Lehane Adele M, Kirk Kiaran
Biochemistry and Molecular Biology, School of Biology, The Australian National University, Canberra ACT 0200, Australia.
Antimicrob Agents Chemother. 2008 Dec;52(12):4374-80. doi: 10.1128/AAC.00666-08. Epub 2008 Oct 13.
Chloroquine resistance in the malaria parasite Plasmodium falciparum is conferred by mutations in the P. falciparum chloroquine resistance transporter (PfCRT). PfCRT localizes to the membrane of the parasite's internal digestive vacuole, an acidic organelle in which chloroquine accumulates to high concentrations and exerts its toxic effect. Mutations in PfCRT are thought to reduce chloroquine accumulation in this organelle. How they do so is the subject of ongoing debate. Recently we have shown that in the presence of chloroquine there is an increased leak of H+ from the digestive vacuole in chloroquine-resistant but not chloroquine-sensitive parasites. Here, using transfectant parasite strains of a single genetic background and differing only in their pfcrt allele, we show that chloroquine resistance-conferring PfCRT mutations are responsible for this chloroquine-associated H+ leak. This is consistent with the hypothesis that the chloroquine resistance-conferring forms of PfCRT mediate the efflux of chloroquine, in association with H+, from the malaria parasite's digestive vacuole.
恶性疟原虫对氯喹的耐药性是由恶性疟原虫氯喹耐药转运蛋白（PfCRT）的突变引起的。PfCRT定位于疟原虫内部消化液泡的膜上，这是一种酸性细胞器，氯喹在其中积累到高浓度并发挥其毒性作用。PfCRT的突变被认为会减少氯喹在该细胞器中的积累。它们如何做到这一点是目前正在争论的话题。最近我们发现，在氯喹存在的情况下，耐氯喹但不耐氯喹的疟原虫消化液泡中H+的泄漏增加。在这里，我们使用单一遗传背景、仅pfcrt等位基因不同的转染疟原虫菌株，表明赋予氯喹抗性的PfCRT突变是这种与氯喹相关的H+泄漏的原因。这与以下假设一致，即赋予氯喹抗性的PfCRT形式介导氯喹与H+一起从疟原虫的消化液泡中流出。
