New Insights into the Biosynthetic Logic of Ribosomally Synthesized and Post-translationally Modified Peptide Natural Products

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large group of structurally diverse natural products. Their biological activities and unique biosynthetic pathways have sparked a growing interest in RiPPs. Furthermore, the relatively low genetic complexity associated with RiPP biosynthesis makes them excellent candidates for synthetic biology applications. This Review highlights recent developments in the understanding of the biosynthesis of several bacterial RiPP family members, the use of the RiPP biosynthetic machinery for generating novel macrocyclic peptides, and the implementation of tools designed to guide the discovery and characterization of novel RiPPs. [Display omitted] •RiPPs provide an excellent platform to uncover unusual chemistry•The activities associated with RiPPs make them useful therapeutic molecules•Structural studies have started to uncover mechanisms of substrate recognition•Many novel RiPPs await discovery via genome-mining approaches Bacterial genome sequencing has demonstrated that ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products. Ortega and van der Donk discuss recent studies that have started to illuminate the often unprecedented mechanisms of RiPP biosynthetic enzymes.