Chloroquine transport via the malaria parasite's chloroquine resistance transporter.
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.
Martin
Rowena E
RE
Research School of Biology, Australian National University, Canberra, Australian Capital Territory 0200, Australia. rowena.martin@anu.edu.au
Marchetti
Rosa V
RV
Cowan
Anna I
AI
Howitt
Susan M
SM
Bröer
Stefan
S
Kirk
Kiaran
K
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002738:Chloroquine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004351:Drug Resistance; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014982:Xenopus laevis
D000962:Antimalarials; D026901:Membrane Transport Proteins; D050505:Mutant Proteins; D009842:Oligopeptides; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C105293:endomorphin 1; D002738:Chloroquine; D014700:Verapamil