Enhanced synthesis of S‐adenosyl‐L‐methionine through combinatorial metabolic engineering and Bayesian optimization in Saccharomyces cerevisiae,Biotechnology Journal

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Enhanced synthesis of S‐adenosyl‐L‐methionine through combinatorial metabolic engineering and Bayesian optimization in Saccharomyces cerevisiae
Biotechnology Journal ( IF 3.2 ) Pub Date : 2024-03-14 , DOI: 10.1002/biot.202300650
Wenhan Xiao _{1,

2,

3,

4} , Xiangliu Shi _{1,

2,

3} , Haowei Huang _{1,

2,

3,

4} , Xiaogang Wang ₅ , Wenshu Liang _{1,

2,

3} , Jianguo Xu _{6,

7} , Fei Liu ₅ , Xiaomei Zhang _{4,

6} , Guoqiang Xu _{1,

2,

3,

4} , Jinsong Shi _{4,

6} , Zhenghong Xu _{1,

2,

3,

4}

Affiliation

S‐Adenosyl‐L‐methionine (SAM) is a substrate for many enzyme‐catalyzed reactions and provides methyl groups in numerous biological methylations, and thus has vast applications in the agriculture and medical field. Saccharomyces cerevisiae has been engineered as a platform with significant potential for producing SAM, but the current production has room for improvement. Thus, a method that consists of a series of metabolic engineering strategies was established in this study. These strategies included enhancing SAM synthesis, increasing ATP supply, down‐regulating SAM metabolism, and down‐regulating competing pathway. After combinatorial metabolic engineering, Bayesian optimization was conducted on the obtained strain C262P6S to optimize the fermentation medium. A final yield of 2972.8 mg·L−1 at 36 h with 29.7% of the L‐Met conversion rate in the shake flask was achieved, which was 26.3 times higher than that of its parent strain and the highest reported production in the shake flask to date. This paper establishes a feasible foundation for the construction of SAM‐producing strains using metabolic engineering strategies and demonstrates the effectiveness of Bayesian optimization in optimizing fermentation medium to enhance the generation of SAM.

中文翻译：

通过组合代谢工程和贝叶斯优化在酿酒酵母中增强 S-腺苷-L-甲硫氨酸的合成

S-腺苷-L-甲硫氨酸（SAM）是许多酶催化反应的底物，并在许多生物甲基化中提供甲基，因此在农业和医学领域具有广泛的应用。酿酒酵母已被设计为具有生产 SAM 巨大潜力的平台，但目前的生产还有改进的空间。因此，本研究建立了一种由一系列代谢工程策略组成的方法。这些策略包括增强 SAM 合成、增加 ATP 供应、下调 SAM 代谢和下调竞争途径。经过组合代谢工程，对获得的菌株C262P6S进行贝叶斯优化，以优化发酵培养基。最终产量2972.8 mg·L −1 36 h，摇瓶中 L-Met 转化率达到 29.7%，比亲本菌株高 26.3 倍，是迄今为止报道的摇瓶中最高产量。本文为利用代谢工程策略构建 SAM 生产菌株奠定了可行的基础，并证明了贝叶斯优化在优化发酵培养基以增强 SAM 生成方面的有效性。

更新日期：2024-03-14

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