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

Genki Hibi, Taro Shiraishi, Tatsuki Umemura, Kenji Nemoto, Yusuke Ogura, Makoto Nishiyama and Tomohisa Kuzuyama ()
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Genki Hibi: The University of Tokyo
Taro Shiraishi: 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
Tomohisa Kuzuyama: The University of Tokyo

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43731-z

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