Cloning, sequencing and functional expression of a novel human thioredoxin reductase

Gasdaska, Pamela Y.; Berggren, Margareta; Berry, Marla J.; Powis, Garth

doi:10.1016/s0014-5793(98)01638-x

Cited by 105 publications

(62 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have examined a set of eight SNPs spanning COMT and partially overlapping the adjacent genes TXNRD2 44,45 and ARVCF. 46 Our LD findings between markers parallel their physical location, with one block at the 5 0 -end of COMT (including the 5 0 -end of TXNRD2) and another block at the 3 0 -end of COMT (including the 3 0 -end of ARVCF) and Val 108/158 Met in LD with all other SNPs examined.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 There are also some linkages here in bipolar disorder studies [40][41][42][43] and meta-analytically. 38 Further interest in the role of COMT, along with its two immediately adjacent genes, proximally thioredoxin reductase 2 (TXNRD2) 44,45 and distally armadillo repeat deleted in velocardiofacial syndrome (ARVCF) 46 in schizophrenia arises from their chromosomal location in the deleted region of chromosome 22q11.2 associated with velocardiofacial syndrome (VCFS), the most common human contiguous gene disorder. Many anomalies have been reported in VCFS, with behavioral manifestations being the most common.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

et al. 2004

View full text Add to dashboard Cite

Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val 108/158 Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P ¼ 0.051) in ARVCF, and a stronger signal (global P ¼ 0.0019-0.0036) from three-marker haplotypes spanning the 3 0 portions of COMT and ARVCF, including Val 108/158 Met with Val 108/158 being the overtransmitted allele, consistent with previous studies. We also find Val 108/158 Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence. Molecular Psychiatry (2005) 10, 353-365.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

et al. 2004

View full text Add to dashboard Cite

show abstract

“…By reduction of hydroperoxides to the corresponding alcohols, these enzymes can prevent the production of reactive oxygen radicals and thus may contribute to the protection of the Selenium in Biology 851 Ursini et al, 1982;Brigelius-Flohé et al, 1994 Plasma GPx (pGPx, GPx-3) Takahashi et al, 1987 Gastrointestinal GPx (GI-GPx, GPx-GI, GPx-2) Chu et al, 1993 Iodothyronine deiodinases 5Ј-deiodinase, type I (5ЈDI) Behne et al, 1990;Arthur et al, 1990 5Ј-deiodinase Lee et al, 1999;Watabe et al, 1999;Miranda-Vizuete et al, 1999;Gasdaska et al, 1999 Thioredoxin reductase homologs (SelZf1; SelZf2) Lescure et al, 1999 Selenophosphate synthetase-2 Guimaraes et al, 1996 Functionally undefined 15 kDa selenoprotein of T cells Gladyshev et al, 1998 Selenoprotein P 10 (SelP) Motsenbocker and Tappel organism's macromolecules and biomembranes against oxidation (Sies et al, 1972;Flohé, 1989;Ursini et al, 1995). The role of the cytoplasmic GPx as an 'emergency enzyme' to fight oxidative stress was verified by reverse genetics (Ho et al, 1997;Cheng et al, 1998;de Haan et al, 1998;Fu et al, 1999;Jaeschke et al, 1999) and, in this role, cGPx cannot be substituted by any of the other selenoproteins.…”

Section: Metabolic Function Of Mammalian Selenoproteinsmentioning

confidence: 99%

“…It needs selenocysteine as the penultimate amino acid residue for its appropriate enzymatic function (Marcocci et al, 1997;Gromer et al, 1998;Lee et al, 2000;Gorlatov and Stadtman, 2000). Recently, two more tissue-specifically expressed isoenzymes were also identified as selenoproteins (Gasdaska et al, 1999;Lee et al, 1999;Watabe et al, 1999) and related proteins were identified by 'in silico' cloning (Lescure et al, 1999). Various natural and synthetic compounds, apart from disulfide groups in peptides and proteins, can be reduced by TrxR Björnstedt et al, 1995).…”

Section: Metabolic Function Of Mammalian Selenoproteinsmentioning

confidence: 99%

Selenium in Biology: Facts and Medical Perspectives

Köhrl¹,

Brigelius‐Flohé²,

Böck³

et al. 2000

Biological Chemistry

247

143

View full text Add to dashboard Cite

Several decades after the discovery of selenium as an essential trace element in vertebrates approximately 20 eukaryotic and more than 15 prokaryotic selenoproteins containing the 21 st proteinogenic amino acid, selenocysteine, have been identified, partially characterized or cloned from several species. Many of these proteins are involved in redox reactions with selenocysteine acting as an essential component of the catalytic cycle. Enzyme activities have been assigned to the glutathione peroxidase family, to the thioredoxin reductases, which were recently identified as selenoproteins, to the iodothyronine deiodinases, which metabolize thyroid hormones, and to the selenophosphate synthetase 2, which is involved in selenoprotein biosynthesis. Prokaryotic selenoproteins catalyze redox reactions and formation of selenoethers in (stress-induced) metabolism and energy production of E. coli, of the clostridial cluster XI and of other prokaryotes. Apart from the specific and complex biosynthesis of selenocysteine, selenium also reversibly binds to proteins, is incorporated into selenomethionine in bacteria, yeast and higher plants, or posttranslationally modifies a catalytically essential cysteine residue of CO dehydrogenase. Expression of individual eukaryotic selenoproteins exhibits high tissue specificity, depends on selenium availability, in some cases is regulated by hormones, and if impaired contributes to several pathological conditions. Disturbance of selenoprotein expression or function is associated with deficiency syndromes (Keshan and Kashin-Beck disease), might contribute to tumorigenesis and atherosclerosis, is altered in several bacterial and viral infections, and leads to infertility in male rodents.

show abstract

“…The sequence contains one active-site sequence motif-Cys 59 -Val-Asn-Val-Gly-Cys 64 -identical to the redox-active disulfide of GR (14). The Cterminal end contains an extension of 16 residues with a penultimate selenocysteine (SeCys) residue within the unique sequence, Gly-Cys-SeCys-Gly conserved in all mammalian TrxR reported to date (12,(15)(16)(17)(18)(19). The SeCys residue is essential for the catalytic activity of TrxR, because either its removal by carboxypeptidase digestion (12) or its modification by alkylation (12,20) leads to inactivation.…”

mentioning

confidence: 99%

Structure and mechanism of mammalian thioredoxin reductase: The active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence

Zhong

Arnér

Holmgren

2000

Proc. Natl. Acad. Sci. U.S.A.

451

343

View full text Add to dashboard Cite

Mammalian thioredoxin reductases (TrxR) are homodimers, homologous to glutathione reductase (GR), with an essential selenocysteine (SeCys) residue in an extension containing the conserved C-terminal sequence -Gly-Cys-SeCys-Gly. In the oxidized enzyme, we demonstrated two nonflavin redox centers by chemical modification and peptide sequencing: one was a disulfide within the sequence -Cys 59 -Val-Asn-Val-Gly-Cys 64 , identical to the active site of GR; the other was a selenenylsulfide formed from Cys 497 -SeCys 498 and confirmed by mass spectrometry. In the NADPH reduced enzyme, these centers were present as a dithiol and a selenolthiol, respectively. Based on the structure of GR, we propose that in TrxR, the C-terminal Cys 497 -SeCys 498 residues of one monomer are adjacent to the Cys 59 and Cys 64 residues of the second monomer. The reductive half-reaction of TrxR is similar to that of GR followed by exchange from the nascent Cys 59 and Cys 64 dithiol to the selenenylsulfide of the other subunit to generate the active-site selenolthiol. Characterization of recombinant mutant rat TrxR with SeCys 498 replaced by Cys having a 100-fold lower kcat for Trx reduction revealed the C-terminal redox center was present as a dithiol when the Cys 59 -Cys 64 was a disulfide, demonstrating that the selenium atom with its larger radius is critical for formation of the unique selenenylsulfide. Spectroscopic redox titrations with dithionite or NADPH were consistent with the structure model. Mechanisms of TrxR in reduction of Trx and hydroperoxides have been postulated and are compatible with known enzyme activities and the effects of inhibitors, like goldthioglucose and 1-chloro-2,4-dinitrobenzene.evolution ͉ thiols ͉ disulfide ͉ selenium ͉ enzyme structure

show abstract

Cloning, sequencing and functional expression of a novel human thioredoxin reductase

Cited by 105 publications

References 28 publications

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

Selenium in Biology: Facts and Medical Perspectives

Structure and mechanism of mammalian thioredoxin reductase: The active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence

Contact Info

Product

Resources

About