Alsayed Shahinda S R, Beh Chau C, Foster Neil R, Payne Alan D, Yu Yu, Gunosewoyo Hendra
School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia.
Western Australia School of Mines: Minerals, Energy and Chemical Engineering, Curtin University, Bentley 6102 WA, Australia.
Curr Mol Pharmacol. 2019;12(1):27-49. doi: 10.2174/1874467211666181025141114.
Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long α-alkyl-β-hydroxylated fatty acids provide protection to the tubercle bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation of regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, InhA, MabA, and FadD32 downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human's, there have been some early drug discovery efforts towards developing potent and selective inhibitors.
Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this mini-review, including their known small molecule inhibitors.
Mycobacterial kinases and phosphatases involved in the MAs regulation may serve as a useful avenue for antitubercular therapy.
分枝菌酸（MAs）是隐匿性细菌病原体结核分枝杆菌（M.tb）菌膜的特征性组成成分。这些C60 - C90长链α - 烷基 - β - 羟基脂肪酸为结核杆菌提供保护，使其免受外界威胁，从而使其得以存活、具备毒力并对现有抗菌药物产生耐药性。在后基因组时代，人们在了解结核分枝杆菌中参与分枝菌酸生物合成的关键酶机制方面取得了进展。然而，这些系统中调节机制的磷酸化和去磷酸化的确切作用仍存在空白。迄今为止，在结核分枝杆菌中总共发现了11种丝氨酸 - 苏氨酸蛋白激酶（STPKs）。大多数参与分枝菌酸合成的酶在体外和/或体内被发现发生了磷酸化。例如，KasA、KasB、mtFabH、InhA、MabA和FadD32的磷酸化下调了它们的酶活性，而VirS的磷酸化则增加了其酶活性。这些观察结果表明，激酶和磷酸酶系统可能在结核分枝杆菌在人类宿主中的适应性反应和生存机制中发挥作用。由于分枝杆菌的STPKs与人类的序列同源性不高，因此已经有一些早期的药物研发工作致力于开发强效且选择性的抑制剂。
本综述将介绍参与分枝菌酸生物合成调控的激酶和磷酸酶的最新进展，包括其已知的小分子抑制剂。
参与分枝菌酸调控的分枝杆菌激酶和磷酸酶可能是抗结核治疗的有效途径。
