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首页> 外文期刊>Journal of Molecular Biology >Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis
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Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

机译：结核分枝杆菌中外壳脂质生物合成所需的TESA生物化学和结构表征

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With the high number of patients infected by tuberculosis and the sharp increase of drug-resistant tuberculosis cases, developing new drugs to fight this disease has become increasingly urgent. In this context, analogs of the naturally occurring enolphosphates Cyclipostins and Cyclophostin (CyC analogs) offer new therapeutic opportunities. The CyC analogs display potent activity both in vitro and in infected macrophages against several pathogenic mycobacteria including Mycobacterium tuberculosis and Mycobacterium abscessus. Interestingly, these CyC inhibitors target several enzymes with active-site serine or cysteine residues that play key roles in mycobacterial lipid and cell wall metabolism. Among them, TesA, a putative thioesterase involved in the synthesis of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), has been identified. These two lipids (PDIM and PGL) are non-covalently bound to the outer cell wall in several human pathogenic mycobacteria and are important virulence factors. Herein, we used biochemical and structural approaches to validate TesA as an effective pharmacological target of the CyC analogs. We confirmed both thioesterase and esterase activities of TesA, and showed that the most active inhibitor CyC17, binds covalently to the catalytic Ser104 residue leading to a total loss of enzyme activity. These data were supported by the X-ray structure, obtained at a 2.6-angstrom resolution, of a complex in which CyC17 is bound to TesA. Our study provides evidence that CyC17 inhibits the activity of TesA, thus paving the way to a new strategy for impairing the PDIM and PGL biosynthesis, potentially decreasing the virulence of associated mycobacterial species. (C) 2018 Elsevier Ltd. All rights reserved.
机译：随着结核病感染的大量患者和耐药结核病病例的急剧增加，开发新药来对抗这种疾病已经越来越紧迫。在这种情况下，天然存在的丙磷酸盐环刺蛋白和环糊精（Cyc类似物）的类似物提供了新的治疗机会。 CYC类似物在体外和感染的巨噬细胞中显示有效的活性，针对几种病原分枝杆菌，包括结核病和分枝杆菌脓肿。有趣的是，这些Cyc抑制剂靶向几种酶，其具有活性位点丝氨酸或半胱氨酸残基，可在分枝杆菌和细胞壁代谢中起关键作用。其中，已经鉴定了参与合成酞菁二核酸酯（PDIMS）和酚醛糖醇（PGLS）的替代硫酯酶。这两种脂质（PDIM和PGL）在几个人致病性分枝杆菌中非共价结合到外部细胞壁上，并且是重要的毒力因子。在此，我们使用生化和结构方法来验证特萨作为CYC类似物的有效药理学靶标。我们证实了TESA的硫酯酶和酯酶活性，并且表明最活跃的抑制剂Cyc17，共价结合到催化Ser104残基中，导致酶活性的总丧失。这些数据由以2.6埃分辨率获得的X射线结构支持，其中CYC17与TESA结合的复合物。我们的研究提供了CYC17抑制特斯的活性，从而铺平了损害PDIM和PGL生物合成的新策略，可能降低相关的分枝杆菌物种的毒力。 （c）2018年elestvier有限公司保留所有权利。

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