Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria
Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria
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DOI：
10.1074/jbc.m115.712612
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发表时间：
2016-04-08
影响因子：
4.8
通讯作者：
Mourey, Lionel
中科院分区：
文献类型：
--
作者：
Guillet, Valerie;Galandrin, Segolene;Mourey, Lionel
霉菌酸是分枝杆菌细胞膜的重要组成部分，其生物合成途径是一线抗结核药物的靶点之一。这条途径包含一些潜在的目标，包括一些最近才发现的、尚未探索的目标。一个这样的靶点，FadD32，是激活长分生菌链所必需的，对分枝杆菌的生长是必不可少的。我们在这里报告了四个FadD32同源物的深入的生化、生物物理和结构特征，包括来自结核分枝杆菌和海洋分枝杆菌的非常同源的酶。对两个烷基腺苷酸抑制剂配合物的结构的测定提供了关于酶的活性部位和相关疏水通道的直接信息，提供了前所未有的详细信息，为了解烷基腺苷和二芳基香豆素的结构-功能关系和抑制机制提供了新的线索。这项工作应该为合理设计FadD32的抑制剂铺平道路，FadD32是一个非常有希望的药物靶点。
Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is one of the targets of first-line antituberculous drugs. This pathway contains a number of potential targets, including some that have been identified only recently and have yet to be explored. One such target, FadD32, is required for activation of the long meromycolic chain and is essential for mycobacterial growth. We report here an in-depth biochemical, biophysical, and structural characterization of four FadD32 orthologs, including the very homologous enzymes from Mycobacterium tuberculosis and Mycobacterium marinum. Determination of the structures of two complexes with alkyl adenylate inhibitors has provided direct information, with unprecedented detail, about the active site of the enzyme and the associated hydrophobic tunnel, shedding new light on structure-function relationships and inhibition mechanisms by alkyl adenylates and diarylated coumarins. This work should pave the way for the rational design of inhibitors of FadD32, a highly promising drug target.