Thioamitide natural products are a group of ribosomally synthesized and post-translational modified peptides (RiPPs) with potent antiproliferative and pro-apoptotic activities. Their biosynthesis remains largely unknown, especially for the characteristic C-terminal 2-aminovinyl-cysteine (AviCys) motifs. Herein, we report the discovery that homologs of class III lanthipeptide synthetases (LanKC t s) encoded outside putative thioamitide biosynthetic gene clusters (BGCs) fully dehydrate the precursor peptides. Remarkably, LanKCt enzymes bind tightly to cysteine decarboxylases encoded inside thioamitide BGCs, and the resulting enzyme complex complete the macrocyclization of AviCys rings. Furthermore, our studies re... More
Thioamitide natural products are a group of ribosomally synthesized and post-translational modified peptides (RiPPs) with potent antiproliferative and pro-apoptotic activities. Their biosynthesis remains largely unknown, especially for the characteristic C-terminal 2-aminovinyl-cysteine (AviCys) motifs. Herein, we report the discovery that homologs of class III lanthipeptide synthetases (LanKC t s) encoded outside putative thioamitide biosynthetic gene clusters (BGCs) fully dehydrate the precursor peptides. Remarkably, LanKCt enzymes bind tightly to cysteine decarboxylases encoded inside thioamitide BGCs, and the resulting enzyme complex complete the macrocyclization of AviCys rings. Furthermore, our studies reveal that LanKC t enzymes are present in the genomes of many thioamitide-producing strains and participate in the generation of AviCys macrocycles, therefore serving as a general biosynthetic strategy. 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, and thus paves the way for the bioengineering of this class of bioactive natural products.
