Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Molecular Conformation
  • Peptide Synthases / chemistry
  • Peptide Synthases / metabolism*
  • Peptides, Cyclic / biosynthesis*
  • Peptides, Cyclic / chemistry
  • Substrate Specificity
  • Thiazoles / chemistry


  • Peptides, Cyclic
  • Thiazoles
  • thiomuracin A
  • Peptide Synthases