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Discovery of type II polyketide synthase-like enzymes for the biosynthesis of cispentacin

Author

Listed:
  • Genki Hibi

    (The University of Tokyo)

  • Taro Shiraishi

    (The University of Tokyo
    The University of Tokyo)

  • Tatsuki Umemura

    (The University of Tokyo)

  • Kenji Nemoto

    (The University of Tokyo)

  • Yusuke Ogura

    (The University of Tokyo)

  • Makoto Nishiyama

    (The University of Tokyo
    The University of Tokyo)

  • Tomohisa Kuzuyama

    (The University of Tokyo
    The University of Tokyo)

Abstract

Type II polyketide synthases (PKSs) normally synthesize polycyclic aromatic compounds in nature, and the potential to elaborate further diverse skeletons was recently revealed by the discovery of a polyene subgroup. Here, we show a type II PKS machinery for the biosynthesis of a five-membered nonaromatic skeleton contained in the nonproteinogenic amino acid cispentacin and the plant toxin coronatine. We successfully produce cispentacin in a heterologous host and reconstruct its biosynthesis using seven recombinant proteins in vitro. Biochemical analyses of each protein reveal the unique enzymatic reactions, indicating that a heterodimer of type II PKS-like enzymes (AmcF–AmcG) catalyzes a single C2 elongation as well as a subsequent cyclization on the acyl carrier protein (AmcB) to form a key intermediate with a five-membered ring. The subsequent reactions, which are catalyzed by a collection of type II PKS-like enzymes, are also peculiar. This work further expands the definition of type II PKS and illuminates an unexplored genetic resource for natural products.

Suggested Citation

  • Genki Hibi & Taro Shiraishi & Tatsuki Umemura & Kenji Nemoto & Yusuke Ogura & Makoto Nishiyama & Tomohisa Kuzuyama, 2023. "Discovery of type II polyketide synthase-like enzymes for the biosynthesis of cispentacin," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43731-z
    DOI: 10.1038/s41467-023-43731-z
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    1. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Author Correction: Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    2. Mairi M. Littleson & Christopher M. Baker & Anne J. Dalençon & Elizabeth C. Frye & Craig Jamieson & Alan R. Kennedy & Kenneth B. Ling & Matthew M. McLachlan & Mark G. Montgomery & Claire J. Russell & , 2018. "Scalable total synthesis and comprehensive structure–activity relationship studies of the phytotoxin coronatine," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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