Chloroquine Transport via the Malaria Parasite's Chloroquine Resistance Transporter
Chloroquine Transport via the Malaria Parasite's Chloroquine Resistance Transporter
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DOI：
10.1126/science.1175667
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发表时间：
2009-09-25
期刊：
影响因子：
56.9
通讯作者：
Kirk, Kiaran
中科院分区：
文献类型：
--
作者：
Martin, Rowena E.;Marchetti, Rosa V.;Kirk, Kiaran
抗氯喹恶性疟原虫疟疾寄生虫的出现和传播对世界卫生造成了灾难。抗药性是由氯喹抗药性转运蛋白（PfCRT）的突变产生的，PfCRT是一种定位于寄生虫内部消化泡的完整膜蛋白。这些突变导致寄生虫对氯喹（CQ）的积累显著减少。然而，这种情况发生的机制尚不清楚。我们在非洲爪蟾卵母细胞表面表达了野生型和抗性形式的PfCRT。抗性形式的PfCRT运输CQ，而野生型蛋白没有。CQ转运通过突变PfCRT抑制CQ类似物和耐药性逆转剂维拉帕米。因此，CQ抗性是由于药物通过突变PfCRT的直接转运。
The emergence and spread of chloroquine-resistant Plasmodium falciparum malaria parasites has been a disaster for world health. Resistance is conferred by mutations in the Chloroquine Resistance Transporter (PfCRT), an integral membrane protein localized to the parasite's internal digestive vacuole. These mutations result in a marked reduction in the accumulation of chloroquine (CQ) by the parasite. However, the mechanism by which this occurs is unclear. We expressed both wild-type and resistant forms of PfCRT at the surface of Xenopus laevis oocytes. The resistant form of PfCRT transported CQ, whereas the wild-type protein did not. CQ transport via the mutant PfCRT was inhibited by CQ analogs and by the resistance-reverser verapamil. Thus, CQ resistance is due to direct transport of the drug via mutant PfCRT.