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 P lasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that as sociate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harb oring a novel K761 mutation point to a central role for the PfCRT protein i n CQR. This transmembrane protein localizes to the parasite digestive vacuo le (DV), the site of Co action, where increased compartment acidification a ssociates with PfCRT point mutations. Mutations in PfCRT may result in alte red chloroquine flux or reduced drug binding to hematin through an effect o n DV pH.