Glutathione S-Transferase of the Malarial Parasite Plasmodium falciparum: Characterization of a Potential Drug Target
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Petra Harwaldt
Abstract
Glutathione Stransferases (GSTs), which occur abundantly in most organisms, are essentially involved in the intracellular detoxification of numerous substances including chemotherapeutic agents, and thus play a major role in the development of drug resistance. A gene encoding a protein with sequence identity of up to 37% with known GSTs was identified on chromosome 14 of the malarial parasite Plasmodium falciparum. It was amplified using gametocyte cDNA and expressed in Escherichia coli as a hexahistidyltagged protein of 26 kDa subunit size. The homodimeric enzyme (PfGST) was found to catalyse the glutathione (GSH)dependent modification of 1-chloro-2,4-dinitrobenzene and other typical GST substrates such as onitrophenyl acetate, ethacrynic acid, and cumene hydroperoxide. The Km value for GSH was 164±20 M. PfGST was inhibited by cibacron blue (Ki=0.5 M), Shexylglutathione (Ki=35 M), and protoporphyrin IX (Ki=10 M). Hemin, a most toxic compound for parasitised erythrocytes, was found to be an uncompetitive ligand of PfGST with a Ki of 6.5 M. Based on the activity of PfGST in extracts of P. falciparum, the enzyme represents 1 to 10% of cellular protein and might therefore serve as an efficient in vivo buffer for parasitotoxic hemin. Destabilising ligands of GST are thus expected to be synergistic with the antimalarial drug chloroquine, which itself was found to be a very weak inhibitor of PfGST (IC50 >200 M). Xray quality crystals of PfGST (25020050 m) will serve as starting point for structurebased drug design.
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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- Analysis of the Structural Determinants for RNA Binding of the Human Protein AUF1/hnRNP D
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- Stage-Specific Antimalarial Activity of Cysteine Protease Inhibitors
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- Design of Inhibitors for Human Tissue Kallikrein Using Non-Natural Aromatic and Basic Amino Acids
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Articles in the same Issue
- Nobuhiko Katunuma: An Outstanding Scientific and Professional Career of a Warm-Hearted Person. Reflections on the Occasion of his 75th Birthday
- Structural and Functional Diversity of Connexin Genes in the Mouse and Human Genome
- Congopain from Trypanosoma congolense: Drug Target and Vaccine Candidate
- Biosynthesis of Lysosomal Proteinases in Health and Disease
- Calpain Function in the Differentiation of Mesenchymal Stem Cells
- Ku Antigen Supports Termination of Mammalian rDNA Replication by Transcription Termination Factor TTF-I
- Thyroid Stimulating Hormone Upregulates Secretion of Cathepsin B from Thyroid Epithelial Cells
- Selective Release of Calpain Produced αII-Spectrin (α-Fodrin) Breakdown Products by Acute Neuronal Cell Death
- Altered Storage of Proteases in Mast Cells from Mice Lacking Heparin: A Possible Role for Heparin Carboxypeptidase A Processing
- Clustering-Induced Signaling of CEACAM1 in PC12 Cells
- Spin Adducts of Superoxide, Alkoxyl, and Lipid-Derived Radicals with EMPO and Its Derivatives
- Glutathione S-Transferase of the Malarial Parasite Plasmodium falciparum: Characterization of a Potential Drug Target
- Analysis of the Structural Determinants for RNA Binding of the Human Protein AUF1/hnRNP D
- Effect of Cysteine Proteinase Inhibitors on Murine B16 Melanoma Cell Invasion in vitro
- Stage-Specific Antimalarial Activity of Cysteine Protease Inhibitors
- Epoxysuccinyl Peptide-Derived Cathepsin B Inhibitors: Modulating Membrane Permeability by Conjugation with the C-Terminal Heptapeptide Segment of Penetratin
- Design of Inhibitors for Human Tissue Kallikrein Using Non-Natural Aromatic and Basic Amino Acids
- Amyloid Fibril Formation by Human Stefin B in vitro: Immunogold Labelling and Comparison to Stefin A
- Lysosomal Peptidases and Glycosidases in Rheumatoid Arthritis
