微生物发酵	⁶⁰Co-γ射线辐照和ARTP诱变协同复合诱变技术；发酵培养基组分及条件优化	摇瓶	32.53 g/L	0.45 g/L/h	[81]
	地衣芽孢杆菌	微生物发酵	代谢工程改善ATP供应	1 L发酵罐	43.81 g/L	1.37 g/L/h	[102]
	特基拉芽胞杆菌	微生物发酵	过表达外源ppc、aceE、pyk、icdh、gltA和gdhA基因；对关键酶Ppc、Pyk和AceE进行组装；低成本糖蜜作为发酵碳源	5 L发酵罐	25.73 g/L	0.48 g/L/h	[118]
	谷氨酸棒杆菌	微生物发酵	异源pgsBCA基因表达强度组合；优化发酵溶氧水平	5 L发酵罐	50.2 g/L	1.05 g/L/h	[96]
γ-氨基丁酸	大肠杆菌	全细胞催化	过表达乳球菌来源gadB基因；敲除gabA和gabB基因阻断竞争通路；发酵条件优化	200 L生物反应器	614.15 g/L	40.94 g/L/h	[103]
	大肠杆菌	全细胞催化	定向进化和高通量筛选；过表达GadE；建立PLP自供系统	5 L生物反应器	307.5 g/L	61.49 g/L/h	[104]
	谷氨酸棒杆菌	微生物发酵	胞外分泌表达大肠杆菌来源突变体GadBmut；阻断GABA降解	3 L发酵罐	77.6 g/L	1.21 g/L/h	[110]
	谷氨酸棒杆菌	微生物发酵	强化甘油利用途径；敲除GABA降解途径并引入外源GABA合成途径；构建GABS动态调控GABA合成途径的基因表达	7.5 L发酵罐	45.6 g/L	0.63 g/L/h	[111]
	谷氨酸棒杆菌	微生物发酵	敲除ldhA、pqo和ack基因；过表达ppc、gltA、acn、icd、gdh和pdxST基因；P_{CP_2836}odhA	5 L发酵罐	81.31 g/L	1.36 g/L/h	[87]
	短乳杆菌	全细胞催化	pH自动维持系统	10 L发酵罐	321.9 g/L	6.71 g/L/h	[107]
反式-4-羟基-L-脯氨酸	大肠杆菌	微生物发酵	将地中海交替单胞菌来源PHP引入脯氨酸途径	5 L发酵罐	45.83 g/L	1.27 g/L/h	[114]
	大肠杆菌	微生物发酵	建立木糖诱导表达体系；强化脯氨酸合成途径；引入小单孢菌属来源P4H	5 L发酵罐	48.6 g/L	1.22 g/L/h	[67]
	大肠杆菌	微生物发酵	增加前体物脯氨酸合成；引入指孢囊菌来源P4H；引入NOG途径；发酵工艺优化	5 L发酵罐	89.4 g/L	2.03 g/L/h	[73]
亚精胺	解淀粉芽孢杆菌	微生物发酵	同源重组共表达异源speD和speE基因；发酵介质优化	摇瓶	227.4 mg/L	3 mg/L/h	[115]
	酿酒酵母	微生物发酵	优化前体物供应；解除反馈抑制；强化转运途径	孔板	2.3 g/L	20 mg/L/h	[116]
	大肠杆菌	全细胞催化	高亚精胺合成酶双重突变	摇瓶	933.5 mg/L	155.6 mg/L/h	[47]
	大肠杆菌	全细胞催化	双酶级联催化系统；优化酶表达条件和反应条件	摇瓶	3.7 g/L	463 mg/L/h	[117]

氨基酸衍生物	底盘菌株	生产方法	主要策略	发酵规模	产量	生产强度	参考文献
对香豆酸	大肠杆菌	微生物发酵	筛选p-CA合成基因；优化蛋白活性；增加辅因子利用率；优化发酵工艺	5 L发酵罐	3.09 g/L	49.05 mg/L/h	[74]
	酿酒酵母	微生物发酵	筛选p-CA合成基因；增加前体物供应；阻断竞争途径；平衡PEP与E4P碳通量	1 L发酵罐	12.50 g/L	130 mg/L/h	[123]
	解脂耶氏酵母	微生物发酵	增加TAL基因拷贝数；强化莽草酸途径通量；阻断苯丙氨酸的竞争途径	摇瓶	1.04 g/L	8.63 mg/L/h	[124]
白藜芦醇	大肠杆菌	微生物发酵	引入异源丙二酸同化途径，增加关键前体丙二酰辅酶A的供应；CRISPRi技术下调脂肪酸合成途径基因，阻断丙二酰辅酶A消耗途径；引入并优化异源TAL途径	摇瓶	304.5 mg/L	6.344 mg/L/h	[137]
	大肠杆菌	微生物发酵	混菌发酵；优化发酵条件（接种比例、碳源比例）	摇瓶	204.8 mg/L	2.44 mg/L/h	[140]
	解脂耶氏酵母	微生物发酵	引入白藜芦醇合成途径相关酶并采用刚性连接肽EAAAK连接；增加前体物供应；优化发酵条件（控制pH以维持酵母正常形态）	5 L发酵罐	22.5 g/L	0.16 g/L/h	[61]
	—	酶催化	虎杖苷-β-D-葡萄糖苷酶催化虎杖苷酶；反应条件优化	摇瓶	22.5 g/L	5.63 g/L/h	[143]
红景天苷	大肠杆菌	微生物发酵	混菌发酵；优化发酵条件以平衡菌株生长（碳源比例、接种比例）	5 L发酵罐	6.03 g/L	0.05 g/L/h	[148]
红景天苷	酿酒酵母	微生物发酵	引入红景天苷合成途径；增加前体物供应；敲除竞争途径	5 L发酵罐	26.55 g/L	0.16 g/L/h	[71]
咖啡酸	大肠杆菌	微生物发酵	引入p-CA合成途径；解除反馈抑制；阻断竞争途径；增加辅因子FAD供应；强化CA转运蛋白表达	5 L发酵罐	7.92 g/L	0.12 g/L/h	[72]
	大肠杆菌	微生物发酵	引入p-CA合成途径；阻断竞争途径；增加前体物酪氨酸供应；增加辅因子FADH₂供应	5 L发酵罐	6.17 g/L	0.07 g/L/h	[157]
	酿酒酵母	微生物发酵	阻断苯丙氨酸和色氨酸合成，增加前体供应	5 L发酵罐	9.3 g/L	0.09 g/L/h	[159]
阿魏酸	大肠杆菌	微生物发酵	引入FA合成酶增加S-腺苷甲硫氨酸供应；强化合成途径；增加前体物供应；减少PEP向丙酮酸转化；阻断竞争途径；增加辅因子FADH₂供应	3 L发酵罐	5.09 g/L	0.07 g/L/h	[160]
阿魏酸	酿酒酵母	微生物发酵	引入FA合成途径；增加前体物p-CA供应；增加辅因子FADH₂供应；增加辅因子NADPH供应；增加S-腺苷甲硫氨酸供应；回补菌株（HIS3, URA3）	1.2 L发酵罐	3.80 g/L	0.03 g/L/h	[75]
没食子酸	大肠杆菌	微生物发酵	引入GA合成所需酶、增加前体物供应	摇瓶	1266.39 mg/L	35.18 mg/L/h	[165]
根皮素	酿酒酵母	微生物发酵	引入根皮素合成途径；增加丙二酰辅酶A供应；优化发酵条件	5 L发酵罐	619.50 mg/L	7.74 mg/L/h	[172]
根皮素	大肠杆菌	微生物发酵	引入根皮素合成基因并对CHS酶进行诱变	摇瓶	1.85 mg/L	—	[173]

氨基酸衍生物	底盘菌株	生产方法	主要策略	发酵规模	产量	生产强度	参考文献
对香豆酸	大肠杆菌	微生物发酵	筛选p-CA合成基因；优化蛋白活性；增加辅因子利用率；优化发酵工艺	5 L发酵罐	3.09 g/L	49.05 mg/L/h	[74]
	酿酒酵母	微生物发酵	筛选p-CA合成基因；增加前体物供应；阻断竞争途径；平衡PEP与E4P碳通量	1 L发酵罐	12.50 g/L	130 mg/L/h	[123]
	解脂耶氏酵母	微生物发酵	增加TAL基因拷贝数；强化莽草酸途径通量；阻断苯丙氨酸的竞争途径	摇瓶	1.04 g/L	8.63 mg/L/h	[124]
白藜芦醇	大肠杆菌	微生物发酵	引入异源丙二酸同化途径，增加关键前体丙二酰辅酶A的供应；CRISPRi技术下调脂肪酸合成途径基因，阻断丙二酰辅酶A消耗途径；引入并优化异源TAL途径	摇瓶	304.5 mg/L	6.344 mg/L/h	[137]
	大肠杆菌	微生物发酵	混菌发酵；优化发酵条件（接种比例、碳源比例）	摇瓶	204.8 mg/L	2.44 mg/L/h	[140]
	解脂耶氏酵母	微生物发酵	引入白藜芦醇合成途径相关酶并采用刚性连接肽EAAAK连接；增加前体物供应；优化发酵条件（控制pH以维持酵母正常形态）	5 L发酵罐	22.5 g/L	0.16 g/L/h	[61]
	—	酶催化	虎杖苷-β-D-葡萄糖苷酶催化虎杖苷酶；反应条件优化	摇瓶	22.5 g/L	5.63 g/L/h	[143]
红景天苷	大肠杆菌	微生物发酵	混菌发酵；优化发酵条件以平衡菌株生长（碳源比例、接种比例）	5 L发酵罐	6.03 g/L	0.05 g/L/h	[148]
红景天苷	酿酒酵母	微生物发酵	引入红景天苷合成途径；增加前体物供应；敲除竞争途径	5 L发酵罐	26.55 g/L	0.16 g/L/h	[71]
咖啡酸	大肠杆菌	微生物发酵	引入p-CA合成途径；解除反馈抑制；阻断竞争途径；增加辅因子FAD供应；强化CA转运蛋白表达	5 L发酵罐	7.92 g/L	0.12 g/L/h	[72]
	大肠杆菌	微生物发酵	引入p-CA合成途径；阻断竞争途径；增加前体物酪氨酸供应；增加辅因子FADH₂供应	5 L发酵罐	6.17 g/L	0.07 g/L/h	[157]
	酿酒酵母	微生物发酵	阻断苯丙氨酸和色氨酸合成，增加前体供应	5 L发酵罐	9.3 g/L	0.09 g/L/h	[159]
阿魏酸	大肠杆菌	微生物发酵	引入FA合成酶增加S-腺苷甲硫氨酸供应；强化合成途径；增加前体物供应；减少PEP向丙酮酸转化；阻断竞争途径；增加辅因子FADH₂供应	3 L发酵罐	5.09 g/L	0.07 g/L/h	[160]
阿魏酸	酿酒酵母	微生物发酵	引入FA合成途径；增加前体物p-CA供应；增加辅因子FADH₂供应；增加辅因子NADPH供应；增加S-腺苷甲硫氨酸供应；回补菌株（HIS3, URA3）	1.2 L发酵罐	3.80 g/L	0.03 g/L/h	[75]
没食子酸	大肠杆菌	微生物发酵	引入GA合成所需酶、增加前体物供应	摇瓶	1266.39 mg/L	35.18 mg/L/h	[165]
根皮素	酿酒酵母	微生物发酵	引入根皮素合成途径；增加丙二酰辅酶A供应；优化发酵条件	5 L发酵罐	619.50 mg/L	7.74 mg/L/h	[172]
根皮素	大肠杆菌	微生物发酵	引入根皮素合成基因并对CHS酶进行诱变	摇瓶	1.85 mg/L	—	[173]

氨基酸衍生物	底盘菌株	生产方法	主要策略	发酵规模	产量	生产强度	参考文献
四氢嘧啶	大肠杆菌	微生物发酵	引入四氢嘧啶合成途径；增加前体物供应；优化补糖速率	15 L发酵罐	131.80 g/L	1.37 g/L/h	[59]
	大肠杆菌	微生物发酵	增加前体物供应；优化培养基（碳氮比例）	2.4 L发酵罐	34.27 g/L	0.57 g/L/h	[193]
	谷氨酸棒杆菌	微生物发酵	采用转录平衡技术设计启动子表达文库对菌株进行优化	1 L发酵罐	65 g/L	1.16 g/L/h	[58]
	谷氨酸棒杆菌	微生物发酵	引入四氢嘧啶合成途径；避免副产物积累；减少反馈抑制	5 L发酵罐	115.87 g/L	1.49 g/L/h	[182]
羟基四氢嘧啶	大肠杆菌	微生物发酵	引入羟基四氢嘧啶合成途径并进行优化；引入esaI/esaR群体感应系统控制sucA表达	摇瓶	14.93 g/L	0.42 g/L/h	[186]
羟基四氢嘧啶	谷氨酸棒杆菌	微生物发酵	双菌株两步发酵	1 L发酵罐	74 g/L	1.37 g/L/h	[185]
ε-聚赖氨酸	小白链霉菌	微生物发酵	增强ε-PL合成酶基因转录；赖氨酸合成过程中关键酶活性增强；优化发酵工艺（酸性pH冲击工艺）	5 L发酵罐	70.3 g/L	0.37 g/L/h	[191]
ε-聚赖氨酸	小白链霉菌	全细胞催化	表达异源lysp基因提升赖氨酸利用能力及底物转化效率；对培养基和培养条件进行优化	摇瓶	17.21 g/L	0.18 g/L/h	[192]
麦角硫因	大肠杆菌	微生物发酵	半理性设计和随机突变EgtD和^TNcEgt1；流加前体氨基酸	5 L发酵罐	5.4 g/L	56.3 mg/L/h	[194]
	大肠杆菌	全细胞催化	构建EGT菌株高密度发酵方法；发酵工艺优化；流加前体氨基酸	2 L发酵罐	7 g/L	90.9 mg/L/h	[195]
	大肠杆菌	微生物发酵	EGT合成模块、前体物组氨酸、半胱氨酸和腺苷蛋氨酸合成模块进行系统的代谢工程改造；发酵工艺优化	2 L发酵罐	7.2 g/L	120 mg/L/h	[196]
	裂殖酵母	微生物发酵	紫外照射和氯化锂突变；流加前体氨基酸	5 L发酵罐	12.5 g/L	84.5 mg/L/h	[197]
肌肽	—	酶催化	定点饱和突变来改善酯酰基转移酶的底物特异性；	摇瓶	105 mM	—	[198]
	—	酶催化	筛选来自粘质沙雷氏菌新型二肽酶SmPepD；反应条件优化；纳滤膜分离	5 L超滤膜反应器	7.23 g/L	—	[33]
	—	酶催化	酶挖掘方法鉴定出来自巨大芽孢杆菌BmPepD并进行定向饱和诱变；反应条件优化	10 mL反应体系	31.3 mM	—	[35]
	大肠杆菌	全细胞催化	在大肠杆菌中表达SmpepD构建细胞工厂；对SmPepD理性设计获得更高活性双突变体Thr168Ser/Gly148Asp；敲除组氨酸输出蛋白yeaS基因	5 L生物反应器	133.2 mM	—	[48]
	谷氨酸棒杆菌	微生物发酵	增加前体组氨酸和β-丙氨酸积累；引入来自哺乳动物的CARNS1基因；发酵优化；肌肽活性验证	2 L发酵罐	323.26 mg/L	6.73 mg/L/h	[199]
谷胱甘肽	酿酒酵母	微生物发酵	适应性进化；使用丙烯醛作为选择剂	发酵罐（1.2 L工作体积）	320 mg/L	8.28 mg/L/h	[200]
	酿酒酵母	微生物发酵	基于氧化应激和能量代谢的逐步控制策略	10 L发酵罐	5.76 g/L	53 mg/L/h	[201]
	大肠杆菌	微生物发酵	异源表达来自嗜热链球菌gshF基因；流加前体氨基酸	5 L发酵罐	15.21 g/L	0.82 g/L/h	[202]
	大肠杆菌	微生物发酵	代谢工程手段促进GSH生物合成；代谢组学分析	5 L发酵罐	22 g/L/h	0.407 g/L/h	[88]