Mechanistic Investigations of Lysine-Tryptophan Cross-Link Formation Catalyzed by Streptococcal Radical S-Adenosylmethionine Enzymes

Kelsey R. Schramma, Clarissa C. Forneris, Alessio Caruso, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Streptide is a ribosomally synthesized and post-translationally modified peptide with a unique cyclization motif consisting of an intramolecular lysine-tryptophan cross-link. Three radical S-adenosylmethionine enzymes, StrB, AgaB, and SuiB from different species of Streptococcus, have been shown to install this modification onto their respective precursor peptides in a leader-dependent fashion. Herein, we conduct detailed investigations to differentiate among several plausible mechanistic proposals, specifically addressing radical versus electrophilic addition to the indole during cross-link formation, the role of substrate side chains in binding in the enzyme active site, and the identity of the catalytic base in the reaction cycle. Our results are consistent with a radical electrophilic aromatic substitution mechanism for the key carbon-carbon bond-forming step. They also elaborate on other mechanistic features that underpin this unique and synthetically challenging post-translational modification.

Original languageEnglish (US)
Pages (from-to)461-468
Number of pages8
JournalBiochemistry
Volume57
Issue number4
DOIs
StatePublished - Jan 30 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry

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