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Metabolic pathways in T. cruzi that could provide targets for drugs against Chagas disease

Isoprenoid pathway

One pathway that has been particularly useful for the identification of new targets against T. cruzi is the isoprenoid pathway (Fig. 17.2). Several enzymes of this pathway, involved in the synthesis of farnesyl diphosphate34 and sterols,20 and in protein prenylation,35 have been reported to be excellent drug targets against these parasites.

Isoprenoids are the most diverse and abundant compounds occurring in nature. Isoprenoids such as steroids, cholesterol, retinoids, carotenoids, ubiquinones, and prenyl proteins are essential components of the cells of all organisms due to their roles in different biological processes. Despite their structural and functional variety, all isoprenoids derive from a common precursor: isopentenyl diphosphate (IPP), and its isomer, dimethylallyl diphosphate (DMAPP). In T. cruzi, IPP is synthesized exclusively via the so-called mevalonate pathway, which has the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase as the key regulatory enzyme36,37 (Fig. 17.2). Mevalonate is then converted to IPP with two continuous phosphorylation steps and one decarboxylation step. Isomerization of IPP by IPP isomerase yields DMAPP.

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