Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in < i > Trypanosoma cruzi < /i >

by Isabel S. Shiratsubaki, Xin Fang, Rodolpho O. O. Souza, Bernhard O. Palsson, Ariel M. Silber, Jair L. Siqueira-Neto Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan calledTrypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with severe side effects. Thus, there is a need for alternative and more efficient drugs. Genome-scale metabolic models (GEMs) can accurately predict metabolic capabilities and aid in drug discovery in metabolic genes. This work developed an extended GEM, hereafter referred to as iIS312, of the published and validatedT.cruzi core metabolism model. From iIS312, we then built three stage-specific models through transcriptomics data integration, and showed that epimastigotes present the most active metabolism among the stages (see S1 –S4 GEMs). Stage-specific models predicted significant metabolic differences among stages, including variations in flux distribution in core metabolism. Moreover, the gene essentiality predictions suggest potential drug targets, among which some have been previously proven lethal, including glutam ate dehydrogenase, glucokinase and hexokinase. To validate the models, we measured the activity of enzymes in the core metabolism of the parasite at different stages, and showed the results were consistent with model predictions. Our results represen...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research