ArticleAntioxidants & redox signaling2013
Glutathione transport: a new role for PfCRT in chloroquine resistance.
Article in Antioxidants & redox signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 56 citations in OpenAlex.
- Article
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- Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity.ACS medicinal chemistry letters · 2025Article
- The Toxoplasma plant-like vacuolar compartment (PLVAC).The Journal of eukaryotic microbiology · 2022Review
- The Knock-Down of the Chloroquine Resistance Transporter PfCRT Is Linked to Oligopeptide Handling in Plasmodium falciparum.Microbiology spectrum · 2022Article
- Peroxide Antimalarial Drugs Target Redox Homeostasis inACS infectious diseases · 2022Article
- An Uninvited Seat at the Dinner Table: How Apicomplexan Parasites Scavenge Nutrients from the Host.Microorganisms · 2021Review
- Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes.International journal for parasitology · 2021Article
- Molecular Mechanisms of Drug Resistance inAnnual review of microbiology · 2020Review
- The natural function of the malaria parasite's chloroquine resistance transporter.Nature communications · 2020Article
- Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter.Scientific reports · 2020Article
- Glutaredoxin 1 Deficiency Leads to Microneme Protein-Mediated Growth Defects inFrontiers in microbiology · 2020Article
- Phosphomimetic substitution at Ser-33 of the chloroquine resistance transporter PfCRT reconstitutes drug responses inThe Journal of biological chemistry · 2019Article
- Multiple genetic loci define CaBMC genomics · 2019Article
- Evidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporter.Scientific reports · 2018Article
- Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites.PLoS pathogens · 2018Article
- Iron is a substrate of theThe Journal of biological chemistry · 2017Article
- Hydrogen peroxide dynamics in subcellular compartments of malaria parasites using genetically encoded redox probes.Scientific reports · 2017Article
- H2O2 dynamics in the malaria parasite Plasmodium falciparum.PloS one · 2017Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
aimsChloroquine (CQ) kills Plasmodium falciparum by binding heme, preventing its detoxification to hemozoin in the digestive vacuole (DV) of the parasite. CQ resistance (CQR) is associated with mutations in the DV membrane protein P. falciparum chloroquine resistance transporter (PfCRT), mediating the leakage of CQ from the DV. However, additional factors are thought to contribute to the resistance phenotype. This study tested the hypothesis that there is a link between glutathione (GSH) and CQR.
resultsUsing isogenic parasite lines carrying wild-type or mutant pfcrt, we reveal lower levels of GSH in the mutant lines and enhanced sensitivity to the GSH synthesis inhibitor l-buthionine sulfoximine, without any alteration in cytosolic de novo GSH synthesis. Incubation with N-acetylcysteine resulted in increased GSH levels in all parasites, but only reduced susceptibility to CQ in PfCRT mutant-expressing lines. In support of a heme destruction mechanism involving GSH in CQR parasites, we also found lower hemozoin levels and reduced CQ binding in the CQR PfCRT-mutant lines. We further demonstrate via expression in Xenopus laevis oocytes that the mutant alleles of Pfcrt in CQR parasites selectively transport GSH. INNOVATION: We propose a mechanism whereby mutant pfcrt allows enhanced transport of GSH into the parasite's DV. The elevated levels of GSH in the DV reduce the level of free heme available for CQ binding, which mediates the lower susceptibility to CQ in the PfCRT mutant parasites.
conclusionPfCRT has a dual role in CQR, facilitating both efflux of harmful CQ from the DV and influx of beneficial GSH into the DV.
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