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J Am Chem Soc. 2016 Dec 7;138(48):15511-15514. doi: 10.1021/jacs.6b08987. Epub 2016 Oct 13.

Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin.

Author information

1
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
2
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA.
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Contributed equally

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.

PMID:
27700071
PMCID:
PMC5148741
DOI:
10.1021/jacs.6b08987
[Indexed for MEDLINE]
Free PMC Article

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