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Dissecting the role of glutathione biosynthesis in Plasmodium falciparum
Author(s) -
Patzewitz EvaMaria,
Wong Eleanor H.,
Müller Sylke
Publication year - 2012
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2011.07933.x
Subject(s) - glutathione , buthionine sulfoximine , biology , glutathione synthetase , biosynthesis , biochemistry , plasmodium falciparum , tripeptide , glutathione reductase , enzyme , amino acid , glutathione peroxidase , malaria , immunology
Summary Glutathione (γ‐glutamylcysteinyl‐glycine, GSH) has vital functions as thiol redox buffer and cofactor of antioxidant and detoxification enzymes. Plasmodium falciparum possesses a functional GSH biosynthesis pathway and contains mM concentrations of the tripeptide. It was impossible to delete in P. falciparum the genes encoding γ‐glutamylcysteine synthetase (γGCS) or glutathione synthetase (GS), the two enzymes synthesizing GSH, although both gene loci were not refractory to recombination. Our data show that the parasites cannot compensate for the loss of GSH biosynthesis via GSH uptake. This suggests an important if not essential function of GSH biosynthesis pathway for the parasites. Treatment with the irreversible inhibitor of γGCS L‐buthionine sulfoximine (BSO) reduced intracellular GSH levels in P. falciparum and was lethal for their intra‐erythrocytic development, corroborating the suggestion that GSH biosynthesis is important for parasite survival. Episomal expression of γgcs in P. falciparum increased tolerance to BSO attributable to increased levels of γGCS. Concomitantly expression of glutathione reductase was reduced leading to an increased GSH efflux. Together these data indicate that GSH levels are tightly regulated by a functional GSH biosynthesis and the reduction of GSSG.