Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance.
The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH.
Fidock
D A
DA
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nomura
T
T
Talley
A K
AK
Cooper
R A
RA
Dzekunov
S M
SM
Ferdig
M T
MT
Ursos
L M
LM
Sidhu
A B
AB
Naudé
B
B
Deitsch
K W
KW
Su
X Z
XZ
Wootton
J C
JC
Roepe
P D
PD
Wellems
T E
TE
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002738:Chloroquine / Q000494:pharmacology*; D004064:Digestive System / Q000378:metabolism; D004351:Drug Resistance; D005091:Exons; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014162:Transfection; D014617:Vacuoles / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology
D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D002738:Chloroquine; D014700:Verapamil; D013762:Tetrahydrofolate Dehydrogenase