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

  • Nat Commun. 2023 Dec 6;14(1):8065. doi: 10.1038/s41467-023-43731-z.
Genki Hibi  1 ,  Taro Shiraishi  1  2 ,  Tatsuki Umemura  1 ,  Kenji Nemoto  1 ,  Yusuke Ogura  1 ,  Makoto Nishiyama  1  2 ,  Tomohisa Kuzuyama  3  4
Affiliations
  • 1. Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.
  • 2. Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.
  • 3. Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan. [email protected].
  • 4. Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan. [email protected].
PMID: 38052796 DOI: 10.1038/s41467-023-43731-z
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.

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