TRANSITION STATE ANAL OF HGPRTASE: DVMT OF NOVEL CHEMOTHERAPEUTICS FOR MALARIA

GPRTase催化5-嘌呤核苷酸的焦磷酸分解。 GPRTase突变与Lesch-Hyhan病有关，Lesch-Hyhan病是一种主要的 临床神经退行性疾病。寄生器官，如 疟疾和血吸虫不能进行从头合成嘌呤 因此依赖于从宿主中回收嘌呤的能力 核苷酸。因此，HGPRTase是一个很好的治疗靶点， 只要能够实现足够的歧视， 人类和寄生虫酶。这一点在这种情况下尤其重要 疟疾，因为对现有抗生素具有抗药性的菌株 在世界范围内流行。我们最近收集了关于 无机焦磷酸与人HGPRTase结合的复合体 X-9B上的过渡态缓蚀剂为2.2E。精致的结构 清楚地识别了过渡态类似物的结合模式， 结合镁离子和焦磷酸盐及其相互作用 蛋白质配体。此结构还标识了交互 负责氧碳正离子中间体的稳定。我们 最近收集了疟疾酶结合的2.0E的数据 到同一组抑制性配体。这是第一个 疟疾酶结晶的报告，并将提供 有机会设计针对疟疾的特定抑制剂。

GPRTase catalyzes the pyrophosphorolysis of 5-purine nucleotides. Mutations in GPRTase are associated with Lesch-Hyhan disease, a major clinical neurodegenerative disorder. Parasitic organsims such as malaria and schistosomes cannot perform de novo purine biosynthesis and thus depend on the ability to salvage purines from host nucleotides. Thus HGPRTase is an excellent therapeutic target, provided that sufficient discrimination can be achieved between the human and parasitic enzymes. This is especially important in the case of malaria, as strains resistant to the existing antibiotics are becoming prevalent world wide. We have recently collected data on the complex between human HGPRTase bound to inorganic pyrophosphate and the transition state inhibitor to 2.2E on X-9B. The refined structure clearly identified the binding mode of the transition state analog, bound magnesium ion and pyrophosphate, as well as the interacting protein ligands. This structure also identifies the interactions responsible for stabilization of the oxycarbonium intermediate. We have very recently collected data to 2.0E of the malarial enzyme bound to the same set of inhibitory ligands. This represents the first report of the malarial enzyme crystallizing and will provide the opportunity to design malaria specific inhibitors.