Pteridine salvage throughout the Leishmania infectious cycle:: implications for antifolate chemotherapy
Pteridine salvage throughout the Leishmania infectious cycle:: implications for antifolate chemotherapy
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DOI：
10.1016/s0166-6851(01)00213-4
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发表时间：
2001-04-06
影响因子：
1.5
通讯作者：
Beverley, SM
中科院分区：
文献类型：
--
作者：
Cunningham, ML;Beverley, SM
利什曼原虫属锥虫属的原生动物寄生虫是翼虫性营养不良者。并且已经进化出了一个复杂而多功能的翼虫碱打捞网络能够积累和减少翼虫碱。这包括生物蝶呤和叶酸转运蛋白（BT1和FT1），蝶呤还原酶（PTR1）和二氢叶酸还原酶-胸苷酸合成酶（DHFR-TS）。值得注意的是，PTR1是一种新的替代蝶啶还原酶，其活性不受标准抗叶酸盐的抑制。在培养的promastigote寄生虫中，PTR1可以在DHFR抑制的条件下作为代谢旁路，从而降低化疗的疗效。为了测试翼虫残留是否发生在寄生虫的感染阶段，我们检查了几种致病性利什曼原虫和寄生在人巨噬细胞内的致病性无毛线虫阶段。为了实现这一目标，我们开发了一种新的基于高效液相色谱的PTR1活性检测方法。这些研究确定了在整个利什曼原虫感染循环中，包括无尾线虫，存在翼啶残留途径。总的来说，活性与RNA转录水平没有很好的相关性，这表明至少存在两种不同的转录后调控模式。因此，无尾线虫挽救翼虫碱可能解释了抗叶酸药物治疗利什曼病的临床无效，并最终为今后如何克服这一问题提供了见解。(C) 2001 Elsevier Science B.V.版权所有
Protozoan parasites of the trypanosomatid genus Leishmania are pteridine auxotrophs. and have evolved an elaborate and versatile pteridine salvage network capable of accumulating and reducing pteridines. This includes biopterin and folate transporters (BT1 and FT1), pteridine reductase (PTR1), and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Notably, PTR1 is a novel alternative pteridine reductase whose activity is resistant to inhibition by standard antifolates. In cultured promastigote parasites, PTR1 can function as a metabolic by-pass under conditions of DHFR inhibition and thus reduce the efficacy of chemotherapy. To test whether pteridine salvage occurred in the infectious stage of the parasite, we examined several pathogenic species of Leishmania and the disease-causing amastigote: stage that resides within human macrophages. To accomplish this we developed a new sensitive HPLC-based assay for PTR1 activity. These studies established the existence of the pteridine salvage pathway throughout the infectious cycle of Leishmania, including amastigotes. In general, activities were not well correlated with RNA transcript levels, suggesting the occurrence of at least two different modes of post-transcriptional regulation. Thus, pteridine salvage by amastigotes may account for the clinical inefficacy of antifolates against leishmaniasis, and ultimately provide insights into how this may be overcome in the future. (C) 2001 Elsevier Science B.V. All rights reserved.