title: Glutathione reductase and glutamate dehydrogenase of Plasmodium falciparum, the causative agent of tropical malaria.
abstract: The use of glutathione reductase inhibitors in chemotherapy is the raison d'être for this study. Two enzymes were purified to homogeneity from the intraerythrocytic malarial parasite Plasmodium falciparum: glutathione disulfide reductase, an antioxidative enzyme, which appears to play an essential role for parasite growth and differentiation, and glutamate dehydrogenase, an enzyme not occurring in the host erythrocyte. The two proteins were copurified and separated by gel electrophoresis with yields of approximately 20%. Malarial glutathione reductase, a homodimer of 110 kDa with a pH optimum of 6.8 and a high preference for NADPH over NADH, was shown to contain FAD as its prosthetic group. The N-terminal sequence, VYDLIVIGGGSGGMA, which can be aligned with residues 20-34 of human glutathione reductase, represents the first beta strand and the diphosphate-fixing helix of the FAD domain. Glutamate dehydrogenase was confirmed as a hexamer with blocked N-termini; it is an enzyme that is highly specific for NADP and NADPH. The copurification of the proteins and the potential of P.falciparum glutathione reductase as a drug target are discussed.
authors.affiliation: Institüt fur Biochemie II der Universität Heidelberg, Germany.
authors.forename: R L
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.forename: J G
authors.initials: JG
authors.lastname: Müller
authors.forename: F
authors.initials: F
authors.lastname: Lottspeich
authors.forename: R H
authors.initials: RH
authors.lastname: Schirmer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004912:Erythrocytes / Q000201:enzymology; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009249:NADP / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D013045:Species Specificity
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D009249:NADP; D005969:Glutamate Dehydrogenase; D005980:Glutathione Reductase