N-Acylation during glidobactin biosynthesis by the tridomain nonribosomal peptide synthetase module GlbF

Heidi J. Imker, Daniel Krahn, Jérôme Clerc, Markus Kaiser, Christopher T. Walsh

Research output: Contribution to journalArticle

Abstract

Glidobactins are hybrid NRPS-PKS natural products that function as irreversible proteasome inhibitors. A variety of medium chain 2(E),4(E)-diene fatty acids N-acylate the peptidolactam core and contribute significantly to the potency of proteasome inhibition. We have expressed the initiation NRPS module GlbF (C-A-T) in Escherichia coli and observe soluble active protein only on coexpression with the 8 kDa MbtH-like protein, GlbE. Following adenylation and installation of Thr as a T-domain thioester, the starter condensation domain utilizes fatty acyl-CoA donors to acylate the Thr1 amino group and generate the fatty acyl-Thr1-S-pantetheinyl-GlbF intermediate to be used in subsequent chain elongation. Previously proposed to be mediated via acyl carrier protein fatty acid donors, direct utilization of fatty acyl-CoA donors for N-acylation of T-domain tethered amino acids is likely a common strategy for chain initiation in NRPS-mediated lipopeptide biosynthesis.

Original languageEnglish (US)
Pages (from-to)1077-1083
Number of pages7
JournalChemistry and Biology
Volume17
Issue number10
DOIs
StatePublished - Oct 29 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'N-Acylation during glidobactin biosynthesis by the tridomain nonribosomal peptide synthetase module GlbF'. Together they form a unique fingerprint.

  • Cite this