Targeting Trypanothione Metabolism in Trypanosomatid Human Parasites

Viridiana      Olin-Sandoval; Rafael      Moreno-Sanchez; Emma      Saavedra

Abstract

The diseases caused by the trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are widely distributed throughout the world. Because of the toxic side-effects and the economically unviable cost of the currently used pharmaceutical treatments, the search for new drug targets continues. Since the antioxidant metabolism in these parasites relies on trypanothione [T(SH)2], a functional analog of glutathione, most of the pathway enzymes involved in its synthesis, utilization and reduction have been proposed as drug targets for therapeutic intervention. In the present review, the antioxidant metabolism and the phenotypic effects of inhibiting by genetic (RNA interference, knockout) or chemical approaches, the T(SH)2 and polyamine pathway enzymes in the parasites are analyzed. Although the genetic strategies are helpful in identifying essential genes for parasite survival/infectivity, they are less useful for drugtarget validation. The effectiveness of targeting each pathway enzyme was evaluated by considering (i) the enzyme kinetic properties and antioxidant metabolite concentrations and (ii) the current knowledge and experimental approaches to the study of the control of fluxes and intermediary concentrations in metabolic pathways. The metabolic control analysis indicates that highly potent and specific inhibitors have to be designed for trypanothione reductase and the peroxide detoxification system, and hence other enzymes emerge (γ-glutamylcysteine synthetase, trypanothione synthetase, ornithine decarboxylase, S-adenosylmethionine decarboxylase and polyamine transporters) as alternative more suitable and effective drug targets in the antioxidant metabolism of trypanosomatids.

Keywords: Leishmania, Trypanosoma, trypanothione, drug-targeting, microbial antioxidant metabolism, Trypanosoma brucei, Trypanosoma cruzi, trypanothione [T(SH)2], phenotypic effects, trypanothione reductase, peroxide detoxification system, ?-glutamylcysteine synthetase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, polyamine transporters, leishmaniasis, difluoromethylornithine (DFMO), melarsoprol, sodium stibogluconate, meglumine antimoniate, glycolysis, sterol biosynthesis, protein prenylation, recycle trypanothione [T(SH)2], glutathione reductase (GR), thioredoxin reductases (TrxR), spermidine (Spd), homotrypanothione, Euglena gracilis, Entamoeba histolytica, γ-glutamylcysteine synthetase, carboxyl group of glutamate (Glu), α-amino group of cysteine (Cys), γ-glutamylcysteine (γEC), Glutathione synthetase, trypanosomatids, ABC transporter (pgpa), Plasmodium falciparum, spermidine synthase, decarboxylated Sadenosylmethionine (dAdoMet), heterotetrameric enzyme, oligomeric form, prozyme, T. brucei gambiense, phylogenetic analyses, L. mexicana amastigotes, T(SH)2 Synthesis, stoichiometric, Trypanosoma cruzi TryS (TcTryS), epimastigotes, amastigotes, tryparedoxin (TXN), thioredoxin (Trx), thioredoxin reductase (TrxR), 2-Cys peroxyredoxins (2-Cys-Prx), non-selenium glutathione peroxidase type A (nsGPxA), glutaredoxins (Grx), TXN-dependent peroxidases (TXNPx), cytosolic isoenzyme, endoplasmic reticulum (ER), Thioredoxin, trypanosomal Trxs, dehydroascorbate (DHA), thiol-molecules, Glutathione-S- transferases (GSTs), xenobiotic detoxification, RNA interference (RNAi), ?ECS Inhibition, buthionine sulfoximine, nifurtimo, benznidazole, Metabolic Control Analysis (MCA), nifurtimox, megazol, allosteric modulators, leishmanial parasites, glutathionyl-spermidine, Difluoromethylornithine