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Lanthipeptide Synthetases Participate the Biosynthesis of 2-Aminovinyl-Cysteine Motifs in Thioamitides

By HUAN WANG, Jingxia Lu, Yuan Wu, Jiao Li, Yuqing Li, Zengbing Bai, Jie Zheng, Jiapeng Zhu

Posted 21 Aug 2020
bioRxiv DOI: 10.1101/2020.08.21.260323

Thioamitides are a group of ribosomally synthesized and post-translational modified peptides with potent antiproliferative and proapoptotic 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 (LanKCts)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 complex complete the macrocyclization of AviCys rings. Furthermore, LanKCt enzymes are present in the genomes of many thioamitide-producing strains and are functional when in complex with cysteine decarboxylases to produce AviCys macrocycles. Thus, our study reveals the participation of lanthipeptide synthetases as a general strategy for dehydration and AviCys formation during thioamitides biosynthesis and thus paves the way for the bioengineering of this class of bioactive natural products. ### Competing Interest Statement The authors have declared no competing interest.

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