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PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX

Bray, Patrick, Mungthin, M., Hastings, Ian ORCID: https://orcid.org/0000-0002-1332-742X, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Saidu, D. K., Lakshmanan, V., Johnson, David, Hughes, Ruth, Stocks, Paul A., O'Neill, P. M., Fidock, D. A., Warhurst, D. C. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2006) 'PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX'. Molecular Microbiology, Vol 62, Issue 1, pp. 238-251.

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Abstract

It is accepted that resistance of Plasmodium falciparum to chloroquine (CQ) is caused primarily by mutations in the pfcrt gene. However, a consensus has not yet been reached on the mechanism by which resistance is achieved. CQ-resistant (CQR) parasite lines accumulate less CQ than do CQ-sensitive (CQS) parasites. The CQR phenotype is complex with a component of reduced energy-dependent CQ uptake and an additional component that resembles energy-dependent CQ efflux. Here we show that the required energy input is in the form of the proton electrochemical gradient across the digestive vacuole (DV) membrane. Collapsing the DV proton gradient (or starving the parasites of glucose) results in similar levels of CQ accumulation in CQS and CQR lines. Under these conditions the accumulation of CQ is stimulated in CQR parasite lines but is reduced in CQS lines. Energy deprivation has no effect on the rate of CQ efflux from CQR lines implying that mutant PfCRT does not function as an efflux pump or active carrier. Using pfcrt-modified parasite lines we show that the entire CQ susceptibility phenotype is switched by the single K76T amino acid change in PfCRT. The efflux of CQ in CQR lines is not directly coupled to the energy supply, consistent with a model in which mutant PfCRT functions as a gated channel or pore, allowing charged CQ species to leak out of the DV.

Item Type: Article
Uncontrolled Keywords: drug/metabolite transporter superfamily resistant plasmodium-falciparum transmembrane protein pfcrt human malaria parasites digestive vacuole chloride channels drug-resistance entamoeba-histolytica antimalarial activity heme polymerization
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1111/j.1365-2958.2006.05368.x
Depositing User: Ms Julia Martin
Date Deposited: 07 Feb 2011 10:33
Last Modified: 19 Sep 2019 11:29
URI: https://archive.lstmed.ac.uk/id/eprint/1455

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