|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
- peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
This enzyme belongs to the family of oxidoreductases, specifically those acting on a sulfur group of donors with other, known, acceptors. The systematic name of this enzyme class is peroxiredoxin-(S-hydroxy-S-oxocysteine):thiol oxidoreductase [ATP-hydrolysing; peroxiredoxin-(S-hydroxycysteine)-forming]. Other names in common use include Srx1, sulphiredoxin, and peroxiredoxin-(S-hydroxy-S-oxocysteine) reductase.
The sulfur atom in the side-chain of the amino acid cysteine can exist in several different oxidation states. The most reduced of these is as a thiol group (Cys-SH). Oxidation of cysteine produces cystine, which is one half of a disulfide bond (Cys-S-S-Cys). These lower oxidation states of cysteine (disulfides) are readily reversible, but higher oxidation states, such as sulfinic acid (Cys-SOOH), were once considered irreversible, biologically speaking. This view changed with the discovery of sulfiredoxin, an enzyme that can reduce sulfinic acid back to thiol, in an ATP-dependent manner. Additional work suggests that it plays a role in resolving mixed disulfide bonds.
Initially discovered in yeast, sulfiredoxin is conserved in all eukaryotes, including mammals. In a perfect example of how multiple gene names can confuse the field, sulfiredoxin (Srxn1) was already known as a gene of unknown function, cloned by differential display of an in vitro model of tumorgenesis, and termed “Neoplastic progression 3/Npn3” although nothing about its actual function was reported. As a result, in most mouse microarray studies, sulfiredoxin is termed neoplastic progression 3, and typically classified as “cancer related” or “other” rather than as “antioxidant”.
Npn3/Srxn1 is upregulated by an exceptionally large fold-magnitude in microarray studies of oxidative stress. Npn3/Srxn1 is induced up to 32-fold by D3T (liver), 12-fold by CdCl2, (liver), 4- to 10-fold by paracetamol (liver) and 3.3-fold by paraquat (heart). A survey of the GEO database also indicates a large induction of Npn3/Srxn1 is observed in injury to the lung by hyperoxia (data set GDS247, ID# 102780_at) or phosgene (GDS1244, 1451680_at). That Npn3 and Sxrn1 are synonyms of the same gene has not been pointed out in any of the 15 papers written on Srxn1 since its discovery.
Because it was discovered so recently, the function of sulfiredoxin is not yet fully known.
Sulfiredoxin knockout mice is available in Dr. Qiou Wei's lab at University of Kentucky and mice are found normal under normal circumstances. On treatment of these mice with carcinogens, Srx knockout mice were found to be less prone to few cancer types compared to wildtype mice. It shows the critical role of Srx in carcinogenesis of human tumors.
- Biteau B, Labarre J, Toledano MB (2003). "ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin". Nature. 425 (6961): 980–4. doi:10.1038/nature02075. PMID 14586471.
- Chang TS, Jeong W, Woo HA, Lee SM, Park S, Rhee SG (2004). "Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine". J. Biol. Chem. 279 (49): 50994–1001. doi:10.1074/jbc.M409482200. PMID 15448164.
- Woo HA, Jeong W, Chang TS, Park KJ, Park SJ, Yang JS, Rhee SG (2005). "Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins". J. Biol. Chem. 280 (5): 3125–8. doi:10.1074/jbc.C400496200. PMID 15590625.
- Findlay, V. J., Townsend, D. M., Morris, T. E., Fraser, J. P., He, L. and Tew, K. D. (2006) A novel role for human sulfiredoxin in the reversal of glutathionylation. Cancer Res. 66, 6800-6806
- Sun, Y., Hegamyer, G. and Colburn, N. H. (1994) Molecular cloning of five messenger RNAs differentially expressed in preneoplastic or neoplastic JB6 mouse epidermal cells: one is homologous to human tissue inhibitor of metalloproteinases-3. Cancer Res. 54, 1139–1144
- Kwak, M. K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M. and Kensler, T. W. (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J. Biol. Chem. 278, 8135-8145
- Wimmer, U., Wang, Y., Georgiev, O. and Schaffner, W. (2005) Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione. Nucleic Acids Res 33, 5715-5727
- Welch, K. D., Reilly, T. P., Bourdi, M., Hays, T., Pise-Masison, C. A., Radonovich, M. F., Brady, J. N., Dix, D. J. and Pohl, L. R. (2006) Genomic identification of potential risk factors during acetaminophen-induced liver disease in susceptible and resistant strains of mice. Chem Res Toxicol 19, 223-233
- Edwards, M. G., Sarkar, D., Klopp, R., Morrow, J. D., Weindruch, R. and Prolla, T. A. (2003) Age-related impairment of the transcriptional responses to oxidative stress in the mouse heart. Physiol Genomics 13, 119-127