Optimization of Milbemycin Component Ratio by Coordinating Acyl-Coenzyme A Supply Pathways in Streptomyces bingchenggensis

文献类型： 外文期刊

第一作者： Yang, Xue

作者： Yang, Xue;Dong, Zhuoxu;Zhang, Yanyan;Xiang, Wensheng;Li, Shanshan;Jin, Pinjiao;Dong, Zhuoxu;Xiang, Wensheng;Jin, Pinjiao

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关键词： Streptomyces; precursors supply; acyl-coenzyme A; component ratio optimization; Streptomyces bingchenggensis; milbemycins

期刊名称：FERMENTATION-BASEL （ 影响因子：3.7； 五年影响因子：4.5 ）

ISSN：

年卷期： 2023 年 9 卷 6 期

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收录情况： SCI

摘要： Milbemycins are a group of macrolide pesticides with great potential in the agricultural field owing to their high insecticidal activity and environmental compatibility. Milbemycin A3 and A4 with high bioactivities are the main components of milbemycin-derived products, which require a component ratio A4:A3 of 2.3- to 4.0-fold. Streptomyces bingchenggensis BC04 is a promising milbemycin producer, whereas the component ratio of its products (A4:A3 of 9.0-fold) could not meet the requirement for industrial production. To address this issue, we reconstructed the precursor biosynthetic pathways to fine tune the supply of different acyl-coenzyme A precursors required for milbemycin biosynthesis. Based on an analysis of the intracellular acyl-coenzyme A precursors, we reconstructed stepwise heterogeneous biosynthetic pathways of extender units for milbemycin biosynthesis. Then, we coordinated the supply of milbemycin biosynthetic starter units with temporal promoters. Thanks to these manipulations, we obtained an engineered strain with 39.5% milbemycin titer improvement to 3417.88 mg/L and a qualified component ratio A4:A3 of 3.3-fold. This work demonstrated that coordinating the precursor supply is a simple and effective approach to optimize the component ratio of A4:A3 in milbemycin fermentation products. Moreover, this strategy might also be useful to construct high-yield strains with optimized component ratios of fermentation products in other Streptomyces.

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