Accessing and exploring the unusual chemistry by radical SAM-RiPP enzymes

Abstract

Radical SAM enzymes involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides catalyze unusual transformations that lead to unique peptide scaffolds and building blocks. Several natural products from these pathways show encouraging antimicrobial activities and represent next-generation therapeutics for infectious diseases. These systems are uniquely configured to benefit from genome-mining approaches because minimal substrate and cognate modifying enzyme expression can reveal unique, chemically complex transformations that outperform late-stage chemical reactions. This report highlights the main strategies used to reveal these enzymatic transformations, which have relied mainly on genome mining using enzyme-first approaches. We describe the general biosynthetic components for rSAM enzymes and highlight emerging approaches that may broaden the discovery and study of rSAM-RiPP enzymes. The large number of uncharacterized rSAM proteins, coupled with their unpredictable transformations, will continue to be an essential and exciting resource for enzyme discovery.