A natural prodrug activation mechanism in nonribosomal peptide synthesis

Cleavage of peptide precursors is well known for ribosomally produced sequences. Investigation of xenocoumacin biosynthesis now points to a similar function in nonribosomal peptide synthesis clusters, explaining one source of mismatches between genetic and chemical information. We have identified a new mechanism for the cleavage and activation of nonribosomally made peptides and peptide-polyketide hybrids that are apparently operational in several different bacteria. This process includes the cleavage of a precursor molecule by a membrane-bound and D -asparagine–specific peptidase, as shown here in the biosynthesis of the antibiotic xenocoumacin from Xenorhabdus nematophila .