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Chloroquine Transport via the Malaria Parasite’s Chloroquine Resistance Transporter

Science  25 Sep 2009:
Vol. 325, Issue 5948, pp. 1680-1682
DOI: 10.1126/science.1175667

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Malaria Chloroquine Resistance Transporter

Malaria is one of the most deadly infectious diseases in the world today, and the emergence and spread of chloroquine-resistant parasites has been a disaster for world health. The Chloroquine Resistance Transporter (PfCRT) was originally identified because mutations in this protein confer chloroquine resistance in the human malaria parasite, Plasmodium falciparum. However, the mechanism by which they do so has been the subject of ongoing debate. Martin et al. (p. 1680) have now succeeded in expressing PfCRT at the surface of Xenopus laevis oocytes, establishing a robust and reproducible heterologous system for the study of this protein. The resistance-conferring form of the protein mediates the transport of chloroquine, whereas wild-type PfCRT does not. Thus, as suspected, chloroquine resistance in the malaria parasite indeed arises as a result of the transport of the drug via mutant PfCRT.

Abstract

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.

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