The Relevance of Proline Metabolism in Trypanosoma cruzi Ariel M. Silber Departamento de Parasitologia, Instituto de Ciências Biomédicas Universidade de São Paulo, São Paulo, SP, Brasil
Abstract The flagellated parasite Trypanosoma cruzi, the etiological agent for Chagas’ disease, has a complex life cycle in mammals and insect vectors. During its life cycle, the parasite alternates between infective non-replicative and replicative non-infective stages. T. cruzi uses proline and glutamate, among other amino acids, as energy sources. Biochemical evidence supports the hypothesis that T. cruzi oxidizes L-proline into glutamate, this being a central pathway for T. cruzi metabolism. Furthermore, proline has been previously implicated in metacyclogenesis, the parasite differentiation process occurring in the insect vector. In the present work, we investigated the role of proline and proline metabolism in several biological processes which are essential for the parasite life cycle. During this research, we discovered that a metabolic switch occurs from a metabolism based on the consumption of glucose to one based on the consumption of proline, where the latter constitutes a major energy supply for growth and differentiation of the intracellular stages. In addition, proline is also a major energy source for host-cell invasion. Our results also showed that the hexose transporter TcHT, the only glucose transporter found in T. cruzi up to now, has a dual function: it is responsible for the uptake of glucose from the extracellular medium into the cytosol, and it is also responsible for the glucose uptake from the cytosol into the intracellular organelle where glycolysis begin: the glycosome. Finally, we learned that the inhibition of proline transport by using structural analogues of proline led to a diminished intracellular free proline concentration, which correlated with an increased sensitivity to oxidative, thermal and nutritional stress. The diversity of processes in which proline is involved in T. cruzi, sugest this metabolite to be particularly relevant for the survival of these organisms, allowing us to propose its transporters and the enzymes involved in its metabolism as interesting targets for the treatment of T. cruzi infection. Keywords amino acid metabolism, proline, glucose transport, host-cell invasion
Original publications: PLoS ONE 4, e4534, 2009. Mol Biochem Parasitol In press, 2009.