title: Plasmodium falciparum-infected red blood cells depend on a functional glutathione de novo synthesis attributable to an enhanced loss of glutathione.
abstract: During the erythrocytic cycle, Plasmodium falciparum is highly dependent on an adequate thiol status for its survival. Glutathione reductase as well as de novo synthesis of GSH are responsible for the maintenance of the intracellular GSH level. The first and rate-limiting step of the synthetic pathway is catalysed by gamma-glutamylcysteine synthetase (gamma-GCS). Using L-buthionine-(S, R)-sulphoximine (BSO), a specific inhibitor of the gamma-GCS, we show that the infection with P. falciparum causes drastic changes in the GSH metabolism of red blood cells (RBCs). Infected RBCs lose GSH at a rate 40-fold higher than non-infected RBCs. The de novo synthesis of the tripeptide was found to be essential for parasite survival. GSH depletion by BSO inhibits the development of P. falciparum with an IC(50) of 73 microM. The effect of the drug is abolished by supplementation with GSH or GSH monoethyl ester. Our studies demonstrate that the plasmodicidal effect of the inhibitor BSO does not depend on its specificity towards its target enzyme in the parasite, but on the changed physiological needs for the metabolite GSH in the P. falciparum-infected RBCs. Therefore the depletion of GSH is proposed as a chemotherapeutic strategy for malaria, and gamma-GCS is proposed as a potential drug target.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Biochemical Parasitology, Bernhard-Nocht-Strasse 74, D-20359 Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Lüersen
authors.forename: R D
authors.initials: RD
authors.lastname: Walter
authors.forename: S
authors.initials: S
authors.lastname: Müller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D005978:Glutathione / Q000097:blood*; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood*; D010963:Plasmodium falciparum
chemical_list: D005978:Glutathione