tRNA-dependent peptide bond formation by the transferase PacB in biosynthesis of the pacidamycin group of pentapeptidyl nucleoside antibiotics

Wenjun Zhang, Ioanna Ntai, Neil L. Kelleher, Christopher T. Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Pacidamycins are a family of uridyl tetra/pentapeptide antibiotics with antipseudomonal activities through inhibition of the translocase MraY in bacterial cell wall assembly. The biosynthetic gene cluster for pacidamycins has recently been identified through genome mining of the producer Streptomyces coeruleorubidus, and the highly dissociated nonribosomal peptide assembly line for the uridyl tetrapeptide scaffold of pacidamycin has been characterized. In this work a hypothetical protein PacB, conserved in known uridyl peptide antibiotics gene clusters, has been characterized by both genetic deletion and enzymatic analysis of the purified protein. PacB catalyzes the transfer of the alanyl residue from alanyl-tRNA to the N terminus of the tetrapeptide intermediate yielding a pentapeptide on the thio-templated nonribosomal peptide synthetase (NRPS) assembly line protein PacH. PacB thus represents a new group of tRNA-dependent peptide bond-forming enzymes in secondary metabolite biosynthesis in addition to the recently identified cyclodipeptide synthases. The characterization of PacB completes the assembly line reconstitution of pacidamycin pentapeptide antibiotic scaffolds, bridging the primary and secondary metabolic pathways by hijacking an aminoacyl-tRNA to the antibiotic biosynthetic pathway.

Original languageEnglish (US)
Pages (from-to)12249-12253
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number30
DOIs
StatePublished - Jul 26 2011

Keywords

  • Aminoacyltransferase
  • Peptidyl carrier protein
  • Uridyl pentapeptide

ASJC Scopus subject areas

  • General

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