Radical Approach to Enzymatic β-Thioether Bond Formation

Alessio Caruso, Leah B. Bushin, Kenzie A. Clark, Ryan J. Martinie, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products that harbor diverse chemical functionalities, usually introduced via the action of a small number of tailoring enzymes. We have been interested in RiPP biosynthetic gene clusters that encode unusual metalloenzymes, as these may install as yet unknown alterations. Using a new bioinformatic search strategy, we recently identified an array of unexplored RiPP gene clusters that are quorum sensing-regulated and contain one or more uncharacterized radical S-adenosylmethionine (RaS) metalloenzymes. Herein, we investigate the reaction of one of these RaS enzymes and find that it installs an intramolecular β-thioether bond onto its substrate peptide by connecting a Cys-thiol group to the β-carbon of an upstream Asn residue. The enzyme responsible, NxxcB, accepts several amino acids in place of Asn and introduces unnatural β-thioether linkages at unactivated positions. This new transformation adds to the growing list of Nature's peptide macrocyclization strategies and expands the already impressive catalytic repertoire of the RaS enzyme superfamily.

Original languageEnglish (US)
Pages (from-to)990-997
Number of pages8
JournalJournal of the American Chemical Society
Volume141
Issue number2
DOIs
StatePublished - Jan 16 2019

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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