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Decoding and reprogramming fungal iterative nonribosomal peptide synthetases

Author

Listed:
  • Dayu Yu

    (College of Chemical Engineering, Northeast Electric Power University
    Utah State University)

  • Fuchao Xu

    (Utah State University)

  • Shuwei Zhang

    (Utah State University)

  • Jixun Zhan

    (Utah State University)

Abstract

Nonribosomal peptide synthetases (NRPSs) assemble a large group of structurally and functionally diverse natural products. While the iterative catalytic mechanism of bacterial NRPSs is known, it remains unclear how fungal NRPSs create products of desired length. Here we show that fungal iterative NRPSs adopt an alternate incorporation strategy. Beauvericin and bassianolide synthetases have the same C1-A1-T1-C2-A2-MT-T2a-T2b-C3 domain organization. During catalysis, C3 and C2 take turns to incorporate the two biosynthetic precursors into the growing depsipeptide chain that swings between T1 and T2a/T2b with C3 cyclizing the chain when it reaches the full length. We reconstruct the total biosynthesis of beauvericin in vitro by reacting C2 and C3 with two SNAC-linked precursors and present a domain swapping approach to reprogramming these enzymes for peptides with altered lengths. These findings highlight the difference between bacterial and fungal NRPS mechanisms and provide a framework for the enzymatic synthesis of non-natural nonribosomal peptides.

Suggested Citation

  • Dayu Yu & Fuchao Xu & Shuwei Zhang & Jixun Zhan, 2017. "Decoding and reprogramming fungal iterative nonribosomal peptide synthetases," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15349
    DOI: 10.1038/ncomms15349
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