Bicyclostreptins are radical SAM enzyme-modified peptides with unique cyclization motifs.

TitleBicyclostreptins are radical SAM enzyme-modified peptides with unique cyclization motifs.
Publication TypeJournal Article
Year of Publication2022
AuthorsBushin, LB, Covington, BC, Clark, KA, Caruso, A, Seyedsayamdost, MR
JournalNat Chem Biol
Date Published2022 Oct
KeywordsAmides, Bacterial Proteins, Biological Products, Carbon, Cyclization, Ethers, Humans, Metalloproteins, Nitrogen, Peptides, S-Adenosylmethionine, Streptococcus

<p>Microbial natural products comprise diverse architectures that are generated by equally diverse biosynthetic strategies. In peptide natural products, amino acid sidechains are frequently used as sites of modification to generate macrocyclic motifs. Backbone amide groups, among the most stable of biological moieties, are rarely used for this purpose. Here we report the discovery and biosynthesis of bicyclostreptins-peptide natural products from Streptococcus spp. with an unprecedented structural motif consisting of a macrocyclic β-ether and a heterocyclic sp-sp linkage between a backbone amide nitrogen and an adjacent α-carbon. Both reactions are installed, in that order, by two radical S-adenosylmethionine (RaS) metalloenzymes. Bicyclostreptins are produced at nM concentrations and are potent growth regulation agents in Streptococcus thermophilus. Our results add a distinct and unusual chemotype to the growing family of ribosomal peptide natural products, expand the already impressive catalytic scope of RaS enzymes, and provide avenues for further biological studies in human-associated streptococci.</p>

Alternate JournalNat Chem Biol
PubMed ID35953547
PubMed Central ID6686864
Grant ListNSF GRFP / / National Science Foundation (NSF) /
NSF CAREER Award 1847932 / / National Science Foundation (NSF) /