Open AccessNatural Occurrence of Hybrid Polyketides from Two Distinct Biosynthetic Pathways in Streptomyces pactum
Author(s) -
Wei Zhou,
Priyapan Posri,
Taifo Mahmud
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.0c00982
Subject(s) - polyketide , polyketide synthase , streptomyces , gene cluster , biosynthesis , biology , biochemistry , thioesterase , gene , chemistry , stereochemistry , genetics , bacteria
Nature has always been seemingly limitless in its ability to create new chemical entities. It provides vastly diverse natural compounds through a biomanufacturing process that involves myriads of biosynthetic machineries. Here we report a case of unusual formations of hybrid natural products that are derived from two distinct polyketide biosynthetic pathways, the NFAT-133 and conglobatin pathways, in Streptomyces pactum ATCC 27456. Their chemical structures were determined by NMR spectroscopy, mass spectrometry, and chemical synthesis. Genome sequence analysis and gene inactivation experiments uncovered the biosynthetic gene cluster of conglobatin in S. pactum . Biochemical studies of the recombinant thioesterase (TE) domain of the conglobatin polyketide synthase (PKS) as well as its S74A mutant revealed that the formation of these hybrid compounds requires an active TE domain. We propose that NFAT-133 can interfere with conglobatin biosynthesis by reacting with the TE-domain-bound intermediates in the conglobatin PKS assembly line to form hybrid NFAT-133/conglobatin products.