The Utilization of Lanthipeptide Synthetases Is a General Strategy for the Biosynthesis of 2-Aminovinyl-Cysteine Motifs in Thioamitides*.

The biosynthesis of thioamitide natural products remains largely unknown, especially for the characteristic C-terminal 2-aminovinyl-cysteine (AviCys) motifs. Herein, we report the discovery that homologues of class-III lanthipeptide synthetases (LanKCt s) encoded outside putative thioamitide biosynthetic gene clusters (BGCs) fully dehydrate the precursor peptides. LanKCt enzymes bind tightly to cysteine decarboxylases encoded inside thioamitide BGCs and the resulting enzyme complex completes the macrocyclization of AviCys rings. Furthermore, LanKCt enzymes are present in the genomes of many thioamitide-producing strains and participate in the generation of AviCys macrocycles. Together, our study reveals an unprecedented system that lanthipeptide synthetases outside thioamitide BGCs participate in their biosynthesis by specific association with cysteine decarboxylases encoded inside BGCs.