Biosynthesis of the RiPP trojan horse nucleotide antibiotic microcin C is directed by the N-formyl of the peptide precursor

Shi Hui Dong, Alexey Kulikovsky, Inna Zukher, Paola Estrada, Svetlana Dubiley, Konstantin Severinov, Satish K. Nair

Research output: Contribution to journalArticle

Abstract

Microcin C7 (McC) is a peptide antibiotic modified by a linkage of the terminal isoAsn amide to AMP via a phosphoramidate bond. Post-translational modification on this ribosomally produced heptapeptide precursor is carried out by MccB, which consumes two equivalents of ATP to generate the N-P linkage. We demonstrate that MccB only efficiently processes the precursor heptapeptide that retains the N-formylated initiator Met (fMet). Binding studies and kinetic measurements evidence the role of the N-formyl moiety. Structural data show that the N-formyl peptide binding results in an ordering of residues in the MccB “crossover loop”, which dictates specificity in homologous ubiquitin activating enzymes. The N-formyl peptide exhibits substrate inhibition, and cannot be displaced from MccB by the desformyl counterpart. Such substrate inhibition may be a strategy to avert unwanted McC buildup and avert toxicity in the cytoplasm of producing organisms.

Original languageEnglish (US)
Pages (from-to)2391-2395
Number of pages5
JournalChemical Science
Volume10
Issue number8
DOIs
StatePublished - Feb 28 2019

ASJC Scopus subject areas

  • Chemistry(all)

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