Trypanosoma Cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals
Source: Free Radical Research, Volume 34, Number 4, 2001 , pp. 363-378(16)
Publisher: Informa Healthcare
Abstract:Trypanosoma cruzi trypanothione reductase (TR) was irreversibly inhibited by peroxidase/H 2 O 2/phenothiazine (PTZ) systems. TR inactivation depended on (a) time of incubation with the phenothiazine system; (b) the peroxidase nature and (c) the PTZ structure and concentration. With the most effective systems, TR inactivation kinetics were biphasic, with a relatively fast initial phase during which about 75% of the enzyme activity was lost, followed by a slower phase leading to total enzyme inactivation. GSH prevented TR inactivation by the peroxidase/H 2 O 2 /PTZ +· systems. Production of PTZ +· cation radicals by PTZ peroxidation was essential for TR inactivation. Horseradish peroxidase, leukocyte myeloperoxidase (MPO) and the pseudo-peroxidase myoglobin (Mb) were effective catalysts of PTZ +· production. Promazine, thioridazine, chlorpromazine, propionylpromazine prochlorperazine, perphenazine and trimeprazine were effective constituents of the HRP/H 2 O 2 /PTZ system. The presence of substituents at the PTZ nucleus position 2 exerted significant influence on PTZ activity, as shown by the different effects of 2-trifluoromethyl and 2-H or 2-chlorophenothiazines. The PTZ +· cation radicals disproportionation regenerated the non-radical PTZ molecule and produced the PTZ sulfoxide that was inactive on TR. Thiol compounds including GSH interacted with PTZ +· cation radicals transferring an electron from the sulfide anion to the PTZ +· , thus nullifying the PTZ +· biological and chemical activities.
Document Type: Research Article
Affiliations: 1: Bioenergetics Research Centre, School of Medicine, University of Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina 2: Division of Molecular Parasitology and Biological Chemistry, Department of Biochemistry, University of Dundee, Dundee, DD1, 5EH, United Kingdom
Publication date: January 1, 2001