Abstract
Trypanosoma brucei, the causative agent of African sleeping sickness, encodes three nearly identical cysteine homologues of the classical selenocysteine-containing glutathione peroxidases. Although one of the sequences, peroxidase III, carries both putative mitochondrial and glycosomal targeting signals, the proteins are detectable only in the cytosol and mitochondrion of mammalian bloodstream and insect procyclic T. brucei. The enzyme is a trypanothione/tryparedoxin peroxidase as are the 2 Cys-peroxiredoxins of the parasite. Hydrogen peroxide, thymine hydroperoxide, and linoleic acid hydroperoxide are reduced with second order rate constants of 8.7 x 10(4), 7.6 x 10(4), and 4 x 10(4) m(-1) s(-1), respectively, and represent probable physiological substrates. Phosphatidylcholine hydroperoxide is a very weak substrate and, in the absence of Triton X-100, even an inhibitor of the enzyme. The substrate preference clearly contrasts with that of the closely related T. cruzi enzyme, which reduces phosphatidylcholine hydroperoxides but not H(2)O(2). RNA interference causes severe growth defects in bloodstream and procyclic cells in accordance with the peroxidases being essential in both developmental stages. Thus, the cellular functions of the glutathione peroxidase-type enzymes cannot be taken over by the 2 Cys-peroxiredoxins that also occur in the cytosol and mitochondrion of the parasite.
Highlights
The causative agents of African sleeping sickness (Trypanosoma brucei gambiense and T. brucei rhodesiense), Nagana cattle disease (Trypanosoma congolense, T. brucei brucei), South-American Chagas’ disease (Trypanosoma cruzi), and the different forms of leishmaniasis, differ from all other known eukaryotes and prokaryotes in their unique thiol redox system
With NADPH as the final electron donor, the reducing equivalents flow via trypanothione onto tryparedoxin and the peroxidase, which catalyzes the reduction of the hydroperoxide [9,10,11, 13, 14, 16]
This means that the 2 Cys-peroxiredoxins and the glutathione peroxidase-type enzymes act as trypanothione-dependent tryparedoxin peroxidases
Summary
The causative agents of African sleeping sickness (Trypanosoma brucei gambiense and T. brucei rhodesiense), Nagana cattle disease (Trypanosoma congolense, T. brucei brucei), South-American Chagas’ disease (Trypanosoma cruzi), and the different forms of leishmaniasis, differ from all other known eukaryotes and prokaryotes in their unique thiol redox system. With NADPH as the final electron donor, the reducing equivalents flow via trypanothione onto tryparedoxin and the peroxidase, which catalyzes the reduction of the hydroperoxide [9,10,11, 13, 14, 16]. This means that the 2 Cys-peroxiredoxins and the glutathione peroxidase-type enzymes act as trypanothione-dependent tryparedoxin peroxidases. An enzyme from the nematode Brugia pahangi reduces linoleic acid hydroperoxide and phosphatidylcholine hydroperoxide but not H2O2 with glutathione as the reducing substrate It is a secreted glycoprotein, and the natural electron source is not known [22]. The results of RNA interference experiments demonstrated that the enzyme is essential for procyclic in addition to bloodstream T. brucei
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