Glutathione dependent metabolism of the malarial parasite Plasmodium falciparum

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For survival and growth of the malarial parasite Plasmodium falciparum (Pf) glutathione homeostasis is of particular importance. The tripeptide glutathione (γ-Glu-Cys-Gly) serves for detoxifying electrophiles such as hemin and methylglyoxal and for quenching reactive oxygen and nitrogen species produced by the high metabolic rate of the parasite, the immune systems of the hosts, and as a byproduct of hemoglobin digestion. Apart from antioxidant defense and redox regulation, the glutathione system has been linked to the detoxification of antimalarial drugs and resistance mechanisms. Within the frame of the proposed project, we plan to continue our work on the glutathione-dependent redox milieu and glutathione-dependent proteins of the malarial parasite. We aim at focusing on the following four aspects: (1) establishing redox sensitive GFP (the glutaredoxin1-roGFP2 fusion protein) as tool for dynamic live imaging of the glutathione redox potential in Plasmodium, (2) determining the subcellular localization of glutathione-related proteins, (3) characterizing glutathionylation patterns in the proteome of malarial parasites under various conditions, and (4) studying the structural, biochemical and kinetic effects of glutathionylation on selected target proteins.