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

TitleStructure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink.
Publication TypeJournal Article
Year of Publication2015
AuthorsSchramma, KR, Bushin, LB, Seyedsayamdost, MR
JournalNat Chem
Volume7
Issue5
Pagination431-437
Date Published2015 May
ISSN1755-4349
KeywordsBiocatalysis, Chromatography, High Pressure Liquid, Lysine, Macrocyclic Compounds, Models, Molecular, Peptides, Cyclic, Spectrometry, Mass, Electrospray Ionization, Tryptophan
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.

DOI10.1038/nchem.2237
Alternate JournalNat Chem
PubMed ID25901822
PubMed Central IDPMC4443489
Grant ListR00 GM098299 / GM / NIGMS NIH HHS / United States
GM098299 / GM / NIGMS NIH HHS / United States