Peptide Prenylation Follows Divergent Substrate Engagement Rules

Abstract

Lipidation of ribosomally synthesized and post-translationally modified peptides (RiPPs) is a bioactivity conferring modification. In this study, we present evidence that prenylation of lanthipeptides─a widely distributed chemical family of RiPPs─proceeds with lanthipeptide prenyltransferases recognizing the entirety of the peptidic substrate including the N-terminal leader region of the RiPP precursor peptide. This mode of substrate recognition is markedly different from that of prenyltransferases that lipidate other RiPPs such as cyanobactins wherein the leader peptide is not engaged at all. Molecular recognition rules dictate catalysis, and we posit that leader peptide recognition imposes substrate selectivity upon lanthipeptide prenyltransferases and narrows their substrate scope as compared to the leader-free prenylation of cyanobactins which proceeds in a hyperpromiscuous manner.