Open AccessThe Isolation of Pyrroloformamide Congeners and Characterization of Their Biosynthetic Gene Cluster
Author(s) -
Wenqing Zhou,
Haoyu Liang,
Xiangjing Qin,
Dong-Yuan Cao,
Xia Zhu,
Jianhua Ju,
Ben Shen,
Yanwen Duan,
Yong Huang
Publication year - 2020
Publication title -
journal of natural products
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.976
H-Index - 139
eISSN - 1520-6025
pISSN - 0163-3864
DOI - 10.1021/acs.jnatprod.9b00321
Subject(s) - nonribosomal peptide , gene cluster , thioesterase , streptomyces , gene , biology , biosynthesis , biochemistry , streptomyces albus , bacteria , genetics
Dithiolopyrrolones are microbial natural products containing a disulfide or thiosulfonate bridge embedded in a unique bicyclic structure. By interfering with zinc ion homeostasis in living cells, they show strong antibacterial activity against a variety of bacterial pathogens, as well as potent cytotoxicity against human cancer cells. In the current study, two new dithiolopyrrolones, pyrroloformamide C ( 3 ) and pyrroloformamide D ( 4 ), were isolated from Streptomyces sp. CB02980, together with the known pyrroloformamides 1 and 2 . The biosynthetic gene cluster for pyrroloformamides was identified from Streptomyces sp. CB02980, which shared high sequence similarity with those of dithiolopyrrolones, including holomycin and thiolutin. Gene replacement of pyfE , which encodes a nonribosomal peptide synthetase (NRPS), abolished the production of 1 - 4 . Overexpression of pyfN , a type II thioesterase gene, increased the production of 1 and 2 . Genome neighborhood network analysis of the characterized and orphan gene clusters of dithiolopyrrolones revealed a unified mechanism for their biosynthesis, involving an iterative-acting NRPS and a set of conserved tailoring enzymes for the bicyclic core formation.