Nature has evolved a wide array of strategies for endowing secondary metabolites with bioactivity. The modification of peptides in particular encompasses a large assortment of varied cyclization methods, and the responsible enzymes can often be seen in the biosynthetic gene clusters of the corresponding metabolites. Our lab recently discovered one such peptide, streptide, in <i>Streptococcus thermophilus</i>, which is produced in a quroum sensing-controlled fashion. In solving the structure of streptide, our lab determined the presence of an unprecedented carbon-carbon crosslink between the beta-carbon of a lysine residue and the indole-C7 of a tryptophan side chain. We further showed that the formation of this unusual bond is dependent on a gene that encodes a radical SAM enzyme. Herein we show that this enzyme, dubbed StrB, contains a number of [4Fe-4S] clusters including the active site cluster, which reductively cleaves SAM to generate a 5'-deoxyadenosyl radical to initiate a radical reaction. Using in vitro assays, we established that StrB installs the novel Lys-to-Trp crosslink in a single step, demonstrating a new route for peptide cyclization. A mechanism for this unusual reaction is proposed and our investigations into similar biosynthetic pathways in pathogenic <i>Streptococci </i>are also outlined.

Unusual Lys-to-Trp crosslink catalyzed by a radical SAM enzyme

251st National Meeting (2016)

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