In Vitro Biosynthesis of the Core Scaffold of the Thiopeptide Thiomuracin

Graham A. Hudson, Zhengan Zhang, Jonathan I. Tietz, Douglas A. Mitchell, Wilfred A. Van Der Donk

Research output: Contribution to journalArticle

Abstract

Thiopeptides are potent antibiotics that inhibit protein synthesis. They are made by a remarkable post-translational modification process that transforms a linear peptide into a polycyclic structure. We present here the in vitro biosynthesis of the core scaffold of thiomuracin catalyzed by six proteins. We show that cyclodehydration precedes dehydration, and that dehydration is catalyzed by two proteins in a tRNAGlu-dependent manner. The enzyme that generates the pyridine core from two dehydroalanines ejects the leader peptide as a C-terminal carboxamide. Mutagenesis studies of the enzyme TbtD identified important residues for a formal [4+2] cycloaddition process. The core structure of thiomuracin exhibits similar antimicrobial activity to other known congeners, illustrating that in vitro biosynthesis is a viable route to potent antibiotics that can be explored for the rapid and renewable generation of analogues.

Original languageEnglish (US)
Pages (from-to)16012-16015
Number of pages4
JournalJournal of the American Chemical Society
Volume137
Issue number51
DOIs
StatePublished - Dec 30 2015

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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