Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts.
2005 (English)In: Biol Chem, ISSN 1431-6730, Vol. 386, no 1, 41-52 p.Article in journal (Refereed) Published
The glyoxalase system consisting of glyoxalase I (GloI) and glyoxalase II (GloII) constitutes a glutathione-dependent intracellular pathway converting toxic 2-oxoaldehydes, such as methylglyoxal, to the corresponding 2-hydroxyacids. Here we describe a complete glyoxalase system in the malarial parasite Plasmodium falciparum. The biochemical, kinetic and structural properties of cytosolic GloI (cGloI) and two GloIIs (cytosolic GloII named cGloII, and tGloII preceded by a targeting sequence) were directly compared with the respective isofunctional host enzymes. cGloI and cGloII exhibit lower K(m) values and higher catalytic efficiencies (k(cat)/K(m) ) than the human counterparts, pointing to the importance of the system in malarial parasites. A Tyr185Phe mutant of cGloII shows a 2.5-fold increase in K(m) , proving the contribution of Tyr185 to substrate binding. Molecular models suggest very similar active sites/metal binding sites of parasite and host cell enzymes. However, a fourth protein, which has highest similarities to GloI, was found to be unique for malarial parasites; it is likely to act in the apicoplast, and has as yet undefined substrate specificity. Various S-(N-hydroxy-N-arylcarbamoyl)glutathiones tested as P. falciparum Glo inhibitors were active in the lower nanomolar range. The Glo system of Plasmodium will be further evaluated as a target for the development of antimalarial drugs.
Place, publisher, year, edition, pages
2005. Vol. 386, no 1, 41-52 p.
Amino Acid Sequence, Animals, Binding Sites, Comparative Study, Gene Expression Regulation, Glutathione/*pharmacology, Humans, Kinetics, Lactoylglutathione Lyase/antagonists & inhibitors/chemistry/genetics, Metals/chemistry, Models; Molecular, Molecular Sequence Data, Plasmodium falciparum/*enzymology, Protein Conformation, Protein Structure; Tertiary, Recombinant Proteins/chemistry/genetics, Research Support; Non-U.S. Gov't, Sequence Alignment, Thiolester Hydrolases/antagonists & inhibitors/chemistry/genetics
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
IdentifiersURN: urn:nbn:se:uu:diva-74495PubMedID: 15843146OAI: oai:DiVA.org:uu-74495DiVA: diva2:102405