Department of Biotechnology, Jaypee Institute of Information Technology, Noida - 201309, India.
Protein Pept Lett. 2022;29(12):1031-1041. doi: 10.2174/0929866529666221006121831.
Isocitrate lyase (ICL), an enzyme of the glyoxylate shunt pathway, is essential for the virulence and persistence of dreaded Mycobacterium tuberculosis (Mtb) in its host. This pathway, along with the methylcitrate cycle, facilitates the utilization of fatty acids as a carbon source inside hostile host environments such as in granulomas, and hence enzymes of this pathway are novel antitubercular targets. The genome sequence of pathogenic Mtb H37Rv presents three ICLs annotated as Rv0467 (prokaryotic homologue), Rv1915 and Rv1916. The latter two, Rv1915 and Rv1916, together constitute the longer version of ICL2, a eukaryotic counterpart. Despite being a well-known drug target, no Mtb ICL inhibitor has reached clinical trials due to challenges associated with targeting all the 3 orthologs. This gap is the result of uncharacterized Rv1915 and Rv1916. This review aims to appreciate chronologically the key studies that have built our comprehension of Mtb ICLs. Recently characterized Mtb Rv1915 and Rv1916, which further open venues for developing effective inhibitors against the persistent and drug-resistant Mtb, are discussed separately.
异柠檬酸裂解酶（ICL）是乙醛酸支路途径的一种酶，对结核分枝杆菌（Mtb）在宿主中的毒力和持久性至关重要。该途径与甲基柠檬酸循环一起，促进了脂肪酸在宿主环境（如肉芽肿）中作为碳源的利用，因此该途径的酶是新型抗结核靶点。致病性 Mtb H37Rv 的基因组序列呈现出三种 ICL，分别注释为 Rv0467（原核同源物）、Rv1915 和 Rv1916。后两者共同构成了 ICL2 的较长版本，是真核生物的对应物。尽管 ICL 是一个众所周知的药物靶点，但由于靶向所有 3 个同源物的相关挑战，没有 Mtb ICL 抑制剂进入临床试验。这一差距是由于 Rv1915 和 Rv1916 尚未被阐明造成的。本综述旨在按时间顺序回顾关键研究，以了解 Mtb ICL。最近对 Mtb Rv1915 和 Rv1916 的特性分析，为开发针对持久性和耐药性 Mtb 的有效抑制剂开辟了新的途径，分别进行了讨论。
