The creatininase homolog MftE from Mycobacterium smegmatis catalyzes a peptide cleavage reaction in the biosynthesis of a novel ribosomally synthesized post-translationally modified peptide (RiPP)

Nathan A. Bruender, Vahe Bandarian

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Most ribosomally synthesized and post-translationally modified peptide (RiPP) natural products are processed by tailoring enzymes to create complex natural products that are still recognizably peptide-based. However, some tailoring enzymes dismantle the peptide en route to synthesis of small molecules. A small molecule natural product of as yet unknown structure, mycofactocin, is thought to be synthesized in this way via the mft gene cluster found in many strains of mycobacteria. This cluster harbors at least six genes, which appear to be conserved across species. We have previously shown that one enzyme from this cluster, MftC, catalyzes the oxidative decarboxylation of the C-terminal Tyr of the substrate peptide MftA in a reaction that requires the MftB protein. Herein we show that mftE encodes a creatininase homolog that catalyzes cleavage of the oxidatively decarboxylated MftA peptide to liberate its final two residues, including the C-terminal decarboxylated Tyr (VY∗). Unlike MftC, which requires MftB for function, MftE catalyzes the cleavage reaction in the absence of MftB. The identification of this novel metabolite, VY∗, supports the notion that the mft cluster is involved in generating a small molecule from the MftA peptide. The ability to produce VY∗ from MftA by in vitro reconstitution of the activities of MftB, MftC, and MftE sets the stage for identification of the novel metabolite that results from the proteins encoded by the mft cluster.

Original languageEnglish (US)
Pages (from-to)4371-4381
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number10
DOIs
StatePublished - Mar 10 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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