ArticleProtein science : a publication of the Protein Society2006
Plasmodium falciparum glutathione S-transferase--structural and mechanistic studies on ligand binding and enzyme inhibition.
Article in Protein science : a publication of the Protein Society, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 68 citations in OpenAlex.
- Revisiting Glutathione Transferases ofPharmaceuticals (Basel, Switzerland) · 2026Review
- Article
- Novel hydrazone compounds with broad-spectrum antiplasmodial activity and synergistic interactions with antimalarial drugs.Antimicrobial agents and chemotherapy · 2024Article
- Development and application of fragment-based de novo inhibitor design approaches against Plasmodium falciparum GST.Journal of molecular modeling · 2023Article
- Two Methods, One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses.ChemMedChem · 2021Article
- Is there a role for tau glutathione transferases in tetrapyrrole metabolism and retrograde signalling in plants?Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2020Article
- Structure-Based Screening ofFrontiers in pharmacology · 2020Article
- The interactome of 2-Cys peroxiredoxins in Plasmodium falciparum.Scientific reports · 2019Article
- The Incomplete Glutathione Puzzle: Just Guessing at Numbers and Figures?Antioxidants & redox signaling · 2017Review
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- Characterization of a Highly pH Stable Chi-Class Glutathione S-Transferase from Synechocystis PCC 6803.PloS one · 2015Article
- Article
- Heme transport and erythropoiesis.Current opinion in chemical biology · 2013Review
- Divergent molecular evolution of the mitochondrial sulfhydryl:cytochrome C oxidoreductase Erv in opisthokonts and parasitic protists.The Journal of biological chemistry · 2013Article
- One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans.Biochimica et biophysica acta · 2012Review
- Studies on filarial GST as a target for antifilarial drug development-in silico and in vitro inhibition of filarial GST by substituted 1,4-naphthoquinones.Journal of molecular modeling · 2011Article
- Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.PLoS computational biology · 2010Article
- Large crystal growth by thermal control allows combined X-ray and neutron crystallographic studies to elucidate the protonation states in Aspergillus flavus urate oxidase.Journal of the Royal Society, Interface · 2009Review
- Inherited glutathione reductase deficiency and Plasmodium falciparum malaria--a case study.PloS one · 2009Article
- Tetramerization and cooperativity in Plasmodium falciparum glutathione S-transferase are mediated by atypic loop 113-119.The Journal of biological chemistry · 2009Article
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6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutathione S-transferase of the malarial parasite Plasmodium falciparum (PfGST) represents a novel class of GST isoenzymes. Since the architecture of the PfGST substrate binding site differs significantly from its human counterparts and there is only this one isoenzyme present in the parasite, PfGST is considered a highly attractive target for antimalarial drug development. Here we report the mechanistic, kinetic, and structural characterization of PfGST as well as its interaction with different ligands. Our data indicate that in solution PfGST is present as a tetramer that dissociates into dimers in the presence of glutathione (GSH). Fluorescence spectroscopy shows that in the presence of GSH GST serves as ligandin for parasitotoxic ferriprotoporphyrin IX with a high- and a low-affinity binding site. This is supported by a clear uncompetitive inhibition type. Site-directed mutagenesis studies demonstrate that neither Cys 86 nor Cys 101 contribute to the peroxidase activity of the enzyme, which is thus performed GSH-dependently at the active site. Tyr 9 is responsible for the deprotonation of GSH and Lys 15, but also Gln 71 are involved in GSH binding. We furthermore report the 2.4 A resolution X-ray structure of PfGST cocrystallized with the inhibitor S-hexylglutathione. In comparison with a previously reported structure obtained by crystal soaking, differences occur at the C-terminal end of helix alpha4 and at the S-hexylmoiety of the inhibitor. We furthermore show that, in contrast to previous reports, the antimalarial drug artemisinin is not metabolized by PfGST.
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