Pteridine salvage throughout the Leishmania infectious cycle:: implications for antifolate chemotherapy

被引:79
作者
Cunningham, ML [1 ]
Beverley, SM [1 ]
机构
[1] Univ Washington, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA
关键词
biopterin transporter; folate transporter; developmental regulation; dihydrofolate reductase; pteridine reductase; HPLC biopterin assay;
D O I
10.1016/S0166-6851(01)00213-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:199 / 213
页数:15
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