Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink

Kelsey R. Schramma, Leah B. Bushin, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Streptococcal bacteria use peptide signals as a means of intraspecies communication. These peptides can contain unusual post-translational modifications, providing opportunities for expanding our understanding of nature's chemical and biosynthetic repertoires. Here, we have combined tools from natural products discovery and mechanistic enzymology to elucidate the structure and biosynthesis of streptide, a streptococcal macrocyclic peptide. We show that streptide bears an unprecedented post-translational modification involving a covalent linkage between two unactivated carbons within the side chains of lysine and tryptophan. The biosynthesis of streptide was addressed by genetic and biochemical studies. The former implicated a new SPASM-domain-containing radical SAM enzyme StrB, while the latter revealed that StrB contains two [4Fe-4S] clusters and installs the unusual lysine-to-tryptophan crosslink in a single step. By intramolecularly stitching together the side chains of lysine and tryptophan, StrB provides a new route for biosynthesizing macrocyclic peptides.

Original languageEnglish (US)
Pages (from-to)431-437
Number of pages7
JournalNature chemistry
Volume7
Issue number5
DOIs
StatePublished - May 1 2015

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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