Hijacking a Linaridin Biosynthetic Intermediate for Lanthipeptide Production
Hijacking a Linaridin Biosynthetic Intermediate for Lanthipeptide Production
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劫持 Linaridin 生物合成中间体用于羊毛硫肽生产
DOI：
10.1021/acschembio.2c00657
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发表时间：
2022
影响因子：
4
通讯作者：
Qi Zhang
中科院分区：
文献类型：
--
作者：
Leixia Chu;Jinduo Cheng;Chengzeng Zhou;Tianlu Mo;Xinjian Ji;Taoting Zhu;Jie Chen;Suze Ma;Jiangtao Gao;Qi Zhang
芳樟木苷和羊毛硫肽是属于核糖体合成和后修饰肽（RiPP）超家族的两类天然产物。虽然这两种RiPP类具有相似的结构基序，如脱氢氨基酸和基于硫醚的交联，但linaridins和lanthipeptide的生物合成涉及不同的酶。在这里，我们报告了一个新的lanthipeptide cypepeptin的重组菌株ofStreptomyces lividans，其中窝藏大多数的环孢霉素（一个原型linaridin）生物合成基因簇，但缺乏脱羧酶基因ypD的鉴定。与通常认为的cypemycin结构相反，在cypeptin和cypemycin中均观察到多个氨基酸和Z-脱氢丁炔，并且通过广泛的结构分析结合遗传敲除和诱变研究建立了每个氨基酸的立体化学。通过对cypemycin和cypeptin的比较分析，发现cypemycin的氨基乙烯基半胱氨酸（AviCys）部分在破坏M. luteus，其不能在功能上被结构上相似的lanthiocyanate部分取代。
Linaridins and lanthipeptides are two classes of natural products belonging to the ribosomally synthesized and posttranslationally modified peptide (RiPP) superfamily. Although these two RiPP classes share similar structural motifs such as dehydroamino acids and thioether-based cross-links, the biosynthesis of linaridins and lanthipeptides involved distinct sets of enzymes. Here, we report the identification of a novel lanthipeptide cypepeptin from a recombinant strain ofStreptomyces lividans, which harbors most of the cypemycin (a prototypic linaridin) biosynthetic gene cluster but lacks the decarboxylase genecypD. In contrast to the generally believed structure of cypemycin, multipled-amino acids and Z-dehydrobutyrines were observed in both cypepeptin and cypemycin, and the stereochemistry of each amino acid was established by the extensive structural analysis in combination with genetic knockout and mutagenesis studies. Comparative analysis of cypemycin and cypepeptin showed that the aminovinyl-cysteine (AviCys) moiety of cypemycin plays an essential role in disrupting the cell integrity ofM. luteus, which cannot be functionally substituted by the structurally similar lanthionine moiety.