Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, No. 5 South Zhongguancun Street, Haidian District, Beijing, 100081, China.
Microb Cell Fact. 2021 Dec 24;20(1):230. doi: 10.1186/s12934-021-01721-0.
Branched chain amino acids (BCAAs) are widely applied in the food, pharmaceutical, and animal feed industries. Traditional chemical synthetic and enzymatic BCAAs production in vitro has been hampered by expensive raw materials, harsh reaction conditions, and environmental pollution. Microbial metabolic engineering has attracted considerable attention as an alternative method for BCAAs biosynthesis because it is environmentally friendly and delivers high yield.
Corynebacterium glutamicum (C. glutamicum) possesses clear genetic background and mature gene manipulation toolbox, and has been utilized as industrial host for producing BCAAs. Acetohydroxy acid synthase (AHAS) is a crucial enzyme in the BCAAs biosynthetic pathway of C. glutamicum, but feedback inhibition is a disadvantage. We therefore reviewed AHAS modifications that relieve feedback inhibition and then investigated the importance of AHAS modifications in regulating production ratios of three BCAAs. We have comprehensively summarized and discussed metabolic engineering strategies to promote BCAAs synthesis in C. glutamicum and offer solutions to the barriers associated with BCAAs biosynthesis. We also considered the future applications of strains that could produce abundant amounts of BCAAs.
Branched chain amino acids have been synthesized by engineering the metabolism of C. glutamicum. Future investigations should focus on the feedback inhibition and/or transcription attenuation mechanisms of crucial enzymes. Enzymes with substrate specificity should be developed and applied to the production of individual BCAAs. The strategies used to construct strains producing BCAAs provide guidance for the biosynthesis of other high value-added compounds.
支链氨基酸（BCAAs）在食品、制药和动物饲料等行业中有着广泛的应用。传统的体外化学合成和酶法生产 BCAAs 受到昂贵的原材料、苛刻的反应条件和环境污染的限制。微生物代谢工程作为一种替代方法，因其环保且产量高，受到了广泛关注。
谷氨酸棒状杆菌（Corynebacterium glutamicum，C. glutamicum）具有明确的遗传背景和成熟的基因操作工具箱，已被用作生产 BCAAs 的工业宿主。乙酰羟酸合酶（Acetohydroxy acid synthase，AHAS）是 C. glutamicum 中 BCAAs 生物合成途径中的关键酶，但反馈抑制是其缺点。因此，我们综述了缓解反馈抑制的 AHAS 修饰，并研究了 AHAS 修饰在调节三种 BCAAs 生产比例中的重要性。我们全面总结和讨论了促进 C. glutamicum 中 BCAAs 合成的代谢工程策略，并为 BCAAs 生物合成相关的障碍提供了解决方案。我们还考虑了能够大量生产 BCAAs 的菌株的未来应用。
通过工程改造 C. glutamicum 的代谢，可以合成支链氨基酸。未来的研究应集中于关键酶的反馈抑制和/或转录衰减机制。应开发并应用具有底物特异性的酶来生产单个 BCAAs。用于构建生产 BCAAs 的菌株的策略为其他高附加值化合物的生物合成提供了指导。
