Trypanosomal Antioxidants and Emerging Aspects of Redox Regulation in the Trypanosomatids

Leishmania and Trypanosoma are two genera of the protozoal Order Kinetoplastida that cause widespread diseases of humans and their lifestock. The production of reactive oxygen and nitrogen intermediates by the host plays an important role in the control of infections by these organisms. Signal transduction and its redox regulation have not been studied in any depth in trypanosomatids, but homologs of the redox-sensitive signal transduction machinery of other eukaryotes have been recognized. These include homologs of activator protein-1, human apurinic endonuclease 1 (Ref-1) endonuclease, iron-responsive protein, protein kinases, and phosphatases. The detoxification of peroxide is catalyzed by a trypanothione-dependent system that has no counterpart in mammals, and thus ranks as one of the biochemical peculiarities of trypanosomatids. There is substantial evidence that trypanothione is essential for the survival of Trypanosoma brucei and for the virulence of Leishmania spp. Apart from trypanothione and its precursors, trypanosomatids also possess significant amounts of N ¹-methyl-4-mercaptohistidine or ovothiol A, but its function in the trypanosomatids is not presently understood. The biosynthesis of ovothiol A in Crithidia fasciculata proceeds by addition of sulfur from cysteine to histidine to form 4-mercaptohistidine. S-(4′-L-Histidyl)-L-cysteine sulfoxide is the transsulfuration intermediate. 4-Mercaptohistidine is subsequently methylated with S-adenosylmethionine as the likely methyl donor.