PDF(Pubmed)
Abstract：
Toxoplasmosis, induced by the intracellular parasite Toxoplasma gondii, holds considerable implications for global health. While treatment options primarily focusing on folate pathway enzymes have notable limitations, current research endeavours concentrate on pinpointing specific metabolic pathways vital for parasite survival. Carbonic anhydrases (CAs, EC 4.2.1.1) have emerged as potential drug targets due to their role in fundamental reactions critical for various protozoan metabolic processes. Within T. gondii, the Carbonic Anhydrase-Related Protein (TgCA_RP) plays a pivotal role in rhoptry biogenesis. Notably, α-CA (TcCA) from another protozoan, Trypanosoma cruzi, exhibited considerable susceptibility to classical CA inhibitors (CAIs) such as anions, sulphonamides, thiols, and hydroxamates. Here, the recombinant DNA technology was employed to synthesise and clone the identified gene in the T. gondii genome, which encodes an α-CA protein (Tg_CA), with the purpose of heterologously overexpressing its corresponding protein. Tg_CA kinetic constants were determined, and its inhibition patterns explored with inorganic metal-complexing compounds, which are relevant for rational compound design. The significance of this study lies in the potential development of innovative therapeutic strategies that disrupt the vital metabolic pathways crucial for T. gondii survival and virulence. This research may lead to the development of targeted treatments, offering new approaches to manage toxoplasmosis.
摘要：
弓形虫病,由胞内寄生虫弓形虫诱导，对全球健康具有相当大的影响。虽然主要关注叶酸途径酶的治疗方案有明显的局限性，当前的研究工作集中在确定对寄生虫生存至关重要的特定代谢途径。碳酸酐酶（CA，EC4.2.1.1）已成为潜在的药物靶标，因为它们在对各种原生动物代谢过程至关重要的基本反应中发挥了作用。在弓形虫内，碳酸酐酶相关蛋白（TgCA_RP）在跳楼生物发生中起着关键作用。值得注意的是,来自另一个原生动物的α-CA（TcCA），克氏锥虫,对经典CA抑制剂（CAIs）如阴离子表现出相当大的敏感性，磺酰胺,硫醇,和异羟肟酸盐。这里,采用重组DNA技术合成和克隆弓形虫基因组中鉴定的基因，编码α-CA蛋白（Tg_CA），目的是异源过表达其相应的蛋白质。确定了Tg_CA动力学常数，用无机金属络合化合物探索其抑制模式，这与合理的复合设计有关。这项研究的意义在于创新治疗策略的潜在发展，这些策略破坏了对弓形虫生存和毒力至关重要的重要代谢途径。这项研究可能会导致靶向治疗的发展，提供新的方法来管理弓形虫病。
