The Thioredoxin-Thioredoxin Reductase System Can Function in Vivo as an Alternative System to Reduce Oxidized Glutathione in Saccharomyces cerevisiae

Tan, Shi‐Xiong; Greetham, Darren; Raeth, Sebastian; Grant, Chris M.; Dawes, Ian W.; Perrone, Gabriel G.

doi:10.1074/jbc.m109.062844

Cited by 87 publications

(56 citation statements)

References 56 publications

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“…Regarding this latter issue, it is relevant to mention that in some GR-less organisms, such as Drosophila melanogaster, GSSG reduction is carried out by Trx, which in turn is recycled by TR (12). This is also the case of Saccharomyces cerevisiae null mutants in GR, where the Trx system compensates for the lack of GR activity (13). In this study we present two major findings.…”

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confidence: 53%

Linked Thioredoxin-Glutathione Systems in Platyhelminth Parasites

Bonilla

Denicola

Marino

et al. 2011

Journal of Biological Chemistry

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In most organisms, thioredoxin (Trx) and/or glutathione (GSH) systems are essential for redox homeostasis and deoxyribonucleotide synthesis. Platyhelminth parasites have a unique and simplified thiol-based redox system, in which the selenoprotein thioredoxin-glutathione reductase (TGR), a fusion of a glutaredoxin (Grx) domain to canonical thioredoxin reductase domains, is the sole enzyme supplying electrons to oxidized glutathione (GSSG) and Trx. This enzyme has recently been validated as a key drug target for flatworm infections. In this study, we show that TGR possesses GSH-independent deglutathionylase activity on a glutathionylated peptide. Furthermore, we demonstrate that deglutathionylation and GSSG reduction are mediated by the Grx domain by a monothiolic mechanism and that the glutathionylated Platyhelminths (also known as flatworms) cause severe human parasitic diseases, such as schistosomiasis, cysticercosis, and hydatid disease. Parasitic platyhelminths share a unique biochemical scenario regarding thiol-based redox pathways (1-4). These organisms possess a linked thioredoxin-glutathione system that provides reducing equivalents to both the thioredoxin (Trx) 2 and the glutathione (GSH) pathways. In contrast to their mammalian hosts, platyhelminth parasites lack thioredoxin reductase (TR) and glutathione reductase (GR) and hence conventional Trx and GSH systems. The distinctive feature of the redox array of platyhelminth parasites is that reduction of Trx and GSSG is carried out by a single selenoenzyme, termed thioredoxin glutathione reductase (TGR). Thus, these organisms have an absolute reliance on TGR for redox homeostasis and DNA synthesis. Furthermore, in parasitic flatworms, mitochondrial and cytosolic TGR variants are derived from a single gene, and the encoded mature polypeptides are identical in sequence (3).TGR is a complex flavoenzyme that contains several thiolbased redox centers and is composed of an N-terminal glutaredoxin (Grx) domain fused to canonical large TR domains (5). In the platyhelminth parasite Echinococcus granulosus (class cestoda), the Grx domain has a dithiol CPYC redox center, and the TR module contains a CX 4 C redox center and the conspicuous C-terminal motif GCUG, where U is the redox active amino acid selenocysteine (Sec) (1). Detailed biochemical studies with sets of mutants of human and E. granulosus TGR have shown the following: (i) both oxidized Trx and oxidized glutathione (GSSG) reduction are dependent on the redox-active C-terminal Sec residue, and (ii) reduction of GSSG, but not of oxidized Trx, requires the Grx domain (6, 7). In the case of E. granulosus and Taenia crassiceps (class cestoda) TGRs, it has also been shown that their GR activity, but not their TR activity, is inhibited at high concentrations of oxidized glutathione (GSSG) (4, 6). This phenomenon has been proposed to be due to glutathionylation of critical Cys residues (6).

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confidence: 53%

Linked Thioredoxin-Glutathione Systems in Platyhelminth Parasites

Bonilla

Denicola

Marino

et al. 2011

Journal of Biological Chemistry

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“…Simultaneous inhibition of more than one antioxidant system for cancer therapy becomes even more important with the growing evidence that the two key redox systems display widespread redundant functions (35,50). Recently, we showed that the cystine/cysteine cycle along with Txnrd1 cooperatively rescue GSH deficiency (35).…”

Section: Discussionmentioning

confidence: 99%

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

et al. 2010

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Tumor cells generate substantial amounts of reactive oxygen species (ROS), engendering the need to maintain high levels of antioxidants such as thioredoxin (Trx)-and glutathione (GSH)-dependent enzymes. Exacerbating oxidative stress by specifically inhibiting these types of ROS-scavenging enzymes has emerged as a promising chemotherapeutic strategy to kill tumor cells. However, potential redundancies among the various antioxidant systems may constrain this simple approach. Trx1 and thioredoxin reductase 1 (Txnrd1) are upregulated in numerous cancers, and Txnrd1 has been reported to be indispensable for tumorigenesis. However, we report here that genetic ablation of Txnrd1 has no apparent effect on tumor cell behavior based on similar proliferative, clonogenic, and tumorigenic potential. This finding reflects widespread redundancies between the Trx-and GSH-dependent systems based on evidence of a bypass to Txnrd1 deficiency by compensatory upregulation of GSH-metabolizing enzymes. Because the survival and growth of Txnrd1-deficient tumors were strictly dependent on a functional GSH system, Txnrd1 −/− tumors were highly susceptible to experimental GSH depletion in vitro and in vivo. Thus, our findings establish for the first time that a concomitant inhibition of the two major antioxidant systems is highly effective in killing tumor, highlighting a promising strategy to combat cancer. Cancer Res; 70(22); 9505-14. ©2010 AACR.

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“…Extensive deletion analyses in yeast have further identified considerable genetic redundancy in these systems Toledano et al 2007;López-Mirabal and Winther 2008). The thioredoxin system has also been shown to function as an alternative reduction system for GSSG, although the physiological significance of this reduction reaction is not yet clear (Tan et al 2010). The reason(s) for this apparent functional redundancy in highly conserved redox systems remains an important unanswered question.…”

Section: Cellular Responses To Rosmentioning

confidence: 99%

The Response to Heat Shock and Oxidative Stress inSaccharomyces cerevisiae

2012

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A common need for microbial cells is the ability to respond to potentially toxic environmental insults. Here we review the progress in understanding the response of the yeast Saccharomyces cerevisiae to two important environmental stresses: heat shock and oxidative stress. Both of these stresses are fundamental challenges that microbes of all types will experience. The study of these environmental stress responses in S. cerevisiae has illuminated many of the features now viewed as central to our understanding of eukaryotic cell biology. Transcriptional activation plays an important role in driving the multifaceted reaction to elevated temperature and levels of reactive oxygen species. Advances provided by the development of whole genome analyses have led to an appreciation of the global reorganization of gene expression and its integration between different stress regimens. While the precise nature of the signal eliciting the heat shock response remains elusive, recent progress in the understanding of induction of the oxidative stress response is summarized here. Although these stress conditions represent ancient challenges to S. cerevisiae and other microbes, much remains to be learned about the mechanisms dedicated to dealing with these environmental parameters.

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The Thioredoxin-Thioredoxin Reductase System Can Function in Vivo as an Alternative System to Reduce Oxidized Glutathione in Saccharomyces cerevisiae

Cited by 87 publications

References 56 publications

Linked Thioredoxin-Glutathione Systems in Platyhelminth Parasites

Linked Thioredoxin-Glutathione Systems in Platyhelminth Parasites

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

The Response to Heat Shock and Oxidative Stress inSaccharomyces cerevisiae

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