Thiocysteine lyases as polyketide synthase domains installing hydropersulfide into natural products and a hydropersulfide methyltransferase

Song Meng, Andrew D. Steele, Wei Yan, Guohui Pan, Edward Kalkreuter, Yu-Chen Liu, Zhengren Xu and Ben Shen ()
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Song Meng: The Scripps Research Institute
Andrew D. Steele: The Scripps Research Institute
Wei Yan: The Scripps Research Institute
Guohui Pan: The Scripps Research Institute
Edward Kalkreuter: The Scripps Research Institute
Yu-Chen Liu: The Scripps Research Institute
Zhengren Xu: The Scripps Research Institute
Ben Shen: The Scripps Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Nature forms S-S bonds by oxidizing two sulfhydryl groups, and no enzyme installing an intact hydropersulfide (-SSH) group into a natural product has been identified to date. The leinamycin (LNM) family of natural products features intact S-S bonds, and previously we reported an SH domain (LnmJ-SH) within the LNM hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line as a cysteine lyase that plays a role in sulfur incorporation. Here we report the characterization of an S-adenosyl methionine (SAM)-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin (GNM) biosynthesis, discovery of hydropersulfides as the nascent products of the GNM and LNM hybrid NRPS-PKS assembly lines, and revelation of three SH domains (GnmT-SH, LnmJ-SH, and WsmR-SH) within the GNM, LNM, and weishanmycin (WSM) hybrid NRPS-PKS assembly lines as thiocysteine lyases. Based on these findings, we propose a biosynthetic model for the LNM family of natural products, featuring thiocysteine lyases as PKS domains that directly install a -SSH group into the GNM, LNM, or WSM polyketide scaffold. Genome mining reveals that SH domains are widespread in Nature, extending beyond the LNM family of natural products. The SH domains could also be leveraged as biocatalysts to install an -SSH group into other biologically relevant scaffolds.

Date: 2021
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DOI: 10.1038/s41467-021-25798-8

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