Exploring the folate pathway in Plasmodium falciparum
Exploring the folate pathway in Plasmodium falciparum
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DOI：
10.1016/j.actatropica.2005.04.002
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发表时间：
2005-06-01
期刊：
影响因子：
2.7
通讯作者：
Hyde, JE
中科院分区：
文献类型：
--
作者：
Hyde, JE
与过去几个世纪一样，对抗人类疟疾感染的主要武器仍然是药物干预，尽管对一种或多种可用化合物具有耐药性的寄生虫种群广泛存在且频率不断增加。这是致命寄生虫-恶性疟原虫-的一个特别问题，恶性疟原虫每年夺去约200万人的生命，并造成巨大的社会和经济问题。在目前临床使用的抗疟药物中，抗叶酸剂具有最明确的分子靶点，即在叶酸代谢途径中起作用的酶二氢叶酸还原酶（DHFR）和二氢蝶酸合酶（DHPS）。该途径的产物，还原叶酸辅因子，是DNA合成和某些氨基酸代谢所必需的。此外，它们的形成和相互转化涉及许多尚未被开发为药物靶点的其他酶。抗叶酸剂非常重要，因为它们是目前防治对氯喹有抗药性的疟疾的唯一廉价疗法，而且现在是一些非洲国家的一线药物。我们了解这一途径和抗叶酸药物耐药性的方面在这里进行审查，特别强调的方法来分析的细节，和之间的平衡，叶酸的生物合成的寄生虫和补救的预先形成的叶酸从外源性来源。(c)2005 Elsevier B. V.保留所有权利。
As in centuries past, the main weapon against human malaria infections continues to be intervention with drugs, despite the widespread and increasing frequency of parasite populations that are resistant to one or more of the available compounds. This is a particular problem with the lethal species of parasite, Plasmodium falciparum, which claims some two million lives per year as well as causing enormous social and economic problems. Amongst the antimalarial drugs currently in clinical use, the antifolates have the best defined molecular targets, namely the enzymes dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), which function in the folate metabolic pathway. The products of this pathway, reduced folate cofactors, are essential for DNA synthesis and the metabolism of certain amino acids. Moreover, their formation and interconversions involve a number of other enzymes that have not as yet been exploited as drug targets. Antifolates are of major importance as they currently represent the only inexpensive regime for combating chloroquine-resistant malaria, and are now first-line drugs in a number of African countries. Aspects of our understanding of this pathway and antifolate drug resistance are reviewed here, with a particular emphasis on approaches to analysing the details of, and balance between, folate biosynthesis by the parasite and salvage of pre-formed folate from exogenous sources. (c) 2005 Elsevier B.V. All rights reserved.