Thioredoxin glutathione reductase: Its role in redox biology and potential as a target for drugs against neglected diseases

Abstract

Background There are two, largely autonomous antioxidant pathways in many organisms, one based on thioredoxin and one based on glutathione, with each pathway having a unique flavoprotein oxidoreductase to maintain them in a reduced state. A recently discovered protein, thioredoxin glutathione reductase (TGR) potentially connects these two pathways. In a large group of parasitic worms, responsible for hundreds of millions of infections in humans and animals, untold morbidity and significant mortality, TGR is the sole enzyme present to maintain redox balance. Scope of Review In this review, the current understanding of the biochemical properties of TGR enzymes is compared to the related enzymes thioredoxin reductase and glutathione reductase. The role of the rare amino acid selenocysteine is discussed. An overview of the potential to target TGR for drug development against a range of parasitic worms and preliminary results to identify TGR inhibitors for schistosomiasis treatment is presented. Major Conclusions TGR has properties that are both unique and common to other flavoprotein oxidoreductases. TGR plays a fundamentally different and essential role in the redox biology of parasitic flatworms. Therefore, TGR is a promising target for drug development for schistosomiasis and other trematode and cestodes infections. General Significance TGR may have differing functions in host organisms, but through analyses to understand its ability to reduce both glutathione and thioredoxin we can better understand the reaction mechanisms of an important class of enzymes. The unique properties of TGR in parasitic flatworms provide promising routes to develop new treatments for diseases.

RNA-seq analyses of the midgut from blood- and serum-fed Ixodes ricinus ticks

“…Yeast cells code for two sets of reductases, glutathione reductase and thioredoxin reductase, with affinities to distinct thiols in order to restore their reduced state59. Platyhelminth parasites, however, were reported to code for an enzyme glutathione-thioredoxin reductase, displaying affinities towards both oxidised thiols in order to restore their reduced forms60. Here, we have found a contig (Ir-111289) encoding a putative glutathione-thioredoxin reductase.…”

X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action

“…The higher inhibitory effect of metal-containing compounds toward high M r TrxRs is attributed to a second selenosulfide redox site which is thought to facilitate metal release (Angelucci et al, 2009). While the precise mechanism and molecular target(s) of Auranofin’s anti-inflammatory activity have not been established, in a number of human parasites Auranofin is believed to inhibit antioxidant pathways maintaining the intracellular redox environment by targeting thiol redox enzymes such as thioredoxin reductase, thioredoxin-glutathione reductase (TGR) or trypanothione reductase (Angelucci et al, 2009; Caroli et al, 2012; Ilari et al, 2012; Prast-Nielsen et al, 2011; Sannella et al, 2008). In addition to E. histolytica and Giardia , unicellular human parasites in which Auranofin induces oxidative stress include Trypanosoma cruzi (da Silva et al, 2015), Leishmania infantum (Ilari et al, 2012), Leishmania donovani (Sharlow et al, 2014) and Plasmodium falciparum (Caroli et al, 2012), as well as parasitic flatworms Schistosoma mansoni (Angelucci et al, 2009), Schistosoma japonicum (Song et al, 2012) and Taenia crassiceps (Martinez-Gonzalez et al, 2015).…”

Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci

“…Due to the different nature of the detoxification systems between flatworms and their vertebrate hosts, TGR has been proposed as a drug target [33]. We have previously demonstrated both in vitro [30] and in vivo the inhibition of TGR by auranofin (AF), as well as its effect on the viability of T. crassiceps cysticerci [34].…”