Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases  

作　　者：Meng Wang Wen-Wei Li Zhe Cao Jianong Sun Jiang Xiong Si-Qin Tao Tinghong Lv Kun Gao Shangwen Luo Shi-Hui Dong 

机构地区：[1]State Key Laboratory of Applied Organic Chemistry,College of Chemistry and Chemical Engineering,Lanzhou University,Lanzhou 730000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2773-2785,共13页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.21907047,22077056,and 21907046);the Fundamental Research Funds for the Central Universities(No.lzujbky2019-ct03,lzujbky-2019-10,and lzujbky-2021-ct05,China).

摘　　要：Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides(RiPPs).Biosynthesis of RiPPs typically entails modification of hydrophilic residues,which substantially increases their chemical stability and bioactivity,albeit at the expense of reducing water solubility.To explore sulfonated RiPPs that may have improved solubility,we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase(ST),and discovered two distinctive biosynthetic gene clusters(BGCs)encoding both lanthipeptide synthetase(LanM)and ST.Upon expressing these BGCs,we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST.We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM.Both LanM and ST are promiscuous towards residues in the A ring,but ST displays strict regioselectivity toward Tyr5.The recognition of cyclic peptide by ST was further discussed.Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation.This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.

关 键 词：Lanthipeptides SULFOTRANSFERASES SULFONATION BIOSYNTHESIS Genome mining 

分 类 号：Q811.4[生物学—生物工程]