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Redox metabolism

Deficient metabolic utilization of H202 in T. cruzi

Almost four decades ago T. cruzi was reported to be deficient in enzyme systems necessary for the removal of hydrogen peroxide (H2O2). ’ ’ ’ Despite extensive studies on the antioxidant defenses of this and other trypanosomatids over subsequent years, this characterization appears to be still valid. T. cruzi lacks genes for catalase, selenocysteine-dependent glutathione peroxidases, glutathione reductase, and thioredoxin reductase.91,92 The two cysteine-dependent glutathione peroxidases that have been described are not able to hydrolyze H2O291,92. One enzyme able to catalyze this reaction is the ascorbate peroxidase (TcAPx), first described in 1976 in T. cruzi.93 The recombinant enzyme was studied more recently.94 The activity of this enzyme in epimastigote homogenates is only 6—15 nmol H2O2/min X mg protein.95 In addition, expression of the enzyme is not correlated to virulence or metacyclogenesis,96 the enzyme is not essential for parasite viability within the mammalian host, and does not have a significant role in establishment and maintenance of chronic infections.97 However, null mutants of TcAPx have decreased ability to infect mammalian cells in vitro and an increased sensitivity to exogenous H2O2.97 TcAPx expression is enhanced in T. cruzi strains resistant to benznida- zole.98 The trypanothione-dependent peroxidase activity with H2O2 as substrate in extracts of epimastigotes (which include the activities of tryparedoxin peroxidases and any other NADPH-dependent peroxidases, i.e., peroxidases dependent on the reduction of T(SH)2), is only 1.86 6 0.54 nmol NADPH oxidized/min X mg protein.99 It has been pointed out that these trypanothione-dependent peroxidase activities are quite low in comparison with approximately 150 nmol/min X mg protein found in lung mitochondria.100 Assuming that 108 epimastigotes are approximately equivalent to 1 mg protein100 it seems that ascorbate peroxidase and other trypanothione-dependent peroxidases are approximately 10 and 80 times less active, respectively, than the equivalent activities in mammalian tissues on a mg protein basis. In other words, trypanosomatids may be protected for dealing with a slow endogenous rate of H2O2 generation but they are probably quite sensitive to an increased steady state concentration of H2O2.100 The reason for this deficiency is probably that there is little need for decomposing H2O2 in the conditions under which the parasite, a facultative aerobe, develops, either in the intestine of the insect vector in the case of epimastigotes, or in the cytosol of the host cell in the case of the intracellular amastigotes. In this regard, transformation of epimastigotes into metacyclic trypomastigotes is accompanied by an increase in expression of antioxidant enzymes, such as ascorbate peroxidase, tryparedoxin peroxidase, tryparedox- in, trypanothione synthase, and iron superoxide dismutase,2 a phenomenon that was proposed to indicate a preadaptation of metacyclic forms to withstand the potential respiratory burst of phagocytic cells in the mammalian host.2 This deficiency in the metabolism of H2O2 also explains in part the susceptibility of T. cruzi to H2O2-generating drugs, such as napthoquinones,89,90,101—108 and nifurtimox,109—111 one of the drugs used against Chagas disease.

Trypanothione synthesis occurs by condensation of spermidine

Figure 17.4 Trypanothione synthesis occurs by condensation of spermidine (A) with GSH to give glutathionyl spermidine (B). Addition of a second GSH leads to the formation of dihydrotrypanothione (T(SH)2) (C). Both reactions consume ATP and are catalyzed by trypanothione synthase.

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