Ting Li-Min, Shi Wuxian, Lewandowicz Andrzej, Singh Vipender, Mwakingwe Agnes, Birck Matthew R, Ringia Erika A Taylor, Bench Graham, Madrid Dennis C, Tyler Peter C, Evans Gary B, Furneaux Richard H, Schramm Vern L, Kim Kami
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Biol Chem. 2005 Mar 11;280(10):9547-54. doi: 10.1074/jbc.M412693200. Epub 2004 Dec 2.
Plasmodium falciparum is unable to synthesize purine bases and relies upon purine salvage and purine recycling to meet its purine needs. We report that purines formed as products of polyamine synthesis are recycled in a novel pathway in which 5'-methylthioinosine is generated by adenosine deaminase. The action of P. falciparum purine nucleoside phosphorylase is a convergent step of purine salvage, converting both 5'-methylthioinosine and inosine to hypoxanthine. We used accelerator mass spectrometry to verify that 5'-methylthioinosine is an active nucleic acid precursor in P. falciparum. Prior studies have shown that inhibitors of purine salvage enzymes kill malaria, but potent malaria-specific inhibitors of these enzymes have not been described previously. 5'-Methylthio-immucillin-H, a transition state analogue inhibitor that is selective for malarial relative to human purine nucleoside phosphorylase, kills P. falciparum in culture. Immucillins are currently in clinical trials for other indications and may also have application as anti-malarials.
恶性疟原虫无法合成嘌呤碱，它依赖嘌呤补救途径和嘌呤循环来满足自身对嘌呤的需求。我们报告称，作为多胺合成产物形成的嘌呤在一条新途径中被循环利用，在该途径中，腺苷脱氨酶生成5'-甲硫基肌苷。恶性疟原虫嘌呤核苷磷酸化酶的作用是嘌呤补救的一个汇聚步骤，它将5'-甲硫基肌苷和肌苷都转化为次黄嘌呤。我们使用加速器质谱法来验证5'-甲硫基肌苷是恶性疟原虫中一种活跃的核酸前体。先前的研究表明，嘌呤补救酶抑制剂可杀死疟原虫，但此前尚未描述过针对这些酶的强效疟疾特异性抑制剂。5'-甲硫基-免疫球蛋白-H是一种相对于人类嘌呤核苷磷酸化酶对疟疾具有选择性的过渡态类似物抑制剂，可在培养物中杀死恶性疟原虫。免疫球蛋白目前正在针对其他适应症进行临床试验，也可能作为抗疟药物应用。
