Peptide Natural Products I: RiPPs

Peptide-based natural products gain stability towards hydrolysis by amidases and peptidases when morphed into frameworks that resist rapid breakdown. There are two major modes of turning the hydrolytically susceptible amide linkages into stable scaffolds: (1) posttranslational modifications of ribosomally released protein precursors or (2) products from nonribosomal protein synthetase (NRPS) assembly lines. This chapter deals with the first, ribosomally-derived peptide precursors, known as RiPPs: ribosomal posttranslationally modified peptides. More than two dozen RiPP-directed, modified stable natural products have been defined over the past two decades, including thioether linkages in lanthionine residues in nisin, and thiazole and oxazole rings in thiopeptide antibiotics that arise from two-electron chemistry. Parallel one-electron chemistry yields α-thioethers (sactionines), cysteine sulfoxides in amatoxic mushrooms, and t-butyl groups in t-butylglycine residues in polytheonamides. Polytheonamides also have arrays of d-amino acid residues, arising from the l-amino acid peptide precursor by radical-based epimerizations. Lasso peptides have carboxy-terminal tails threaded through macrocyclic rings, functioning as nature's rotaxanes. Other macrocyclization strategies can be at work to convert linear, floppy precursor RiPP nascent peptides to cyclized, compact stable end products.