Lysine-Tryptophan-Crosslinked Peptides Produced by Radical SAM Enzymes in Pathogenic Streptococci.

TitleLysine-Tryptophan-Crosslinked Peptides Produced by Radical SAM Enzymes in Pathogenic Streptococci.
Publication TypeJournal Article
Year of Publication2017
AuthorsSchramma, KR, Seyedsayamdost, MR
JournalACS Chem Biol
Volume12
Issue4
Pagination922-927
Date Published2017 04 21
ISSN1554-8937
KeywordsAmino Acid Sequence, Electron Spin Resonance Spectroscopy, Enzymes, Lysine, Peptides, S-Adenosylmethionine, Sequence Homology, Amino Acid, Spectrophotometry, Ultraviolet, Streptococcus agalactiae, Streptococcus suis, Tryptophan
Abstract

Macrocycles represent a common structural framework in many naturally occurring peptides. Several strategies exist for macrocyclization, and the enzymes that incorporate them are of great interest, as they enhance our repertoire for creating complex molecules. We recently discovered a new peptide cyclization reaction involving a crosslink between the side chains of lysine and tryptophan that is installed by a radical SAM enzyme. Herein, we characterize relatives of this metalloenzyme from the pathogens Streptococcus agalactiae and Streptococcus suis. Our results show that the corresponding enzymes, which we call AgaB and SuiB, contain multiple [4Fe-4S] clusters and catalyze Lys-Trp crosslink formation in their respective substrates. Subsequent high-resolution-MS and 2D-NMR analyses located the site of macrocyclization. Moreover, we report that AgaB can accept modified substrates containing natural or unnatural amino acids. Aside from providing insights into the mechanism of this unusual modification, the substrate promiscuity of AgaB may be exploited to create diverse macrocyclic peptides.

DOI10.1021/acschembio.6b01069
Alternate JournalACS Chem. Biol.
PubMed ID28191919