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Polyprenyl diphosphate synthases

Once IPP is formed polyprenyl diphosphate synthases are responsible for chain elongation and catalyze the sequential condensation of IPP with allylic prenyl diphosphates.36 So far, only the genes encoding farnesyl diphosphate synthase (FPPS),38 and solanesyl diphosphate synthase (SPPS)39 have been cloned from T. cruzi. Both of these genes are single copy. While the FPP synthase is localized in the cytosol,40 the SPP synthase is localized in the glycosomes.39 Glycosomes are specialized peroxisomes that, like them, contain several enzymes in pathways of ether lipid synthesis, fatty acid (3-oxidation, and peroxide metabolism, and, in addition, contain the Embden-Meyerhof segment of glycolysis.41

Isoprenoid pathway in T. cruzi. Enzyme names are in gray (blue in web version), products in black, and inhibitors in light gray (red in web version)

Figure 17.2 Isoprenoid pathway in T. cruzi. Enzyme names are in gray (blue in web version), products in black, and inhibitors in light gray (red in web version).

T. cruzi farnesyl diphosphate synthase (TcFPPS) catalyzes the consecutive condensation of IPP with DMAPP and with geranyl diphosphate (GPP) to form the 15-carbon isoprenoid compound, farnesyl diphosphate (FPP) (Fig. 17.2). FPP is the substrate for enzymes catalyzing the first committed step for biosynthesis of sterols (which in T. cruzi is mainly ergosterol42), ubiquinones (which in T. cruzi is mainly ubiquinone-939), dolichols (which are required for the synthesis of complex carbohydrates and are present in T. cruzi43), heme A (a component of the cytochrome oxidase, also present in T. cruzi44), and prenylated proteins (also present in T. cruzi45-48). FPP could be condensed with an additional molecule of IPP by the geranylgeranyl diphosphate synthase (GGPPS) to form the 20-carbon isoprenoid GGPP (Fig. 17.2), although this enzyme has not been studied in T. cruzi. The FPPS gene appears to be essential in all organisms.49,50 As most FPPSs that have been characterized, T. cruzi FPPS is an homodimeric enzyme, and requires divalent metal ions such as Mg21 or Mn21 for activity.38 The 3D structure of TcFPPS has been solved in complex with different substrates and inhibitors.51-53

TcFPPS is the main target of bisphosphonates in T. cruzi.34,38 Bisphosphonates are pyrophosphate analogues in which a carbon atom replaces the oxygen atom bridge between the two phosphorus atoms of the pyrophosphate. The substitution of carbon with different side chains has generated a large family of compounds (Fig. 17.3). Several bisphosphonates are potent inhibitors of bone resorption and are in clinical use for the treatment and prevention of osteoporosis, Paget’s disease, hypercalcemia, tumor bone metastases, and other bone diseases.54 Selective action

Structure of pyrophosphate

Figure 17.3 Structure of pyrophosphate (diphosphate) and selected bisphosphonates. First- (clodronate and etidronate), second- (pamidronate, alendronate, and ibandronate), and third- (risedronate, zolendronate, and YM 529) generation bisphosphonates are shown.

on bone is based on the binding of the bisphosphonate to the bone mineral.54 It has been postulated that the acidocalcisomes, organelles rich in phosphorus and calcium in trypanosomes, are equivalent in composition to the bone mineral and that accumulation of bisphosphonates in these organelles, as they do in bone mineral, facilitates their antiparasitic action.55 Nitrogen-containing bisphosphonates were first found to be effective in the inhibition of T. cruzi in vitro and in vivo without toxicity to the host cell.56,57 In vivo testing of bisphosphonates against T. cruzi in mice has shown that risedronate can significantly increase the survival of mice infected by T. cruzi.5,859 All these results indicate that bisphosphonates are promising candidate drugs to treat infections by T. cruzi.

T. cruzi solanesyl diphosphate synthase (TcSPPS) catalyzes the formation of the 45-carbon compound solanesyl diphosphate (SPP), which is an intermediate in the synthesis of ubiquinone-9. Ubiquinone is synthesized de novo in both prokaryotes and eukaryotes. The two parts of the molecule, the benzoquinone ring and the iso- prene chain, are synthesized independently and assembled in a reaction catalyzed by a prenyl-4-hydroxybenzoate-transferase.60 4-Hydroxybenzoate originates from tyrosine or phenylalanine in eukaryotes.61 In T. cruzi it was shown that epimasti- gotes synthesize and keep mainly UQ9 in their membranes.39 Human tissues have mostly UQ10 while rat tissues have UQ9. Valuable functions have been adjudicated to this molecule, including acting as a component of the mitochondrial electron transfer system, as the only lipid-soluble antioxidant that is endogenously synthesized in both unicellular and multicellular organisms, and as an acceptor of electrons from sulfide.62 Two genes with homology to the yeast63 and human64 prenyl-4-hydroxybenzoate-transferases are present in the genome of T. cruzi differing in only two amino acids and possessing a mitochondrial targeting signal (TcCLB.510903.60 and TcCBL.505965.30). The protein has a putative polyprenyl diphosphate-binding domain similar to those found in other enzymes known to bind isoprenoid substrates. Bisphosphonates can also inhibit the activity of TcSPPS and amastigote growth in culture cells.65

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