Aspartimide Modification in RiPP Natural Products

Multiple classes of ribosomally synthesized and post-translationally modified peptides (RiPPs) are chemically modified with an enigmatic functional group, the aspartimide. This modification occurs via the action of an enzyme related to the protein repair catalyst protein isoaspartyl methyltransferase (PIMT). Contrary to canonical PIMTs which methylate isoaspartate residues within a protein, RiPP-associated PIMTs directly methylate specific Asp residues within the RiPP substrate, resulting in the formation of an aspartimide. The biochemical details of aspartimidylation in three RiPP classes, lanthipeptides, lasso peptides, and graspetides, are described herein. The discovery of a new class of RiPPs, the imiditides or type I pamtides, with aspartimide as the class-defining post-translational modification, is also described. Finally, knowledge gaps as well as suggestions for future research are discussed.