Trypanosoma cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals

Jose Gutierrez-Correa, Alan Fairlamb, Andres O.M. Stoppani (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    51 Citations (Scopus)

    Abstract

    Trypanosoma cruzi trypanothione reductase (TR) was irreversibly inhibited by peroxidase/H2O2/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/H2O2/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, perpenazine and trimeprazine were effective constituents of the HRP/H2O2/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.

    Original languageEnglish
    Pages (from-to)363-378
    Number of pages16
    JournalFree Radical Research
    Volume34
    Issue number4
    DOIs
    Publication statusPublished - 2001

    Keywords

    • Cationic radicals
    • Horseradish peroxidase
    • Myeloperoxidase
    • Myoglobin
    • Phenothiazine
    • Trypanothione reductase

    ASJC Scopus subject areas

    • Biochemistry

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