New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity
New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity
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DOI：
10.1017/s0031182097001133
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发表时间：
1997-01-01
期刊：
影响因子：
2.4
通讯作者：
Beverley, S
中科院分区：
文献类型：
--
作者：
Nare, B;Luba, J;Beverley, S
利什曼原虫和其他锥虫原生动物需要减少的蝶啶（蝶呤和叶酸）的生长，这表明这些途径的抑制可能是有效化疗的目标。这一目标尚未实现，表明蝶啶代谢在这种低等真核生物中可能是不寻常的。我们已经调查了这种可能性，使用野生型和实验室选择的抗叶酸剂耐药菌株，并与确定的几个蝶啶代谢基因的基因敲除。在利什曼原虫中，对抗叶酸剂甲氨蝶呤的耐药性是通过多种机制单独或组合介导的，包括转运改变导致药物内流减少、二氢叶酸还原酶-胸苷酸合酶（DHFR-TS）的过度产生（R区扩增）或点突变，以及新型蝶啶还原酶（PTR 1，由H区编码）的扩增。所有涉及的蛋白质都是抗叶酸化疗的潜在靶点。值得注意的是，其中编码二氢叶酸还原酶（DHFR）的基因已被删除（dhfr-ts（-）敲除）的寄生虫在动物模型中无法存活，从而验证了这种酶作为有效化疗的靶点。然而，蝶啶还原酶1（PTR 1）的特性表明了抗叶酸化疗迄今为止在锥虫中不成功的原因。PTR 1通过其提供还原的蝶呤和叶酸的能力，具有在生理条件下充当DHFR抑制的旁路和/或调节剂的潜力。此外，PTR 1对主要针对DHFR的许多抗叶酸剂不太敏感。这些发现表明，成功的抗叶酸化疗利什曼原虫将不得不同时靶向DHFR和PTR 1。
Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected antifolate-resistant strains, and with defined genetic knockouts of several pteridine metabolic genes. In Leishmania, resistance to the antifolate methotrexate is mediated through several mechanisms singly or in combination, including alterations in transport leading to reduced drug influx, overproduction (R-region amplification) or point mutation of dihydrofolate reductase-thymidylate synthase (DHFR-TS), and amplification of a novel pteridine reductase (PTR1, encoded by the H-region). All of the proteins involved are potential targets for antifolate chemotherapy. Notably, parasites in which the gene encoding dihydrofolate reductase (DHFR) has been deleted (dhfr-ts(-) knockouts) do not survive in animal models, validating this enzyme as a target for effective chemotherapy. However, the properties of pteridine reductase 1 (PTR1) suggest a reason why antifolate chemotherapy has so far not been successful in trypanosomatids. PTR1, by its ability to provide reduced pterins and folates, has the potential to act as a by-pass and/or modulator of DHFR inhibition under physiological conditions. Moreover, PTR1 is less sensitive to many antifolates targeted primarily against DHFR. These findings suggest that successful antifolate chemotherapy in Leishmania will have to target simultaneously both DHFR and PTR1.