Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid
Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid
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DOI：
10.1016/j.molcel.2005.02.009
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发表时间：
2005-03-04
期刊：
影响因子：
16
通讯作者：
Gokhale, RS
中科院分区：
文献类型：
--
作者：
Trivedi, OA;Arora, P;Gokhale, RS
结核分枝杆菌细胞包膜是一个具有迷人分子结构的生物活性脂质的宝库。虽然遗传学研究暗示了一系列基因参与复杂脂质的生物合成，但它们的机制、结构和生化原理尚未得到研究。在这里，我们剖析了一种毒力脂质酞醇二真菌酸酯（PDIM）生物合成的分子逻辑。无细胞重构研究表明，通常参与次级代谢物生物合成的聚酮合成酶负责分枝杆菌中复杂脂质的生成。我们发现，PapA5蛋白直接将蛋白结合的真菌酸类似物转移到邻苯二酚上，催化最后的酯化步骤。基于对Pps簇蛋白生物学功能的精确鉴定，我们合理地制备了一种非甲基化的真菌酸酯变体。除了阐明pdim产生化学异质性的机制外，本研究还提出了一种通过改变分枝杆菌表面涂层来探索宿主-病原体相互作用的有吸引力的方法。
Mycobacterium tuberculosis cell envelope is a treasure house of biologically active lipids of fascinating molecular architecture. Although genetic studies have alluded to an array of genes in biosynthesis of complex lipids, their mechanistic, structural, and biochemical principles have not been investigated. Here, we have dissected the molecular logic underlying the biosynthesis of a virulence lipid phthiocerol dimycocerosate (PDIM). Cell-free reconstitution studies demonstrate that polyketide synthases, which are usually involved in the biosynthesis of secondary metabolites, are responsible for generating complex lipids in mycobacteria. We show that PapA5 protein directly transfers the protein bound mycocerosic acid analogs on phthiocerol to catalyze the final esterification step. Based on precise identification of biological functions of proteins from Pps cluster, we have rationally produced a nonmethylated variant of mycocerosate esters. Apart from elucidating mechanisms that generate chemical heterogeneity with PDIMs, this study also presents an attractive approach to explore host-pathogen interactions by altering mycobacterial surface coat.