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Regulatory and biosynthetic effects of the bkd gene clusters on the production of daptomycin and its analogs A21978C1–3

  • Genetics and Molecular Biology of Industrial Organisms - Original Paper
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus in an acidic peptide complex A21978C. In this complex, A21978C1–3 is most abundant and contains branched-chain fatty acyl groups, while daptomycin has a straight decanoic acyl group. The branched-chain α-keto acid dehydrogenase complex (BCDH complex), encoded by bkd gene clusters in Streptomyces, is responsible for the early step of converting branched-chain amino acids into branched-chain fatty acids. In a daptomycin industrial producer S. roseosporus L30, two alleles of bkd gene clusters, bkdA1B1C1/bkdA2B2C2, and a regulatory gene bkdR located upstream of bkdA2B2C2 are identified. We show that BkdR positively regulated bkdA2B2C2 expression and was negatively auto-regulated, but is not directly involved in regulation of daptomycin gene cluster expression. However, BkdR is required for both daptomycin and A21978C1–3 production. Furthermore, deletion of bkdA2B2C2 only led to partial reduction of A21978C1–3 production, while the ΔbkdA1B1C1 mutant shows very weak production of A21978C1–3, and the double bkd mutant has a similar production profile as the single ΔbkdA1B1C1 mutant, suggesting that bkdA1B1C1 gene cluster plays a dominant role in branched-chain fatty acid biosynthesis. So we reveal a unique regulatory function of BkdR and genetic engineered a bkd null strain for daptomycin production with reduced impurities.

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (31730002, 31520103901) to Yong-Quan Li, and National Natural Science Foundation of China (31571284, 31770071) to Xu-Ming Mao.

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Authors and Affiliations

  1. Institute of Pharmaceutical Biotechnology, Zhejiang University, Hangzhou, 310058, China

    Shuai Luo, Xin-Ai Chen, Xu-Ming Mao & Yong-Quan Li

  2. Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, 310058, China

    Shuai Luo, Xin-Ai Chen, Xu-Ming Mao & Yong-Quan Li

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  1. Shuai Luo
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Correspondence to Xu-Ming Mao or Yong-Quan Li.

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Luo, S., Chen, XA., Mao, XM. et al. Regulatory and biosynthetic effects of the bkd gene clusters on the production of daptomycin and its analogs A21978C1–3. J Ind Microbiol Biotechnol 45, 271–279 (2018). https://doi.org/10.1007/s10295-018-2011-y

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