Adenylating enzymes in Mycobacterium tuberculosis as drug targets.
Adenylating enzymes in Mycobacterium tuberculosis as drug targets.
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DOI：
10.2174/156802612799984571
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发表时间：
2012
影响因子：
3.4
通讯作者：
Aldrich CC
中科院分区：
文献类型：
--
作者：
Duckworth BP;Nelson KM;Aldrich CC
腺苷酸化或腺苷酸形成酶 (AE) 广泛存在于自然界中，负责将羧酸活化为中间体酰基腺苷酸，后者是 AMP 的混合酸酐。在第二个反应中，AE 催化酰基腺苷酸的酰基转移到受体分子的亲核氨基、醇或硫醇基上，分别产生酰胺、酯和硫酯产物。结核分枝杆菌编码 60 多种腺苷酸化酶，其中许多由于其已证实的必要性或毒力要求而成为潜在的药物靶点。已使用多种策略来开发有效的选择性 AE 抑制剂，包括高通量筛选、基于片段的筛选以及模拟酰基腺苷酸的双底物抑制剂的基本原理设计。在这篇综述中，将对分枝杆菌腺苷酸化酶进行全面分析，重点是小分子抑制剂的鉴定。具体来说，本综述将涵盖氨酰 tRNA 合成酶 (aaRS)、甲基萘醌合成所需的 MenE、FadD 酶家族，包括参与脂质代谢的脂肪酰基-AMP 连接酶 (FAAL) 和脂肪酰基-CoA 连接酶 (FACL)，以及非核糖体肽合成酶腺苷酸化酶 MbtA 是分枝杆菌素合成所必需的。此外，还将讨论参与 NAD、鸟嘌呤、泛酸和菌硫醇合成的酶 NadE、GuaA、PanC 和 MshC，以及负责酰基辅酶 A 羧化酶生物素化的 BirA。
Adenylation or adenylate-forming enzymes (AEs) are widely found in nature and are responsible for the activation of carboxylic acids to intermediate acyladenylates, which are mixed anhydrides of AMP. In a second reaction, AEs catalyze the transfer of the acyl group of the acyladenylate onto a nucleophilic amino, alcohol, or thiol group of an acceptor molecule leading to amide, ester, and thioester products, respectively. Mycobacterium tuberculosis encodes for more than 60 adenylating enzymes, many of which represent potential drug targets due to their confirmed essentiality or requirement for virulence. Several strategies have been used to develop potent and selective AE inhibitors including high-throughput screening, fragment-based screening, and the rationale design of bisubstrate inhibitors that mimic the acyladenylate. In this review, a comprehensive analysis of the mycobacterial adenylating enzymes will be presented with a focus on the identification of small molecule inhibitors. Specifically, this review will cover the aminoacyl tRNA-synthetases (aaRSs), MenE required for menaquinone synthesis, the FadD family of enzymes including the fatty acyl-AMP ligases (FAAL) and the fatty acyl-CoA ligases (FACLs) involved in lipid metabolism, and the nonribosomal peptide synthetase adenylation enzyme MbtA that is necessary for mycobactin synthesis. Additionally, the enzymes NadE, GuaA, PanC, and MshC involved in the respective synthesis of NAD, guanine, pantothenate, and mycothiol will be discussed as well as BirA that is responsible for biotinylation of the acyl CoA-carboxylases.