Abstract
Gaburedins, a family of γ-aminobutyrate (GABA)-derived ureas, have been discovered by deletion of gbnR, an arpA-like putative transcriptional repressor in Streptomyces venezuelae ATCC 10712. Comparison of metabolite profiles in the wild type and mutant strains revealed six metabolites in the mutant that are lacking from the wild type. The structure of gaburedin A was established by HRMS combined with 1- and 2-D NMR spectroscopy and was confirmed by total synthesis. The other metabolites were confirmed as congeners using HRMS, MS/MS and feeding of putative biosynthetic precursors. Two genes, gbnA and gbnB, are proposed to be involved in gaburedin biosynthesis. Consistent with this hypothesis, deletion of gbnB in the gbnR mutant abolished gaburedin production. This is the first report to disclose the discovery of novel natural products via rational deletion of a putative pathway-specific regulatory gene.
Highlights
View Article OnlineConsistent with this hypothesis, deletion of gbnB in the gbnR mutant abolished gaburedin production
Discovery of a family of γ-aminobutyrate ureas via rational derepression of a silent bacterial gene cluster
Mining the genomes of Streptomyces bacteria has revealed a vast number of gene clusters proposed to direct the biosynthesis of novel antibiotic-like natural products
Summary
Consistent with this hypothesis, deletion of gbnB in the gbnR mutant abolished gaburedin production This is the first report to disclose the discovery of novel natural products via rational deletion of a putative pathway-specific regulatory gene. ArpA-like proteins have been shown to sense and respond to speci c ligands such as g-butyrolactones, 2-alkyl-4-hydroxymethylfuran-3-carboxylic acids (AHFCAs) and butenolides.[13,14,15,16,17] In particular, the methylenomycin furans, assembled by the products of the mmfLHP genes, act as methylenomycin production inducers in S. coelicolor These signaling molecules are thought to interact with the ArpA-like transcriptional repressors MmfR and/ or MmyR.[12,14] Even though MmfR and MmyR share 35% identity and 56% similarity, the phenotypes of mmfR and mmyR mutants are distinct.
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