New Insights into the Role of the Trypanosoma cruzi Aldo-Keto Reductase Tc AKR.

Chagas disease is a zoonotic infectious disease caused by the protozoan parasite Trypanosoma cruzi . It is distributed worldwide, affecting around 7 million people; there is no effective treatment, and it constitutes a leading cause of disability and premature death in the Americas. Only two drugs are currently approved for the treatment, Benznidazole and Nifurtimox, and both have to be activated by reducing the nitro-group. The T. cruzi aldo-keto reductase ( Tc AKR) has been related to the metabolism of benznidazole. Tc AKR has been extensively studied, being most efforts focused on characterizing its implication in trypanocidal drug metabolism; however, little is known regarding its biological role. Here, we found that Tc AKR is confined, throughout the entire life cycle, into the parasite mitochondria providing new insights into its biological function. In particular, in epimastigotes, Tc AKR is associated with the kinetoplast, which suggests additional roles of the protein. The upregulation of Tc AKR, which does not affect Tc OYE expression, was correlated with an increase in PGF 2 α, suggesting that this enzyme is related to PGF 2 α synthesis in T. cruzi . Structural analysis showed that Tc AKR contains a catalytic tetrad conserved in the AKR superfamily. Finally, we found that Tc AKR is also involved in Nfx metabolization.