ID   TRXR2_HUMAN             Reviewed;         524 AA.
AC   Q9NNW7; O95840; Q96IJ2; Q9H2Z5; Q9NZV3; Q9NZV4; Q9P2Y0; Q9P2Y1;
AC   Q9UQU8;
DT   19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT   26-FEB-2008, sequence version 3.
DT   09-DEC-2015, entry version 155.
DE   RecName: Full=Thioredoxin reductase 2, mitochondrial;
DE            EC=1.8.1.9;
DE   AltName: Full=Selenoprotein Z;
DE            Short=SelZ;
DE   AltName: Full=TR-beta;
DE   AltName: Full=Thioredoxin reductase TR3;
DE   Flags: Precursor;
GN   Name=TXNRD2; Synonyms=KIAA1652, TRXR2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606 {ECO:0000312|EMBL:AAD51324.1};
RN   [1] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=10455115; DOI=10.1074/jbc.274.35.24522;
RA   Sun Q.-A., Wu Y., Zappacosta F., Jeang K.-T., Lee B.J., Hatfield D.L.,
RA   Gladyshev V.N.;
RT   "Redox regulation of cell signaling by selenocysteine in mammalian
RT   thioredoxin reductases.";
RL   J. Biol. Chem. 274:24522-24530(1999).
RN   [2] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP   VARIANT SER-66.
RC   TISSUE=Fetal heart, and Placenta;
RX   PubMed=9923614; DOI=10.1016/S0014-5793(98)01638-X;
RA   Gasdaska P.Y., Berggren M.M., Berry M.J., Powis G.;
RT   "Cloning, sequencing and functional expression of a novel human
RT   thioredoxin reductase.";
RL   FEBS Lett. 442:105-111(1999).
RN   [3] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, AND
RP   TISSUE SPECIFICITY.
RC   TISSUE=Adrenal gland, and Testis;
RX   PubMed=10215850; DOI=10.1046/j.1432-1327.1999.00286.x;
RA   Miranda-Vizuete A., Damdimopoulos A.E., Pedrajas J.R.,
RA   Gustafsson J.-A., Spyrou G.;
RT   "Human mitochondrial thioredoxin reductase: cDNA cloning, expression
RT   and genomic organization.";
RL   Eur. J. Biochem. 261:405-412(1999).
RN   [4] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2), AND VARIANT THR-370.
RA   Toji S., Yano M., Tamai K.;
RL   Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN   [5] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4), ALTERNATIVE SPLICING,
RP   TISSUE SPECIFICITY, AND VARIANT THR-370.
RC   TISSUE=Cervix carcinoma;
RX   PubMed=10608886; DOI=10.1074/jbc.274.53.38147;
RA   Lescure A., Gautheret D., Carbon P., Krol A.;
RT   "Novel selenoproteins identified in silico and in vivo by using a
RT   conserved RNA structural motif.";
RL   J. Biol. Chem. 274:38147-38154(1999).
RN   [6] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE (ISOFORM 1), AND VARIANTS SER-66 AND THR-370.
RA   Kim J.-R., Lee Y.H., Lee S.-R., Kim B.H., Rhee S.G., Kim J.H.;
RL   Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10591208; DOI=10.1038/990031;
RA   Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA   Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA   Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA   Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA   Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA   Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA   Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA   Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA   Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA   Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA   Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA   Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA   Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA   Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA   Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA   Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA   Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA   Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA   Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA   Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA   Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA   Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA   Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA   Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA   Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA   Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA   Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA   Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA   Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA   Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA   Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA   Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA   Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA   Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA   Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA   Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA   Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA   Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA   Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA   O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA   Khan A.S., Lane L., Tilahun Y., Wright H.;
RT   "The DNA sequence of human chromosome 22.";
RL   Nature 402:489-495(1999).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 40-524, AND VARIANT SER-66.
RC   TISSUE=Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   ALTERNATIVE SPLICING.
RX   PubMed=11060283; DOI=10.1074/jbc.M004750200;
RA   Sun Q.-A., Zappacosta F., Factor V.M., Wirth P.J., Hatfield D.L.,
RA   Gladyshev V.N.;
RT   "Heterogeneity within animal thioredoxin reductases: evidence for
RT   alternative first exon splicing.";
RL   J. Biol. Chem. 276:3106-3114(2001).
RN   [10]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA   Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [11]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
RA   Wang L., Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human
RT   liver phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M.,
RA   Ayoub D., Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
CC   -!- FUNCTION: Maintains thioredoxin in a reduced state. Implicated in
CC       the defenses against oxidative stress. May play a role in redox-
CC       regulated cell signaling.
CC   -!- CATALYTIC ACTIVITY: Thioredoxin + NADP(+) = thioredoxin disulfide
CC       + NADPH.
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000255|RuleBase:RU000402, ECO:0000305};
CC   -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P38816}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:10215850}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=4;
CC       Name=1; Synonyms=Alpha {ECO:0000305};
CC         IsoId=Q9NNW7-1; Sequence=Displayed;
CC       Name=2; Synonyms=Beta {ECO:0000305};
CC         IsoId=Q9NNW7-2; Sequence=VSP_008304;
CC       Name=3; Synonyms=SelZf2;
CC         IsoId=Q9NNW7-3; Sequence=VSP_008305;
CC       Name=4; Synonyms=SelZf1;
CC         IsoId=Q9NNW7-4; Sequence=VSP_008306;
CC   -!- TISSUE SPECIFICITY: Highly expressed in the prostate, ovary,
CC       liver, testis, uterus, colon and small intestine. Intermediate
CC       levels in brain, skeletal muscle, heart and spleen. Low levels in
CC       placenta, pancreas, thymus and peripheral blood leukocytes.
CC       According to PubMed:10608886, high levels in kidney, whereas
CC       according to PubMed:9923614, levels are low.
CC       {ECO:0000269|PubMed:10215850, ECO:0000269|PubMed:10608886,
CC       ECO:0000269|PubMed:9923614}.
CC   -!- MISCELLANEOUS: The active site is a redox-active disulfide bond.
CC       The selenocysteine residue is essential for enzymatic activity (By
CC       similarity). {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the class-I pyridine nucleotide-disulfide
CC       oxidoreductase family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAD25167.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC       Sequence=AAG47635.1; Type=Erroneous termination; Positions=523; Note=Translated as Sec.; Evidence={ECO:0000305};
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DR   EMBL; AF171054; AAD51324.1; -; mRNA.
DR   EMBL; AF106697; AAD19597.1; -; mRNA.
DR   EMBL; AF044212; AAD25167.1; ALT_INIT; mRNA.
DR   EMBL; AB019694; BAA77601.2; -; mRNA.
DR   EMBL; AB019695; BAA77602.2; -; mRNA.
DR   EMBL; AF166126; AAF21431.1; -; mRNA.
DR   EMBL; AF166127; AAF21432.1; -; mRNA.
DR   EMBL; AF201385; AAG47635.1; ALT_SEQ; mRNA.
DR   EMBL; AC000078; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC000080; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC000090; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC007489; AAH07489.3; -; mRNA.
DR   CCDS; CCDS42981.1; -. [Q9NNW7-1]
DR   RefSeq; NP_001269441.1; NM_001282512.1.
DR   RefSeq; NP_006431.2; NM_006440.4. [Q9NNW7-1]
DR   UniGene; Hs.443430; -.
DR   PDB; 1W1E; Model; -; A/B=36-524.
DR   PDBsum; 1W1E; -.
DR   ProteinModelPortal; Q9NNW7; -.
DR   SMR; Q9NNW7; 37-518.
DR   BioGrid; 115836; 15.
DR   IntAct; Q9NNW7; 1.
DR   STRING; 9606.ENSP00000383365; -.
DR   ChEMBL; CHEMBL2096978; -.
DR   PhosphoSite; Q9NNW7; -.
DR   BioMuta; TXNRD2; -.
DR   DMDM; 182705230; -.
DR   MaxQB; Q9NNW7; -.
DR   PaxDb; Q9NNW7; -.
DR   PRIDE; Q9NNW7; -.
DR   DNASU; 10587; -.
DR   Ensembl; ENST00000400521; ENSP00000383365; ENSG00000184470. [Q9NNW7-1]
DR   GeneID; 10587; -.
DR   KEGG; hsa:10587; -.
DR   UCSC; uc002zqq.1; human. [Q9NNW7-4]
DR   UCSC; uc021wlj.1; human. [Q9NNW7-1]
DR   CTD; 10587; -.
DR   GeneCards; TXNRD2; -.
DR   H-InvDB; HIX0016244; -.
DR   HGNC; HGNC:18155; TXNRD2.
DR   HPA; CAB002007; -.
DR   HPA; HPA003323; -.
DR   MalaCards; TXNRD2; -.
DR   MIM; 606448; gene.
DR   neXtProt; NX_Q9NNW7; -.
DR   Orphanet; 361; Familial glucocorticoid deficiency.
DR   Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR   PharmGKB; PA38302; -.
DR   eggNOG; KOG0405; Eukaryota.
DR   eggNOG; COG1249; LUCA.
DR   GeneTree; ENSGT00390000007578; -.
DR   HOVERGEN; HBG004959; -.
DR   InParanoid; Q9NNW7; -.
DR   KO; K00384; -.
DR   OMA; GLHFTGP; -.
DR   PhylomeDB; Q9NNW7; -.
DR   TreeFam; TF314782; -.
DR   BRENDA; 1.8.1.9; 2681.
DR   Reactome; R-HSA-3299685; Detoxification of Reactive Oxygen Species.
DR   ChiTaRS; TXNRD2; human.
DR   GenomeRNAi; 10587; -.
DR   NextBio; 40203; -.
DR   PRO; PR:Q9NNW7; -.
DR   Proteomes; UP000005640; Chromosome 22.
DR   Bgee; Q9NNW7; -.
DR   ExpressionAtlas; Q9NNW7; baseline and differential.
DR   GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR   GO; GO:0004791; F:thioredoxin-disulfide reductase activity; ISS:UniProtKB.
DR   GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR   GO; GO:0007507; P:heart development; IEA:Ensembl.
DR   GO; GO:0030097; P:hemopoiesis; IEA:Ensembl.
DR   GO; GO:0000305; P:response to oxygen radical; TAS:UniProtKB.
DR   GO; GO:0000302; P:response to reactive oxygen species; TAS:Reactome.
DR   Gene3D; 3.30.390.30; -; 1.
DR   Gene3D; 3.50.50.60; -; 2.
DR   InterPro; IPR023753; FAD/NAD-binding_dom.
DR   InterPro; IPR016156; FAD/NAD-linked_Rdtase_dimer.
DR   InterPro; IPR004099; Pyr_nucl-diS_OxRdtase_dimer.
DR   InterPro; IPR012999; Pyr_OxRdtase_I_AS.
DR   InterPro; IPR006338; Thioredoxin/glutathione_Rdtase.
DR   Pfam; PF07992; Pyr_redox_2; 1.
DR   Pfam; PF02852; Pyr_redox_dim; 1.
DR   SUPFAM; SSF51905; SSF51905; 1.
DR   SUPFAM; SSF55424; SSF55424; 1.
DR   TIGRFAMs; TIGR01438; TGR; 1.
DR   PROSITE; PS00076; PYRIDINE_REDOX_1; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Complete proteome; Disulfide bond;
KW   FAD; Flavoprotein; Mitochondrion; NADP; Oxidoreductase; Polymorphism;
KW   Redox-active center; Reference proteome; Selenocysteine;
KW   Transit peptide.
FT   TRANSIT       1     36       Mitochondrion. {ECO:0000255}.
FT   CHAIN        37    524       Thioredoxin reductase 2, mitochondrial.
FT                                /FTId=PRO_0000030288.
FT   NP_BIND      41     70       FAD. {ECO:0000250}.
FT   ACT_SITE    497    497       Proton acceptor. {ECO:0000250}.
FT   NON_STD     523    523       Selenocysteine.
FT   MOD_RES     175    175       N6-succinyllysine.
FT                                {ECO:0000250|UniProtKB:Q9JLT4}.
FT   MOD_RES     329    329       N6-succinyllysine.
FT                                {ECO:0000250|UniProtKB:Q9JLT4}.
FT   DISULFID     86     91       Redox-active. {ECO:0000250}.
FT   CROSSLNK    522    523       Cysteinyl-selenocysteine (Cys-Sec).
FT                                {ECO:0000250}.
FT   VAR_SEQ       1    247       Missing (in isoform 4).
FT                                {ECO:0000303|PubMed:10608886}.
FT                                /FTId=VSP_008306.
FT   VAR_SEQ       1     96       Missing (in isoform 3).
FT                                {ECO:0000303|PubMed:10608886}.
FT                                /FTId=VSP_008305.
FT   VAR_SEQ       1     30       MAAMAVALRGLGGRFRWRTQAVAGGVRGAA -> MEDQ
FT                                (in isoform 2). {ECO:0000305}.
FT                                /FTId=VSP_008304.
FT   VARIANT      14     14       R -> L (in dbSNP:rs45593642).
FT                                /FTId=VAR_051777.
FT   VARIANT      66     66       A -> S (in dbSNP:rs5748469).
FT                                {ECO:0000269|PubMed:15489334,
FT                                ECO:0000269|PubMed:9923614,
FT                                ECO:0000269|Ref.6}.
FT                                /FTId=VAR_051778.
FT   VARIANT     299    299       S -> R (in dbSNP:rs5992495).
FT                                /FTId=VAR_051779.
FT   VARIANT     370    370       I -> T (in dbSNP:rs1139793).
FT                                {ECO:0000269|PubMed:10608886,
FT                                ECO:0000269|Ref.4, ECO:0000269|Ref.6}.
FT                                /FTId=VAR_051780.
FT   CONFLICT     33     33       Missing (in Ref. 6; AAG47635).
FT                                {ECO:0000305}.
FT   CONFLICT    285    285       R -> K (in Ref. 6; AAG47635).
FT                                {ECO:0000305}.
SQ   SEQUENCE   524 AA;  56507 MW;  B575A185A2183DAC CRC64;
     MAAMAVALRG LGGRFRWRTQ AVAGGVRGAA RGAAAGQRDY DLLVVGGGSG GLACAKEAAQ
     LGRKVAVVDY VEPSPQGTRW GLGGTCVNVG CIPKKLMHQA ALLGGLIQDA PNYGWEVAQP
     VPHDWRKMAE AVQNHVKSLN WGHRVQLQDR KVKYFNIKAS FVDEHTVCGV AKGGKEILLS
     ADHIIIATGG RPRYPTHIEG ALEYGITSDD IFWLKESPGK TLVVGASYVA LECAGFLTGI
     GLDTTIMMRS IPLRGFDQQM SSMVIEHMAS HGTRFLRGCA PSRVRRLPDG QLQVTWEDST
     TGKEDTGTFD TVLWAIGRVP DTRSLNLEKA GVDTSPDTQK ILVDSREATS VPHIYAIGDV
     VEGRPELTPI AIMAGRLLVQ RLFGGSSDLM DYDNVPTTVF TPLEYGCVGL SEEEAVARHG
     QEHVEVYHAH YKPLEFTVAG RDASQCYVKM VCLREPPQLV LGLHFLGPNA GEVTQGFALG
     IKCGASYAQV MRTVGIHPTC SEEVVKLRIS KRSGLDPTVT GCUG
//