Genome Mining of Myxopeptins Reveals a Class of Lanthipeptide-Derived Linear Dehydroamino Acid-Containing Peptides from sp. MCy9171.

Myxobacteria exhibit a substantial capacity to produce bioactive natural products. The biosynthetic potential of ribosomally synthesized and post-translationally modified peptides (RiPPs) from myxobacteria remains largely underexplored. In our study, we identified a novel lanthipeptide-like biosynthetic pathway, from sp. MCy9171, which was reconstituted in and proteolysis. Structural elucidation demonstrated that a series of dehydroamino acids were installed by an orphan McyB dehydratase onto the five McyA core peptides, named myxopeptins. Interestingly, compared with the canonical biosynthetic machinery of class I lanthipeptides, neither Cys residues existed in the diverse core regions, nor any LanC cyclase homologue was encoded in the pathway. Thus, we propose myxopeptins as members of a new subclass of RiPPs, named lanthipeptide-derived linear dehydroamino acid-containing peptides (LDPs), which contain dehydrated amino acids as the class-defining post-translational modifications. Furthermore, sequence similarity network (SSN) analysis revealed the wide distribution of the biosynthetic potential of LDPs in various microbial phyla, implying a co-evolutionary scenario between the precursor peptide and class I lanthipeptide biosynthetic enzymes.