Possible Differences in the Regenerative Roles Played by Thioltransferase and Thioredoxin for Oxidatively Damaged Proteins

Yoshitake, Shin-ichiro; Nanri, Hiroki; Fernando, M. Rohan; Minakami, Shigeki

doi:10.1093/oxfordjournals.jbchem.a124500

Cited by 85 publications

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“…In addition, in vitro experiments indicate that glutaredoxins can reactivate a number of oxidized enzymes by reducing the mixed disulfides formed as a result of thiol oxidation (Terada et al, 1992;Terada, 1994;Yoshitake et al, 1994). This repair activity is not restricted to enzymes, because glutaredoxin from human erythrocytes is able to reactivate membrane proteins and to regenerate hemoglobin from the mixed disulfide hemoglobin-S-S-glutathione (Mieyal et al, 1991;Terada et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

The YeastSaccharomyces cerevisiaeContains Two Glutaredoxin Genes That Are Required for Protection against Reactive Oxygen Species

Luikenhuis

Perrone

Dawes

et al. 1998

MBoC

216

212

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Glutaredoxins are small heat-stable proteins that act as glutathione-dependent disulfide oxidoreductases. Two genes, designated GRX1 and GRX2, which share 40 -52% identity and 61-76% similarity with glutaredoxins from bacterial and mammalian species, were identified in the yeast Saccharomyces cerevisiae. Strains deleted for both GRX1 and GRX2 were viable but lacked heat-stable oxidoreductase activity using ␤-hydroxyethylene disulfide as a substrate. Surprisingly, despite the high degree of homology between Grx1 and Grx2 (64% identity), the grx1 mutant was unaffected in oxidoreductase activity, whereas the grx2 mutant displayed only 20% of the wild-type activity, indicating that Grx2 accounted for the majority of this activity in vivo. Expression analysis indicated that this difference in activity did not arise as a result of differential expression of GRX1 and GRX2. In addition, a grx1 mutant was sensitive to oxidative stress induced by the superoxide anion, whereas a strain that lacked GRX2 was sensitive to hydrogen peroxide. Sensitivity to oxidative stress was not attributable to altered glutathione metabolism or cellular redox state, which did not vary between these strains. The expression of both genes was similarly elevated under various stress conditions, including oxidative, osmotic, heat, and stationary phase growth. Thus, Grx1 and Grx2 function differently in the cell, and we suggest that glutaredoxins may act as one of the primary defenses against mixed disulfides formed following oxidative damage to proteins. INTRODUCTIONGlutaredoxin from Escherichia coli was first discovered as a small, heat-stable protein required for the glutathione-dependent synthesis of deoxyribonucleotides catalyzed by ribonucleotide reductase (Holmgren, 1976). Glutaredoxin 1 is a 9-kDa protein that acts as a reduced glutathione (GSH)-dependent disulfide oxidoreductase by virtue of the two cysteine residues in its active site (Holmgren and Aslund, 1995). Later studies in mutants that lacked both glutaredoxin and thioredoxin revealed that E. coli actually contains three glutaredoxins (Grx1-3), with glutaredoxin 3 also able to function in ribonucleotide synthesis (Aslund et al., 1994). In contrast, glutaredoxin 2 was proposed to be the first member of a novel class of glutaredoxins that lack activity as hydrogen donors for ribonucleotide reductase (Vlamis-Gardikas et al., 1997). Glutaredoxins have subsequently been identified and isolated from various eukaryotes, including human, bovine, pig, yeast, and rice (Minakuchi et al., 1994;Holmgren and Aslund, 1995). The structure of these proteins has been highly conserved throughout evolution, particularly in the region of the active site (Wells et al., 1993;Holmgren and Aslund, 1995). However, despite extensive structural analysis, little is known regarding the biochemical function of these eukaryotic glutaredoxins in vivo.There appears to be considerable functional overlap between the glutaredoxin and thioredoxin systems. Similar to glutaredoxin, thioredoxin is a small, heatstable pro...

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Section: Discussionmentioning

confidence: 99%

The YeastSaccharomyces cerevisiaeContains Two Glutaredoxin Genes That Are Required for Protection against Reactive Oxygen Species

Luikenhuis

Perrone

Dawes

et al. 1998

MBoC

216

212

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“…Although both Trx1 and Grx1 exhibit activity in regeneration of oxidatively damaged proteins, further studies have shown that they have different substrate preferences [14,15]. Trx has been reported to preferentially reduce protein sulfenic acids as well as intra-and inter-protein disulfides.…”

Section: Introductionmentioning

confidence: 99%

Targeted disruption of the glutaredoxin 1 gene does not sensitize adult mice to tissue injury induced by ischemia/reperfusion and hyperoxia

Xiong

et al. 2007

Free Radical Biology and Medicine

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To understand the physiological function of glutaredoxin, a thiotransferase catalyzing the reduction of mixed disulfides of protein and glutathione (protein-SSG), we generated a line of knockout mice deficient in the cytosolic glutaredoxin 1 (Grx1). To our surprise, mice deficient in Grx1 were not more susceptible to acute oxidative insults in models of heart and lung injury induced by ischemia/ reperfusion and hyperoxia, respectively; suggesting that changes in S-glutathionylation status of cytosolic proteins are not the major cause of such tissue injury. On the other hand, mouse embryonic fibroblasts (MEFs) isolated from Grx1-deficient mice displayed an increased vulnerability to diquat and paraquat, but they were not more susceptible to cell death induced by hydrogen peroxide (H 2 O 2 ) and diamide. A deficiency in Grx1 also sensitized MEFs to protein S-glutathionylation in response to H 2 O 2 treatment and retarded deglatuthionylation of the S-glutathionylated proteins, especially evident for an unspecified protein of approximately 44 kDa. Additional experiments showed that MEFs lacking Grx1 were more tolerant to apoptosis induced by tumor necrosis factor α plus actinomycin D. These findings suggest that different oxidants may damage the cells via distinct mechanisms in which Grx1-dependent de-glutathionylation may or may not be protective, and Grx1 may exert its function on specific target proteins.

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“…In general, reduced Trx catalyzes the reduction of intra-or intermolecular protein disulfides [8,9,12] and possibly other thiol intermediates such as sulfenic acid and S-nitrosothiols [10]. By comparison, Grx mainly catalyzes the reduction of protein-mixed disulfides [1,2,11,13]. Since a major function of Trx and Grx is to convert oxidized proteins to their reduced form, it is proposed that oxidoreductase systems act as a thiol repair mechanism that regulates the physiological function of proteins susceptible to oxidation.…”

Section: Introductionmentioning

confidence: 99%

Oxidoreductase regulation of Kv currents in rat ventricle

Liang

et al. 2008

Journal of Molecular and Cellular Cardiology

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Oxidative stress contributes to the arrhythmogenic substrate created by myocardial ischemiareperfusion partly through a shift in cell redox state, a key modulator of protein function. The activity of many oxidation-sensitive proteins is controlled by oxidoreductase systems that regulate the redox state of cysteine thiol groups, but the impact of these systems on ion channel function is not well defined. Thus, we examined the roles of the thioredoxin and glutaredoxin systems in controlling K + channels in the ventricle. An oxidative shift in redox state was elicited in isolated rat ventricular myocytes by brief exposure to diamide, a thiol-specific, membrane-permeable oxidant. Voltageclamp studies showed that diamide decreased peak outward K + current (I peak ) evoked by depolarizing test pulses by 41% (+60 mV; p<0.05) while steady-state outward current (I ss ) measured at the end of the test pulse was decreased by 45% (p<0.05). These electrophysiological effects were not prevented by protein kinase C blockers, but the tyrosine kinase inhibitors genistein or lavendustin A blocked the suppression of both K + currents by diamide. Moreover, inhibition of I peak and I ss by diamide was reversed by dichloroacetate and an insulin-mimetic. The effect of dichloroacetate to normalize I peak after diamide was blocked by the thioredoxin system inhibitors auranofin or 13-cisretinoic acid, but I ss was not affected by either compound. A pan-specific inhibitor of glutaredoxin and thioredoxin systems, 1,3-bis-(2-chloroethyl)-1-nitrosourea, also blocked the dichloroacetate effect on I peak but only partially inhibited the recovery of I ss . These data suggest that acute regulation of cardiac K + channels by oxidoreductase systems is mediated by redox-sensitive tyrosine kinase/ phosphatase pathways. The pathways controlling I peak channels are targets of the thioredoxin system whereas those regulating I ss channels are likely controlled by the glutaredoxin system. Thus, cardiac oxidoreductase systems may be important regulators of ion channels affected by pathogenic oxidative stress.

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Possible Differences in the Regenerative Roles Played by Thioltransferase and Thioredoxin for Oxidatively Damaged Proteins

Cited by 85 publications

References 0 publications

The YeastSaccharomyces cerevisiaeContains Two Glutaredoxin Genes That Are Required for Protection against Reactive Oxygen Species

The YeastSaccharomyces cerevisiaeContains Two Glutaredoxin Genes That Are Required for Protection against Reactive Oxygen Species

Targeted disruption of the glutaredoxin 1 gene does not sensitize adult mice to tissue injury induced by ischemia/reperfusion and hyperoxia

Oxidoreductase regulation of Kv currents in rat ventricle

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