Biosynthesis-guided discovery reveals enteropeptins as alternative sactipeptides containing N-methylornithine

Kenzie A. Clark, Brett C. Covington, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


The combination of next-generation DNA sequencing technologies and bioinformatics has revitalized natural product discovery. Using a bioinformatic search strategy, we recently identified ∼600 gene clusters in otherwise overlooked streptococci that code for ribosomal peptide natural products synthesized by radical S-adenosylmethionine enzymes. These grouped into 16 subfamilies and pointed to an unexplored microbiome biosynthetic landscape. Here we report the structure, biosynthesis and function of one of these natural product groups, which we term enteropeptins, from the gut microbe Enterococcus cecorum. We show three reactions in the biosynthesis of enteropeptins that are each catalysed by a different family of metalloenzymes. Among these, we characterize the founding member of a widespread superfamily of Fe–S-containing methyltransferases, which, together with an Mn2+-dependent arginase, installs N-methylornithine in the peptide sequence. Biological assays with the mature product revealed bacteriostatic activity only against the producing strain, extending an emerging theme of fratricidal or self-inhibitory metabolites in microbiome firmicutes. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)1390-1398
Number of pages9
JournalNature chemistry
Issue number12
StatePublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Chemical Engineering


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