Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co-activation controlled by Streptomyces antibiotic regulatory protein family regulator in Streptomyces bingchenggensis

文献类型： 外文期刊

第一作者： Wang, Haiyan

作者： Wang, Haiyan;Cheng, Xu;Zhang, Yanyan;Li, Shanshan;Xiang, Wensheng;Liu, Yuqing;Wang, Xiangjing;Xiang, Wensheng

作者机构：

关键词： metabolic competition; milbemycins; Streptomyces; titer improvement; transcriptional coregulation

期刊名称：BIOTECHNOLOGY AND BIOENGINEERING （ 影响因子：4.395； 五年影响因子：4.639 ）

ISSN： 0006-3592

年卷期： 2022 年 119 卷 5 期

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收录情况： SCI

摘要： Streptomyces bingchenggensis is a promising producer of milbemycins (MILs), the macrolide pesticide used widely in agriculture. The relationship between different biosynthetic gene clusters (BGCs) and the MIL BGC remains unclear, which hinders the precise metabolic engineering of S. bingchenggensis for titer improvement. To address this issue, this study discovered the regulatory function of a previously unidentified regulator KelR on a type-II polyketide BGC, MIL BGC, and two other BGCs, and caused titer improvement. First, a type II polyketide synthase (PKS) gene cluster kel with a bidirectional effect on MIL biosynthesis was found using transcriptome analysis. A Streptomyces antibiotic regulatory protein (SARP) family regulator KelR from the kel cluster was then characterized as an activator of several BGCs including mil and kel clusters. Metabolic competition between mil and kel clusters at the late fermentation stage was confirmed. Finally, KelR and those BGCs were manipulated in S. bingchenggensis, which led to a 71.7% titer improvement of MIL A3/A4 to 4058.2 +/- 71.0 mg/L. This study deciphered the regulatory function of a previously unidentified regulatory protein KelR on several BGCs including mil in S. bingchenggensis and provided an example of coordinating metabolic competition and coregulation for titer improvement of secondary metabolites.

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