Pathway Summary
The glutathione/glutaredoxin and thioredoxin systems help maintain the reduced environment of the cell and play a significant role in defending the cell against oxidative stress. They also have been proposed to play a role in DNA synthesis, protein folding and regulation, and sulfur metabolism Glutaredoxins and thioredoxins are small heat-stable proteins that can reduce disulfides by way of conserved cysteines. Glutaredoxins catalyze reductions of intracellular disulfides or glutathione-mixed disulfides in a coupled system with glutathione, NADPH and glutathione reductase. Unlike the thioredoxin system where oxidized thioredoxin disulfide is reduced directly by thioredoxin reductase with electrons from NADPH, oxidized glutaredoxin is reduced by glutathione with electrons donated by NADPH Yeast, similar to bacteria, plants, and humans have monothiol and dithiol glutaredoxins with the conserved active site motif Cys-Pro-Tyr-Cys and Cys-Gly-Phe-Ser, respectively Monothiol glutaredoxins (Grx-SH) catalyze the reduction of thiol-glutathione mixed disulfides (Protein-S-S-G) only, while dithiol glutaredoxins (Grx-(SH)2) reduce both protein disulfides (Protein-S2) and GSH-mixed disulfides (Protein-S-S-G) Five glutaredoxins have been identified in S. cerevisiae, two dithiol glutaredoxins, Grx1p and Grx2p, and three monothiol glutaredoxins, Grx3p, Grx4p, and Grx5p All five glutaredoxins participate in the response against oxidative stress GRX1 and GRX2 mutants are sensitive to the oxidants superoxide anions and hydrogen peroxide respectively, suggesting that they have different roles in protecting the cells The defensive roles of Grx1p and Grx2p may overlap with those of the cytosolic thioredoxins, Trx1p and Trx2p as at least one Grx1pGrx2p glutaredoxin or one Trx1pTrx2p thioredoxin is required for yeast cell viability Although GRX3 and GRX4 mutants do not have strong sensitivity to oxidants, mutants lacking GRX5 do. GRX5 mutants also have increased protein oxidative damage, growth defects in minimal medium, and inability for respiratory growth Grx5p has also been found to be a mitochondrial glutaredoxin required for the activity of ironsulfur enzymes
Genes Involved
Genes whose products participate in this pathway, with their systematic names, EC numbers (where the gene product is an enzyme with an assigned EC number), and the gene's SGD description.
| Gene | Systematic Name | EC Number | Description |
|---|---|---|---|
| GLR1 | YPL091W | 1.8.1.7 | Cytosolic and mitochondrial glutathione oxidoreductase |
| GRX1 | YCL035C | 1.11.1.9, 2.5.1.18 | Glutathione-dependent disulfide oxidoreductase |
| GRX2 | YDR513W | 1.11.1.9, 2.5.1.18 | Cytoplasmic glutaredoxin |
| GRX3 | YDR098C | Glutathione-dependent oxidoreductase | |
| GRX4 | YER174C | Glutathione-dependent oxidoreductase and glutathione S-transferase | |
| GRX5 | YPL059W | Glutathione-dependent oxidoreductase |
Functional Networks
Functional Networks show how the genes in this pathway work together: a graph linking the pathway to its genes and their shared GO biological-process terms and phenotype observables, and the GO-CAM causal activity models that involve these genes.
Shared Annotations
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GO-CAMs
GO-CAM (Gene Ontology Causal Activity Model) pathway models that involve the genes in this pathway. A gene can participate in more than one model, so use the dropdown to switch between them; the model for this pathway is shown by default.
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References
List of references used specifically to curate the information on this page.
- Grant CM (2001) Role of the glutathione/glutaredoxin and thioredoxin systems in yeast growth and response to stress conditions. Mol Microbiol 39(3):533-41 PMID: 11169096
- Holmgren A (1989) Thioredoxin and glutaredoxin systems. J Biol Chem 264(24):13963-6 PMID: 2668278
- Vlamis-Gardikas A and Holmgren A (2002) Thioredoxin and glutaredoxin isoforms. Methods Enzymol 347:286-96 PMID: 11898418
- Luikenhuis S, et al. (1998) The yeast Saccharomyces cerevisiae contains two glutaredoxin genes that are required for protection against reactive oxygen species. Mol Biol Cell 9(5):1081-91 PMID: 9571241
- RodrÃguez-Manzaneque MT, et al. (1999) Grx5 glutaredoxin plays a central role in protection against protein oxidative damage in Saccharomyces cerevisiae. Mol Cell Biol 19(12):8180-90 PMID: 10567543
- Draculic T, et al. (2000) A single glutaredoxin or thioredoxin gene is essential for viability in the yeast Saccharomyces cerevisiae. Mol Microbiol 36(5):1167-74 PMID: 10844700
- RodrÃguez-Manzaneque MT, et al. (2002) Grx5 is a mitochondrial glutaredoxin required for the activity of iron/sulfur enzymes. Mol Biol Cell 13(4):1109-21 PMID: 11950925
Resources
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