Trypanothione reductase, inhibition

Polyamine metabolism by parasites differs in several significant ways from the mammalian host these include, but are not limited to, enzyme half-life, turnover, substrate specificity, types and quantities of polyamines produced. The production of the novel bis glutathionyl spermidine adduct by trypanosomatids, its role as an antioxidant and the protein structure of trypanothione reductase is discussed with respect to the more conventional glutathione reductase system. The role of S-adenosylmethionine and decarboxylated S-adenosylmethionine as critical precursors in the biosynthesis of the higher polyamines is explored with respect to differences in the function and control of the pathway by various parasites. Polyamine biosynthesis in parasites is sufficiently different from that of the host to afford multiple opportunities for drug development, these may be aimed directly at circumventing polyamine biosynthesis or at inhibiting precursors necessary for polyamine synthesis. 

ANTIPROTOZOAL EFFECTS Melarsoprol is a prodrug that is metabolized rapidly (t j of 30 minutes) to melarsen oxide, the active form. Arsenoxides react avidly and reversibly with sulfhydryl groups and thereby inactivate many enzymes. Melarsoprol reacts with trypanothione to form melarsen oxide-trypanothione adduct, which potently inhibits trypanothione reductase. Both the sequestering of trypanothione and the inhibition of trypanothione reductase are expected to have lethal consequences to the cell, but this remains unproven. 

C. Nifurtimox This drug is a nitrofurazone derivative that inhibits the parasite-unique enzyme trypanothione reductase. Nifurtimox is the drug of choice in American trypanosomiasis and has also been effective in mucocutaneous leishmaniasis. The drug causes severe toxicity, including allergies, gastrointestinal irritation, and CNS effects. 

Nifurtimox is selectively toxic to some protozoans because it inhibits trypanothione reductase... 

As discussed for metronidazole, nifurtimox is thought to undergo reduction followed by oxidation and, in the process, generate ROS, such as the superoxide radical anion, hydrogen peroxide, and hydroxyl radical (Fig. 39.3) (5). These species are potent oxidants, producing oxidative stress that may produce damage to DNA and lipids that may affect cellular membranes. In addition, Henderson et al. (27) have reported that nifurtimox inhibits trypanothione reductase, which results in the inhibition of trypanothione formation (93% inhibition). Trypanothione is a critical protective enzyme found uniquely in trypanosomal parasites. 

Bonse, S. Santelli-Rouvier, C. Barbe, J. Krauth-Siegel, R. L. Inhibition of Trypanosoma cruzi Trypanothione Reductase by Acridines Kinetic studies and structure-activity relationships. J. Med. Chem. 1999, 42, 5448-5454. 

Reduction of trypanothione levels in the cells may be achieved in two ways (a) by inhibition of trypanothione peroxidase/reductase activity, or (b) by interference with the polyamine biosynthesis. Interference with the polyamine synthesis will not only lead to a decreased turnover of various polyamines, but will also bring down trypanothione levels in cells, thereby, exposing the parasites to the toxic effects of peroxides and free radicals generated by the host. 

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