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MBE Advance Access published online on July 7, 2004
Molecular Biology and Evolution, doi:10.1093/molbev/msh205
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2004; all rights reserved
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Accepted June 28, 2004

Original Articles

The Malaria Parasite's Chloroquine Resistance Transporter Is a Member of the Drug/Metabolite Transporter Superfamily

Rowena E. Martin 1 Kiaran Kirk 1*

1 School of Biochemistry and Molecular Biology, Faculty of Science, Australian National University, Canberra ACT 0200, Australia

* To whom correspondence should be addressed. E-mail: kiaran.kirk{at}anu.edu.au.


  Abstract

The malaria parasite's ‘chloroquine resistance transporter’ (CRT) is an integral membrane protein localised to the parasite's acidic ‘digestive vacuole’. The function of CRT is not known and the protein is described as a transporter simply because it possesses ten transmembrane domains. In wild-type (chloroquine-sensitive) parasites, chloroquine accumulates to high concentrations within the digestive vacuole and it is through interactions in this compartment that it exerts its antimalarial effect. Mutations in CRT can cause a decreased intra-vacuolar concentration of chloroquine, and thereby confer chloroquine resistance. However the mechanism by which they do so is not understood. In this paper we present the results of a detailed bioinformatic analysis which reveals that CRT is a member of a previously undefined family of proteins, falling within the Drug/Metabolite Transporter superfamily. Comparisons between CRT and other members of the superfamily provide insight into the possible role of the protein and into the significance of the mutations associated with the chloroquine resistance phenotype. The protein is predicted to function as a dimer and to be oriented with its termini in the parasite cytosol. The key chloroquine-resistance-conferring mutation (K76T) is localised in a region of the protein implicated in substrate selectivity. The mutation is predicted to alter the selectivity of the protein such that it is able to transport the cationic (protonated) form of chloroquine down its steep concentration gradient, out of the acidic vacuole, and therefore away from its site of action.

Keywords: Malaria; Plasmodium falciparum; chloroquine; drug resistance; PfCRT; drug/metabolite transporter.
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