Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts

Biol Chem. 2005 Jan;386(1):41-52. doi: 10.1515/BC.2005.006.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Gene Expression Regulation
  • Glutathione / pharmacology*
  • Humans
  • Kinetics
  • Lactoylglutathione Lyase* / antagonists & inhibitors
  • Lactoylglutathione Lyase* / chemistry
  • Lactoylglutathione Lyase* / genetics
  • Metals / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Plasmodium falciparum / enzymology*
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sequence Alignment
  • Thiolester Hydrolases* / antagonists & inhibitors
  • Thiolester Hydrolases* / chemistry
  • Thiolester Hydrolases* / genetics


  • Metals
  • Recombinant Proteins
  • Thiolester Hydrolases
  • hydroxyacylglutathione hydrolase
  • Lactoylglutathione Lyase
  • Glutathione