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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antimalarials / metabolism*
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Antimalarials / pharmacology
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Biological Transport / drug effects
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Cell Membrane / metabolism
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Chloroquine / analogs & derivatives
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Chloroquine / metabolism*
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Chloroquine / pharmacology
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Drug Resistance
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Hydrogen-Ion Concentration
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Membrane Potentials
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Membrane Transport Proteins / chemistry
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism*
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Molecular Sequence Data
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Mutation
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Oligopeptides / pharmacology
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Oocytes / metabolism
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / genetics
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Plasmodium falciparum / metabolism*
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Protozoan Proteins / chemistry
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Protozoan Proteins / genetics
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Protozoan Proteins / metabolism*
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Verapamil / pharmacology
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Xenopus laevis
Substances
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Antimalarials
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Membrane Transport Proteins
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Mutant Proteins
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Oligopeptides
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PfCRT protein, Plasmodium falciparum
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Protozoan Proteins
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Recombinant Proteins
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endomorphin 1
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Chloroquine
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Verapamil