Streptide, a Microbial Cyclic Peptide Containing a Novel Post-Translational Modification

Abstract

Natural products represent a prolific source of therapeutic compounds. While these have mostly focused on non-ribosomally-generated peptides and polyketides, the recent explosion in bacterial genome sequences has revealed a previously underestimated number of ribosomally-generated peptides. In general, these are synthesized as precursors, which are acted upon by unique tailoring enzymes, which install structurally complex modifications that convert mundane peptides into highly bioactive molecules. In this work, I have characterized one such biosynthetic locus, in which a precursor peptide is tailored by a putative radical SAM enzyme, StrB. To examine the modification installed by StrB, the product of the str gene cluster was purified using mass- and UV/Vis-guided fractionation. Multi-dimensional NMR analysis coupled with high resolution MS allowed structural elucidation of a novel peptide, which has been named streptide. This peptide contains an unprecedented post-translational modification encompassing C-C bond formation between Cβ of Lys and Cζ2 of Trp. Computational studies confirmed this structure and have begun to uncover the geometric constraints imposed by this unusual cyclization.