Plasmodium falciparum glutathione reductase exhibits sequence similarities with the human host enzyme in the core structure but differs at the ligand-binding sites.
The homodimeric flavoenzyme glutathione reductase (GR) which catalyzes the reduction of glutathione disulfide is a cornerstone of the malaria parasite antioxidant defense and repair mechanisms. Here we report on the identification of the GR gene from Plasmodium falciparum. A 1.4-kb fragment of the gene was amplified by polymerase chain reaction (PCR). Using this PCR fragment as a probe a full length cDNA clone (2085 bp) was isolated from a P. falciparum gametocyte library. The deduced amino acid sequence of 541 residues shows an overall identity of 35% when compared to the human enzyme. Most amino acids of known function are identical. However, notable differences between human and parasite protein occur in the glutathione-binding pocket (for instance, Glu374 instead of the expected basic residue) and at the intersubunit contact area. These regions are of particular interest since they represent binding sites of known GR inhibitors. Consequently, parasite GR can serve as a target structure for the design of antimalarial drugs.
Müller
S
S
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Becker
K
K
Bergmann
B
B
Schirmer
R H
RH
Walter
R D
RD
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D016054:DNA, Protozoan / Q000235:genetics; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D017125:Genes, Protozoan; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D005980:Glutathione Reductase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D016054:DNA, Protozoan; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D005980:Glutathione Reductase; D005978:Glutathione; D019803:Glutathione Disulfide