Alternative titles; symbols
HGNC Approved Gene Symbol: TXNRD1
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38) : 12:104,215,779-104,350,307 (from NCBI)
Thioredoxin reductase (EC 1.6.4.5) is a key enzyme in the regulation of the intracellular redox environment and plays an important role in cell proliferation (summary by Gasdaska et al., 1995).
Gasdaska et al. (1995) purified human thioredoxin reductase from placenta and obtained amino acid sequence from tryptic peptides. Based on protein sequence data, the authors designed degenerate PCR primers and used them to screen a human placenta cDNA library. The authors obtained a 3.8-kb cDNA encoding a predicted 495-amino acid protein that is 40% identical to glutathione reductase (GSR; 138300) and 24% identical to thioredoxin reductase from E. coli. The protein has a predicted FAD-binding domain, but this activity could not be demonstrated with recombinantly expressed enzyme. By Northern blot analysis, Gasdaska et al. (1996) found that thioredoxin reductase was expressed in all tissues examined, but at varying levels. The authors found no correlation between the relative expression levels of thioredoxin and thioredoxin reductase.
Tamura and Stadtman (1996) purified a selenocysteine-containing enzyme from a human lung adenocarcinoma cell line. The protein was purified as a homodimer of 57-kD subunits with no detectable N-linked oligosaccharides. Tamura and Stadtman (1996) identified a prosthetic FAD group in the protein, and they found that the protein catalyzed NADPH-dependent reduction of insulin in the presence of thioredoxin. The subunit composition and catalytic properties of the selenoprotein were similar to those of mammalian thioredoxin reductase, but it failed to crossreact with anti-rat liver thioredoxin reductase polyclonal antibodies in immunoblot assays.
Selenium has been indirectly implicated in immunologic function and numerous nutritional studies over many years. Furthermore, human immunodeficiency virus (HIV)-infected persons have been reported to have decreased levels of plasma selenium and selenium-containing glutathione peroxidase (e.g., 138321). For this reason, Gladyshev et al. (1996) initiated studies on selenium metabolism in human T cells. They identified one of the selenoproteins detected in T cells as thioredoxin reductase and demonstrated that the location of selenocysteine in this protein corresponds to a TGA codon in the cloned placental gene. The finding that T-cell thioredoxin reductase is a selenoenzyme that contains selenium in a conserved C-terminal region provides another example of the role of selenium in the major antioxidant enzyme system (i.e., thioredoxin-thioredoxin reductase), in addition to the well-known glutathione peroxidase enzyme system.
Dammeyer et al. (2008) stated that there are at least 3 TXNRD1 splice variants with different 5-prime ends that encode TXNRD1 isoforms with unique N-terminal domains. They studied variant-3 (v3), which includes alternative exons upstream of the core promoter that encode an atypical N-terminal monothiol glutaredoxin (GRX, or GLRX; 600443) domain fused to the thioredoxin module. Northern blot analysis detected a 4.5-kb v3 transcript in testis only. PCR analysis also showed v3 expression in ovary, spleen, heart, liver, kidney, pancreas, and some cancer cell lines of various tissue origin. Immunohistochemical analysis of human testis detected v3 predominantly in Leydig cells. Dammeyer et al. (2008) stated that orthologs of v3 are found in chimpanzee and dog, but not in mouse or rat.
Gorlatov and Stadtman (1998) demonstrated the essential role of selenocysteine in thioredoxin reductase isolated from HeLa cells by alkylation studies. Selective alkylation of selenocysteine in the protein inhibited enzyme activity, and reduction with NADPH influenced affinity to heparin.
Dammeyer et al. (2008) found that treatment of HeLa cells with estradiol or testosterone induced expression of TXNRD1 v3. Fluorescence-tagged v3, or its isolated GRX domain, localized to distinct cellular sites in proximity to actin (see ACTG1; 102560) and had the capacity to rapidly induce cell membrane protrusions. Analysis of these structures suggested that the GRX domain of TXNRD1 v3 localized first to the emerging protrusion and was followed into the protrusion by actin and subsequently by tubulin (see TUBA1A; 602529). Dammeyer et al. (2008) concluded that TXNRD1 v3 can guide actin polymerization in relation to cell membrane restructuring.
By fluorescence in situ hybridization, Gasdaska et al. (1996) mapped the TXNRD1 gene to chromosome 12q23-q24.1.
Dammeyer, P., Damdimopoulos, A. E., Nordman, T., Jimenez, A., Miranda-Vizuete, A., Arner, E. S. J. Induction of cell membrane protrusions by the N-terminal glutaredoxin domain of a rare splice variant of human thioredoxin reductase 1. J. Biol. Chem. 283: 2814-2821, 2008. [PubMed: 18042542] [Full Text: https://doi.org/10.1074/jbc.M708939200]
Gasdaska, J. R., Gasdaska, P. Y., Gallegos, A., Powis, G. Human thioredoxin reductase gene localization to chromosomal position 12q23-q24.1 and mRNA distribution in human tissue. Genomics 37: 257-259, 1996. [PubMed: 8921404] [Full Text: https://doi.org/10.1006/geno.1996.0554]
Gasdaska, P. Y., Gasdaska, J. R., Cochran, S., Powis, G. Cloning and sequencing of a human thioredoxin reductase. FEBS Lett. 373: 5-9, 1995. [PubMed: 7589432] [Full Text: https://doi.org/10.1016/0014-5793(95)01003-w]
Gladyshev, V. N., Jeang, K.-T., Stadtman, T. C. Selenocysteine, identified as the penultimate C-terminal residue in human T-cell thioredoxin reductase, corresponds to TGA in the human placental gene. Proc. Nat. Acad. Sci. 93: 6146-6151, 1996. [PubMed: 8650234] [Full Text: https://doi.org/10.1073/pnas.93.12.6146]
Gorlatov, S. N., Stadtman, T. C. Human thioredoxin reductase from HeLa cells: selective alkylation of selenocysteine in the protein inhibits enzyme activity and reduction with NADPH influences affinity to heparin. Proc. Nat. Acad. Sci. 95: 8520-8525, 1998. [PubMed: 9671710] [Full Text: https://doi.org/10.1073/pnas.95.15.8520]
Tamura, T., Stadtman, T. C. A new selenoprotein from human lung adenocarcinoma cells: purification, properties, and thioredoxin reductase activity. Proc. Nat. Acad. Sci. 93: 1006-1011, 1996. [PubMed: 8577704] [Full Text: https://doi.org/10.1073/pnas.93.3.1006]