Mutations in the P. Falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2000 Nov 25

PMID 11090624

Citations 611

Authors

D A Fidock

T Nomura

A K Talley

R A Cooper

S M Dzekunov

M T Ferdig

L M Ursos

A B Sidhu

B Naude

K W Deitsch

X Z Su

J C Wootton

P D Roepe

T E Wellems

Affiliations

Soon will be listed here.

Abstract

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.

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