Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin

Zhengan Zhang, Graham A. Hudson, Nilkamal Mahanta, Jonathan I. Tietz, Wilfred A. Van der Donk, Douglas A. Mitchell

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)15511-15514
Number of pages4
JournalJournal of the American Chemical Society
Issue number48
StatePublished - Dec 7 2016

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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