Discovery and Biosynthesis of Lipolasso Peptides Reveal CoA-transferase for Tyrosine Lipidation of Ribosomal Peptides

Lipopeptides are bioactive molecules typically produced via nonribosomal pathways. Only four types of lipidated ribosomally synthesized and post-translationally modified peptides (RiPPs) are known, all modified on amine groups by GNAT enzymes. We report an unprecedented biosynthetic gene cluster combining lasso peptide biosynthesis and acyl-CoA metabolism that produces a novel family of lipolasso peptides. A crotonobetainyl-CoA:carnitine CoA-transferase lipidates the Tyr hydroxy group within precursor peptides, revealing a distinct RiPP lipidation strategy. This work expands the paradigm of ribosomal lipopeptide biosynthesis.