(2) Thioredoxin-Glutathione Reductase

To carry out peroxide hydrogen reduction, both the GPx and Prx (TPx) need to take electrons from GSH and Trx and then generate their oxidized forms, the substrates (i.e., GSSG and Trx-S2, respectively). Reductases responsible for reducing these substrates again and helping to maintain the homeostatic redox cycle are significantly necessary. In mammals, there are two enzymes called glutathione reductase (GR) and thioredoxin reductase (TrxR), both are NADPH-dependent for the reduction of GSSG and Trx-S2, respectively [147]. However, in 2001, Gladyshev et al. identified an enzyme capable of reducing both Trx-S2 and GSSG in the mouse testis. This enzyme was called thioredoxinglutathione reductase (TGR) [148].

Although this enzyme has been identified in vertebrate organisms, including humans (hTGR) [149], it is in the group of parasitic flatworms where its study has gained relevance. Early on, it was isolated and characterized in the trematode *S. mansoni* (SmTGR) [150], as well as in the cestodes *E. granulosus* (EgTGR) [151] and *T. crassiceps* (TcTGR) [152]. Later on, it was possible to deduce its presence in other parasitic flatworms thanks to genomic advances [92]. Unlike their vertebrate hosts and their free-living counterparts [153], these organisms depend exclusively on this enzyme to carry out the reduction of GSSG and Trx-S2. Although it has been proposed that having an enzyme capable of reducing substrates belonging to two independent redox systems represents an evolutionary advantage [148], it is also possible to note that the dependence of parasitic flatworms on this enzyme makes it an excellent pharmacological target [154–161].

The genomes of trematodes and cestodes [76,87,92,129,162], as well as of the monogenean *Gyrodactylus salaris* [21], have corroborated the classic GRs and TrxRs in this group of parasites and have revealed that the TGR is encoded by a single gene; therefore, the cytosolic and mitochondrial forms must be generated by alternative splicing [163]. Despite being exactly of the same sequence, the environment in which it is located (either the cytosol or the mitochondrial matrix) affects its kinetic constants [164]. This enzyme is expressed in all stages of the life cycle, as reported in *S. mansoni* [125]. We previously reported that the in vivo inhibition of the TGR in *T. crassiceps* cysticerci is sufficient to compromise the viability of the parasite by altering its redox state and glutathione metabolism [165], which agrees with observations made when incubating schistosomula in the presence of anti TGR iRNA [166]. Due to its importance, TGR has been crystallized [167], promoting the search for drugs capable of inhibiting it [154–161].
