Trypanosoma cruzi , the disease-causing agent of Chagas disease, depends on glycolysis for ATP production. As such, the glycolytic enzymes of this parasite are attractive targets for the development of new therapies. Despite their essential role in parasite survival, the structural features of T. cruzi glycolytic enzymes remain poorly understood. In our study, we present high-resolution X-ray crystal structures of two central glycolytic enzymes in T. cruzi : glucose-6-phosphate isomerase (TcGPI, 1.8 Å) and enolase (TcEno, 2.4 Å). Tc GPI adopts a dimeric αβα sandwich fold and features a parasite-specific 53-residue N-terminal extension and a unique C-terminal hook region, which both distinguish it from its human ortholog. Tc enolase exhibits the conserved (α/β) 8 TIM barrel fold but harbors minor, distinct structural deviations, including an extended α17 helix and a structured α1 region, which differentiate it from human isoforms. CD-spectroscopy thermal stability assays demonstrated that these two enzymes also exhibited high thermostability, consistent with adaptation to the parasite’s elaborate life cycle. Collectively, these findings reveal the unique features of T. cruzi glycolytic enzymes, laying the groundwork for the development of selective antiparasitic therapeutics.
Austin et al. (Sun,) studied this question.