In vivo functions of the intra-organellar glutathione peroxidase-type enzymes in African trypanosomes

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In African trypanosomes hydroperoxide detoxification relies exclusively on 2-Cys-peroxiredoxins and non-selenium glutathione peroxidase-type (Px) enzymes which both obtain their reducing equivalents from the unique trypanothione/tryparedoxin system. Whereas the cytosolic peroxidases have been studied in detail, nearly nothing is known about the Px-type enzymes in the different subcellular compartments. Within this work we will investigate the in vivo functions of the mitochondrial and putatively glycosomal Px III. Since in the mammalian bloodstream form of Trypanosoma brucei, deletion of the gene did not result in a proliferation defect, we will knock-out the gene in the procyclic insect form which possesses a fully functional mitochondrion; virulence of the Px III-deficient bloodstream parasites will be studied in the animal model. Characterisation of the probably ER-resident Px IV should reveal if the enzyme is essential and if it catalyzes the detoxification of lipid hydroperoxides or may reduce hydrogen peroxide with protein disulfide isomerases as electron source. This latter reaction has recently been reported for ER-localized mammalian glutathione peroxidases and would offer a totally new function of this type of peroxidases. The planned work should provide us with a comprehensive picture of the distinct roles of these thiol peroxidases within the trypanothione-based redox metabolism of trypanosomes.