Glutathione S-transferase from malarial parasites: structural and functional aspects.
Malaria represents an emerging disease because of increasing parasite resistance against available drugs and because of increasing geographical distribution of the causative agent, Plasmodium falciparum. The complete genome of Plasmodium was sequenced recently, revealing that the parasite harbors only one glutathione S-transferase (PfGST). This observation was of particular interest: First, certain antimalarial drugs such as chloroquine and methylene blue presumably influence the glutathione metabolism in which PfGST is involved. Second, PfGST might play a significant role in drug resistance. PfGST was studied in parasite extracts and as recombinant protein, and its x-ray structure has been solved. The available data indicate that the homodimeric PfGST cannot be assigned to any of the previously known GST classes. PfGST exhibits significant structural differences to human GSTs, particularly at the so-called hydrophobic binding pocket (H-site) where the second substrate binds. Inhibition of PfGST is expected to act at different vulnerable metabolic sites of the parasite in parallel; it is likely to disturb GSH-dependent detoxification processes, to increase the levels of cytotoxic peroxides, and possibly to increase the concentration of toxic hemin. In this chapter, we summarize the current knowledge on PfGST, including aspects of structure, function, and future drug development.
Deponte
Marcel
M
Interdisciplinary Research Center, Giessen University, Germany.
Becker
Katja
K
D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000627:therapeutic use; D004351:Drug Resistance / Q000502:physiology; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000201:enzymology / Q000469:parasitology; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D015800:Protozoan Proteins; D005982:Glutathione Transferase