Discovery and Biosynthesis of Dehydroalanine-Containing Lasso Peptide by a Hybrid Biosynthetic System

Lasso peptides and lanthipeptides are two major classes of ribosomally synthesized and post-translationally modified peptides (RiPPs), each defined by distinct post-translational modification (PTM) enzymes. We identify a hybrid biosynthetic gene cluster that integrates PTM enzymes from both pathways to produce a unique lasso peptide featuring a dehydroalanine residue and C-terminal Asp side-chain methylation. Elucidation of its biosynthesis uncovers unprecedented combinatorial RiPP maturation. This study establishes a paradigm for hybrid RiPP biosynthesis and enables discovery and engineering of novel RiPPs.