Home Economics American Trypanosomiasis Chagas Disease, Second Edition: One Hundred Years of Research
Several novel trypanothione analogues derived from spermine or other physiological polyamines have also been found in T. cruzi when supplemented with polyamines in the culture medium, among them homotrypanothione, N1, N12-bis(glutathionyl)sper- mine, N1-glutathionyl-N8-acetylspermidine, and N1-glutathionyl-N12-acetylsper-
mine.116,121 These compounds result from the condensation of GSH with polyamines other than spermidine such as cadaverin, spermine, N-acetylspermine, and N1- and N8- acetylspermine in reactions catalyzed by the trypanothione synthetase.121 The physiological relevance of these thiols as well as ovothiol (N1-methyl-4-mercaptohistidine),120 which is also present in all three life cycle stages of this parasite is not known.
Superoxide dismutases (SODs) catalyze the dismutation of superoxide anion (O2_) to H2O2 and O2. T. cruzi has four genes encoding for iron-dependent SODs, two of which have been cloned and the recombinant proteins characterized.165,166 One of these enzymes is cytosolic (TcSODA) while the other (TcSODB) is mitochondrially- localized. The recombinant enzymes are inactivated by peroxynitrite and the crystal structure of TcSODA has been reported.167 Inhibitors of the iron-containing superoxide dismutases of trypanosomatids have been found and proposed as possible trypanocidal agents.168 However, it is not self-evident that in an organism deficient in hydrogen peroxide detoxification, superoxide dismutase inhibition will be toxic. This assumption takes for granted that superoxide is the ultimate toxic species. However, it is conceivable that the hydrogen peroxide formed by the action of superoxide dis- mutase, and the hydroxyl radical eventually derived from it, are more cytotoxic than superoxide itself. If this is so, superoxide dismutase produces the toxic agent and superoxide dismutase inhibition may be protective as long as hydrogen peroxide cannot adequately be detoxified. Interestingly, a superoxide dismutase inhibitor was shown to decrease the parasitemia levels of T. cruzi in infected mice.169 Overexpression of cytosolic/glycosomal SOD (SODB1) in T. cruzi increases their susceptibility to benznidazole and crystal violet but has no effect on the action of nifurtimox.166 The reason for these effects is unknown.
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