Disease relevance of GLRX

• In contrast to Escherichia coli and yeast, a single human glutaredoxin is known [1].
• Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease [2].
• Expression of glutaredoxin is highly cell specific in human lung and is decreased by transforming growth factor-beta in vitro and in interstitial lung diseases in vivo [3].
• The expression of Grx1 decreased in alveolar macrophages of sarcoidosis and allergic alveolitis compared with the case for controls (P < 0.001), and bronchial epithelium of these diseases revealed no Grx1 immunoreactivity [3].
• Decreased expression of Grx1 further suggests the impairment of this system both in inflammatory and fibrotic lung diseases, consistent with the down-regulation of Grx1 by TGF-beta in vitro [3].

High impact information on GLRX

• Glutaredoxin (Grx) belongs to the thioredoxin fold superfamily and catalyzes glutathione-dependent oxidoreductions [4].
• However, no differences were detected after treatment with cadmium, a known inhibitor of Grx1 [4].
• Parallel experiments with glutaredoxin and cystatin, phloem sap proteins from Ricinus communis, established that these proteins can also traffic through cucurbit mesophyll plasmodesmata [5].
• The postreplicative synthesis of vaccinia virus GRX and its association with virions suggest that the enzyme may have novel roles in the virus growth cycle [6].
• We demonstrate that the vaccinia virus O2L open reading frame encodes a functional GRX, as predicted by Johnson et al [6].

Chemical compound and disease context of GLRX

• The 125-residue Grx domain and the two full-length variants were expressed in E. coli and exhibited GSH-dependent hydroxyethyl disulfide and dehydroascorbate reducing activities [1].
• The three dithiol glutaredoxins of E. coli with the active-site sequence CPYC and a glutathione binding site in a thioredoxin/glutaredoxin fold display surprisingly different properties [7].
• To overexpress human glutaredoxin in Escherichia coli, a cDNA encoding human Grx was modified and cloned into the vector pET-3d and expressed in E. coli BL21 (DE3) by IPTG induction [8].
• Thioltransferase, a small redox protein with thiol-disulfide oxidoreductase and dehydroascorbate reductase activities, has been reported to be expressed at higher levels in Adriamycin-resistant MCF-7 human breast tumor cells (MCF-7 ADR(R)) when compared with Adriamycin sensitive MCF-7 WT (MCF-7 WT) cells [9].
• EVM053 also exhibits a novel cis-proline (Pro53) in a loop that has been shown to contribute to R1-binding in Escherichia coli Grx-1 [10].

Biological context of GLRX

• Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2 [11].
• GRX active site cysteine residues (Cys(22) and Cys(25)) were required for dissociation of GRX from ASK1 during glucose deprivation [11].
• Collectively, these data suggest that thioltransferase has a vital role in sulfhydryl homeostasis and cell survival [12].
• Acute cadmium exposure inactivates thioltransferase (Glutaredoxin), inhibits intracellular reduction of protein-glutathionyl-mixed disulfides, and initiates apoptosis [12].
• Moreover, transfection with antisense thioltransferase cDNA was incompatible with cell survival [12].

Anatomical context of GLRX

• In this study 30-min exposure of H9 and Jurkat cells to cadmium inhibited intracellular protein-SSG reduction, and this correlated with inhibition of the thioltransferase system, consistent with thioltransferase being the primary intracellular catalyst of deglutathionylation [12].
• Most importantly, it has been demonstrated that thioltransferase has a remarkable resistance to oxidation (H(2)O(2)) in cultured human and rabbit lens epithelial cells under oxidative stress conditions when other oxidation defense systems of GSH peroxidase and GSH reductase are severely inactivated [13].
• The intense immunostaining concomitant with the presence of pinopodes suggests that Grx plays an important role during implantation, possibly by protecting the epithelial cells from apoptotic actions of the trophoblast cells [14].
• Immunohistochemical localization of glutaredoxin and thioredoxin in human endometrium: a possible association with pinopodes [14].
• Both Grx1 and Grx2 were present in placenta extracts and in cell lysates prepared from various tumor cell lines [15].

Associations of GLRX with chemical compounds

• Disruption of the vicinal dithiol on thioltransferase (via oxidation to C22-SS-C25; or C25S mutation) protected against cadmium, consistent with a dithiol chelation mechanism of inactivation [12].
• Thioltransferase and GSSG reductase in situ displayed similar dose-response curves (50% inhibition near 10 micrometer cadmium in extracellular buffer) [12].
• Treatment with l-buthionine-(S,R)-sulfoximine reduced glutathione content by 99% and prevented glucose deprivation-induced dissociation of GRX from ASK1 [11].
• These results support the hypothesis that the GRX-ASK1 interaction is redox sensitive and regulated in a glutathione-dependent fashion by H(2)O(2) [11].
• Increasing levels of Grx immunoreactivity were seen in the luminal and glandular epithelial cells concomitant with pinopode formation [14].

Physical interactions of GLRX

• Deletion mutants showed the C-terminal portion of apoptosis signal-regulating kinase 1 (ASK1) bound GRX, and glucose deprivation disrupted binding [11].
• In addition, the pattern of AP-1 binding under the oxidative stress was similar to the pattern of TTase activity and mRNA synthesis modulation [16].

Enzymatic interactions of GLRX

• To investigate the catalytic mechanism of the Grx-dependent reduction of hydroperoxides catalyzed by Prx, a series of cysteinic mutants was constructed [17].
• Here we show that restoration of the DNA-binding activity of oxidized NFI-C can be catalyzed in vitro by the cellular enzyme thioltransferase (glutaredoxin) coupled to GSH and GSSG reductase [18].

Regulatory relationships of GLRX

• GRX-overexpressing cells demonstrated resistance to glucose deprivation-induced cytotoxicity and decreased activation of c-Jun N-terminal kinase (JNK1) [11].
• In A549 cells, Grx1 was down-regulated by TGF-beta, whereas TNF-alpha caused no clear effect [3].
• Abeta toxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1 [2].
• Also to examine whether depleting the primary cellular antioxidant glutathione (GSH) in these cells has any influence on TTase expression under the same conditions [19].
• It is also shown that the efficiency of S-glutathionylation of either native or oxidised GAPDH is enhanced by the presence of recombinant glutaredoxin (thiol transferase) of either bacterial or human origin [20].

Other interactions of GLRX

• Glutaredoxin-dependent peroxiredoxin from poplar: protein-protein interaction and catalytic mechanism [17].
• Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress-induced activation of apoptosis signal-regulating kinase 1 [21].
• Overexpression of GRX or catalase inhibited activation of ASK1-SEK1-JNK1 signaling during glucose deprivation [11].
• Plasma from healthy blood donors contained 13.4+/-7.9ng/ml of Grx1, while Grx2 was not detected [15].
• Most cells contain high levels of glutathione and multiple glutaredoxins, which utilize the reducing power of glutathione to catalyze disulfide reductions in the presence of NADPH and glutathione reductase (the glutaredoxin system) [7].

Analytical, diagnostic and therapeutic context of GLRX

• The biopsies were examined by scanning electron microscopy for detection of pinopodes and by immunohistochemistry for the expression of Grx and Trx [14].
• Cellular and plasma levels of human glutaredoxin 1 and 2 detected by sensitive ELISA systems [15].
• The affinity-purified material from human plasma displayed a band of 12 kDa identical to recombinant human Grx by Western blotting and its glutathione-dependent reducing activity of beta-hydroxyethyl disulfide [22].
• In cardiac surgical patients (n = 17), plasma Grx levels did not significantly change during cardiopulmonary bypass (CPB) [22].
• The ultrastructural localization of Grx1 was assessed by immunoelectron microscopy [3].

References