Characterization of class II fumarase from Schistosoma mansoni provides the molecular basis for selective inhibition

Schistosomiasis is a neglected tropical disease that affects more than 250 million people worldwide. The only drug available for its treatment undergoes first-pass hepatic metabolism and is not capable of preventing reinfection, which makes the search of new therapies urgently needed. Due to the essential role of fumarases in metabolism, these enzymes represent potential targets for developing novel schistosomiasis treatments. Here, we evaluate the expression profiles for class I and class II fumarases from Schistosoma mansoni (SmFH_I and SmFH_II, respectively), and report the complete characterization of SmFH_II. The first SmFH_II structure in complex with L-malate was determined at 1.85 Å resolution. The significant thermoshift observed for SmFH_II in the presence of identified ligands makes the differential scanning fluorimetry an adequate technique for ligand screening. A complete kinetic characterization of SmFH_II was performed, and comparison with the human fumarase (HsFH) revealed differences regarding the turnover number (k_cat). Structural characterization allowed us to identify differences between SmFH_II and HsFH that could be explored to design new selective inhibitors. This work represents the very first step towards validate the fumarases as drug targets to treat schistosomiasis. Our results provide the structural basis to rational search for selective ligands.