Purine and pyrimidine metabolism in Leishmania
Purine and pyrimidine metabolism in Leishmania
复制标题
DOI：
10.1007/978-0-387-77570-8_12
复制
发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Ullman, Buddy
中科院分区：
文献类型：
--
作者：
Carter, Nicola S.;Yates, Phillip;Ullman, Buddy
嘌呤和嘧啶是所有生命不可或缺的，为细胞执行许多重要功能：ATP作为细胞能量的通用货币，cAMP和cGMP是关键的第二信使分子，嘌呤和嘧啶核苷酸是碳水化合物和脂质的活化形式的前体，维生素的核苷酸衍生物是代谢过程中的必需辅因子，核苷三磷酸是DNA和RNA合成的直接前体。与它们的哺乳动物和昆虫宿主不同，利什曼原虫缺乏从头制造嘌呤核苷酸的代谢机制，必须依赖于它们的宿主来制造预先形成的嘌呤。因此，嘌呤补救的强制性性质为药物靶向提供了过多的潜在靶标，并且该途径因此成为大量科学研究的焦点。相比之下，利什曼原虫对嘧啶是原养型的，并且还表达嘧啶补救酶的小补充。由于利什曼原虫和人类的嘧啶核苷酸生物合成途径相似，因此利什曼原虫中的嘧啶代谢通常被认为比嘌呤补救途径更不适合治疗操作。然而，从各种寄生原生动物收集的证据表明，嘧啶生物合成酶的选择性抑制提供了一个合理的治疗范例。在这一章中，我们提出了一个概述的嘌呤和嘧啶途径在利什曼原虫，在他们的哺乳动物宿主的等效途径进行比较，并探讨这些途径可能适合选择性治疗靶向。
Purines and pyrimidines are indispensable to all life, performing many vital functions for cells: ATP serves as the universal currency of cellular energy, cAMP and cGMP are key second messenger molecules, purine and pyrimidine nucleotides are precursors for activated forms of both carbohydrates and lipids, nucleotide derivatives of vitamins are essential cofactors in metabolic processes, and nucleoside triphosphates are the immediate precursors for DNA and RNA synthesis. Unlike their mammalian and insect hosts, Leishmania lack the metabolic machinery to make purine nucleotides de novo and must rely on their host for preformed purines. The obligatory nature of purine salvage offers, therefore, a plethora of potential targets for drug targeting, and the pathway has consequently been the focus of considerable scientific investigation. In contrast, Leishmania are prototrophic for pyrimidines and also express a small complement of pyrimidine salvage enzymes. Because the pyrimidine nucleotide biosynthetic pathways of Leishmania and humans are similar, pyrimidine metabolism in Leishmania has generally been considered less amenable to therapeutic manipulation than the purine salvage pathway. However, evidence garnered from a variety of parasitic protozoa suggests that the selective inhibition of pyrimidine biosynthetic enzymes offers a rational therapeutic paradigm. In this chapter, we present an overview of the purine and pyrimidine pathways in Leishmania, make comparisons to the equivalent pathways in their mammalian host, and explore how these pathways might be amenable to selective therapeutic targeting.