ABSTRACT
Kinetoplastids are primitive eukaryotes that can be found either as free-living organisms or as obligate parasites in a diverse range of invertebrates or vertebrates (Stevens, 2008). For instance, the parasites Leishmania donovani, Leishmania amazoniensis, Leishmania infantum, Trypanosoma cruzi, and Trypanosoma brucei, well known for causing leishmaniasis, visceral leishmaniasis, American trypanosomiasis or Chagas disease and African trypanosomiasis or sleeping sickness, respectively, belong to the trypanosomatid group of kinetoplastids. In these organisms, most of the low-molecular-weight thiol content is found as a singular derivative of glutathione (GSH): N 1,N 8-bis(glutathionyl)-spermidine or trypanothione. * Initially described in 1985 by Fairlamb (Fairlamb et al., 1985), it is a dithiol product of the conjugation of two molecules of GSH with one molecule of spermidine by the enzymes mono-glutathionyl spermidine synthetase (GspS) and trypanothione synthetase (TryS) or by TryS alone catalyzing both conjugation reactions (Manta et al., 2013a). Although Escherichia coli is able to synthesize mono-glutathionyl spermidine (Bollinger et al., 1995), a complete biosynthetic pathway for trypanothione is exclusive to kinetoplastids (see Chapter 17). Among them, almost all members of the trypanosomatid phylum contain the gene encoding for TryS, and some members, remarkably Trypanosoma brucei lacks the gene encoding GspS (Comini et al., 2004; Manta et al., 2018). Bodonids, model free-living heterotroph among kinetoplastids (https://www.sanger.ac.uk" xmlns:xlink="https://www.w3.org/1999/xlink">www.sanger.ac.uk) found worldwide in freshwater and marine habitats, contain both genes, and prokinetoplastids contain partial sequences with similarity to GspS and TryS (Jackson et al., 2008; Manta et al., 2018). Trypanothione disulfide (TS2) is reduced by trypanothione reductase (TR) at the expense of NADPH. Most of the characterized functions of trypanothione rely on (1) direct reactions with metabolites or (2) its participation as substrate in various enzyme-catalyzed reactions. Here, we summarize the current knowledge on the biochemistry of this particular dithiol, with emphasis on its reactivity toward relevant oxidants, its interactions with proteins and its participation as cofactor for a wide range of enzymatic reactions with relevance in cellular-, drug-metabolism, and infectivity.
