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Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin.

ABSTRACT: The biosynthesis of the thiopeptide thiomuracin is a well-orchestrated process involving a multitude of posttranslational modifications. We show that six Cys residues of a precursor peptide are first cyclodehydrated and oxidized to thiazoles in an ordered, but nonlinear fashion that is leader-peptide-dependent. Then four alcohols are glutamylated and converted to alkenes in a C-to-N terminal directional process that is leader-peptide-independent. Finally, two of these alkenes undergo a formal [4 + 2] cycloaddition to form a trithiazole-substituted pyridine macrocycle. We describe here the factors that govern the substrate specificity and order of biosynthetic events that turn a ribosomal peptide into a powerful antibiotic.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC5148741 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin.

Zhang Zhengan Z Hudson Graham A GA Mahanta Nilkamal N Tietz Jonathan I JI van der Donk Wilfred A WA Mitchell Douglas A DA

Journal of the American Chemical Society 20161013 48

The biosynthesis of the thiopeptide thiomuracin is a well-orchestrated process involving a multitude of posttranslational modifications. We show that six Cys residues of a precursor peptide are first cyclodehydrated and oxidized to thiazoles in an ordered, but nonlinear fashion that is leader-peptide-dependent. Then four alcohols are glutamylated and converted to alkenes in a C-to-N terminal directional process that is leader-peptide-independent. Finally, two of these alkenes undergo a formal [4 ...[more]

PMID: 27700071

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