Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa.
Chloroquine resistance in a P. falciparum cross maps as a Mendelian trait to a 36 kb segment of chromosome 7. This segment harbors cg2, a gene encoding a unique approximately 330 kDa protein with complex polymorphisms. A specific set of polymorphisms in 20 chloroquine-resistant parasites from Asia and Africa, in contrast with numerous differences in 21 sensitive parasites, suggests selection of a cg2 allele originating in Indochina over 40 years ago. One chloroquine-sensitive clone exhibited this allele, suggesting another resistance component. South American parasites have cg2 polymorphisms consistent with a separate origin of resistance. CG2 protein is found at the parasite periphery, a site of chloroquine transport, and in association with hemozoin of the digestive vacuole, where chloroquine inhibits heme polymerization.
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National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0425, USA.
Kirkman
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Fujioka
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Wellems
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D000349:Africa; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001210:Asia, Southeastern; D002738:Chloroquine / Q000494:pharmacology*; D002874:Chromosome Mapping; D003434:Crossing Over, Genetic; D016054:DNA, Protozoan / Q000032:analysis; D004276:DNA, Satellite / Q000032:analysis; D004352:Drug Resistance, Microbial; D004912:Erythrocytes / Q000469:parasitology; D008040:Genetic Linkage; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000032:analysis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
D000962:Antimalarials; C109423:CG1 protein, Plasmodium falciparum; C109422:CG2 protein, Plasmodium falciparum; D016054:DNA, Protozoan; D004276:DNA, Satellite; D015800:Protozoan Proteins; D002738:Chloroquine