Discovery of a family of γ-aminobutyrate ureas via rational derepression of a silent bacterial gene cluster

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Gaburedins, a family of g-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 pro fi les 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 con firmed by total synthesis. The other metabolites were confi rmed 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 fi rst report to disclose the discovery of novel natural products via rational deletion of a putative pathway-specifi c regulatory gene.