Biosynthesis of thiocarboxylic acid-containing natural products

Liao-Bin Dong, Jeffrey D. Rudolf, Dingding Kang, Nan Wang, Cyndi Qixin He, Youchao Deng, Yong Huang, K. N. Houk, Yanwen Duan and Ben Shen ()
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Liao-Bin Dong: The Scripps Research Institute
Jeffrey D. Rudolf: The Scripps Research Institute
Dingding Kang: Central South University
Nan Wang: The Scripps Research Institute
Cyndi Qixin He: University of California
Youchao Deng: Central South University
Yong Huang: Central South University
K. N. Houk: University of California
Yanwen Duan: Central South University
Ben Shen: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.

Date: 2018
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DOI: 10.1038/s41467-018-04747-y

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