Distinct mitochondrial and cytosolic enzymes mediate trypanothione-dependent peroxide metabolism in Trypanosoma cruzi

The American trypanosome Trypanosoma cruzi is exposed to toxic oxygen metab olites that are generated by drug metabolism and immune responses in additi on to those produced by endogenous processes. However, much remains to be r esolved about the parasite oxidative defense system, including the mechanis m(s) of peroxide reduction. Here we show that reduction of peroxides in T. cruzi is catalyzed by two distinct trypanothione-dependent enzymes. These w ere localized to the cytosol and mitochondrion. Both are members of the per oxiredoxin family of antioxidant proteins and are characterized by the pres ence of two conserved domains containing redox active cysteines. The role o f these proteins in protecting T. cruzi from peroxide-mediated damage was d emonstrated following overexpression of enzyme activity. The parasite-speci fic features of T. cruzi cytoplasmic peroxiredoxin and T. cruzi mitochondri al peroxiredoxin may be exploitable in terms of drug development.