ID   TRXR3_HUMAN             Reviewed;         643 AA.
AC   Q86VQ6; Q6PIS8; Q9NNW6; Q9P101;
DT   26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   29-MAY-2013, sequence version 4.
DT   27-MAR-2024, entry version 180.
DE   RecName: Full=Thioredoxin reductase 3;
DE            EC=1.8.1.9;
DE   AltName: Full=Thioredoxin and glutathione reductase;
DE   AltName: Full=Thioredoxin reductase TR2;
GN   Name=TXNRD3 {ECO:0000312|EMBL:AAH50032.1};
GN   Synonyms=TGR {ECO:0000250|UniProtKB:Q99MD6}, TRXR3
GN   {ECO:0000312|EMBL:AAD39929.1};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16641997; DOI=10.1038/nature04728;
RA   Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA   Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA   Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA   Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA   Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA   Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA   Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA   Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA   Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA   Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA   Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA   Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA   Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA   Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA   Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA   Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA   Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA   Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA   Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT   "The DNA sequence, annotation and analysis of human chromosome 3.";
RL   Nature 440:1194-1198(2006).
RN   [2] {ECO:0000305, ECO:0000312|EMBL:AAH50032.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Testis {ECO:0000312|EMBL:AAH50032.1};
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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3] {ECO:0000305, ECO:0000312|EMBL:AAD51325.1}
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 65-643, AND SELENOCYSTEINE AT SEC-642.
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   [4] {ECO:0000305, ECO:0000312|EMBL:AAD39929.1}
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 67-643.
RA   Miranda-Vizuete A.;
RT   "TrxR3, a novel human thioredoxin reductase.";
RL   Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-41 AND SER-42, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [6]
RP   PROBABLE NON-AUG INITIATOR START CODON.
RX   PubMed=20018845; DOI=10.1074/jbc.m109.070532;
RA   Gerashchenko M.V., Su D., Gladyshev V.N.;
RT   "CUG start codon generates thioredoxin/glutathione reductase isoforms in
RT   mouse testes.";
RL   J. Biol. Chem. 285:4595-4602(2010).
CC   -!- FUNCTION: Displays thioredoxin reductase, glutaredoxin and glutathione
CC       reductase activities. Catalyzes disulfide bond isomerization. Promotes
CC       disulfide bond formation between GPX4 and various sperm proteins and
CC       may play a role in sperm maturation by promoting formation of sperm
CC       structural components (By similarity). {ECO:0000250|UniProtKB:Q99MD6}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[thioredoxin]-dithiol + NADP(+) = [thioredoxin]-disulfide +
CC         H(+) + NADPH; Xref=Rhea:RHEA:20345, Rhea:RHEA-COMP:10698, Rhea:RHEA-
CC         COMP:10700, ChEBI:CHEBI:15378, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058,
CC         ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.8.1.9;
CC         Evidence={ECO:0000250|UniProtKB:Q99MD6};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:O89049};
CC       Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:O89049};
CC   -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:O89049}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q99MD6}. Nucleus
CC       {ECO:0000250|UniProtKB:Q99MD6}. Microsome
CC       {ECO:0000250|UniProtKB:Q99MD6}. Endoplasmic reticulum {ECO:0000250}.
CC       Note=Detected in cytoplasm and nucleus in late spermatids.
CC       {ECO:0000250|UniProtKB:Q99MD6}.
CC   -!- DOMAIN: The N-terminal glutaredoxin domain does not contain the C-X-X-C
CC       redox-active motif normally found in glutaredoxins but activity may be
CC       mediated through a single cysteine. The C-terminal Cys-Sec motif of one
CC       subunit of the homodimer may transfer electrons from the thiol-
CC       disulfide center to the glutaredoxin domain of the other subunit (By
CC       similarity). {ECO:0000250|UniProtKB:Q99MD6}.
CC   -!- MISCELLANEOUS: The thioredoxin reductase active site is a redox-active
CC       disulfide bond. The selenocysteine residue is also essential for
CC       catalytic activity (By similarity). {ECO:0000250|UniProtKB:Q16881}.
CC   -!- SIMILARITY: Belongs to the class-I pyridine nucleotide-disulfide
CC       oxidoreductase family. {ECO:0000305}.
CC   -!- CAUTION: This sequence initiates at a CTG codon.
CC       {ECO:0000305|PubMed:20018845}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH30028.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAH30028.1; Type=Miscellaneous discrepancy; Note=Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.; Evidence={ECO:0000305};
CC       Sequence=AAH50032.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAH50032.1; Type=Miscellaneous discrepancy; Note=Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.; Evidence={ECO:0000305};
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DR   EMBL; AC024558; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC030028; AAH30028.1; ALT_SEQ; mRNA.
DR   EMBL; BC050032; AAH50032.1; ALT_SEQ; mRNA.
DR   EMBL; AF171055; AAD51325.1; -; mRNA.
DR   EMBL; AF133519; AAD39929.1; -; mRNA.
DR   CCDS; CCDS77811.1; -.
DR   RefSeq; NP_001166984.1; NM_001173513.1.
DR   RefSeq; NP_443115.1; NM_052883.1.
DR   PDB; 3H8Q; X-ray; 2.21 A; A/B=51-156.
DR   PDBsum; 3H8Q; -.
DR   SMR; Q86VQ6; -.
DR   BioGRID; 125281; 20.
DR   IntAct; Q86VQ6; 1.
DR   STRING; 9606.ENSP00000430031; -.
DR   BindingDB; Q86VQ6; -.
DR   ChEMBL; CHEMBL2096978; -.
DR   iPTMnet; Q86VQ6; -.
DR   PhosphoSitePlus; Q86VQ6; -.
DR   BioMuta; TXNRD3; -.
DR   DMDM; 510120859; -.
DR   EPD; Q86VQ6; -.
DR   jPOST; Q86VQ6; -.
DR   MassIVE; Q86VQ6; -.
DR   MaxQB; Q86VQ6; -.
DR   PeptideAtlas; Q86VQ6; -.
DR   ProteomicsDB; 70059; -.
DR   Pumba; Q86VQ6; -.
DR   Antibodypedia; 60139; 157 antibodies from 17 providers.
DR   DNASU; 114112; -.
DR   Ensembl; ENST00000524230.9; ENSP00000430031.4; ENSG00000197763.20.
DR   GeneID; 114112; -.
DR   KEGG; hsa:114112; -.
DR   MANE-Select; ENST00000524230.9; ENSP00000430031.4; NM_052883.3; NP_443115.1.
DR   AGR; HGNC:20667; -.
DR   CTD; 114112; -.
DR   DisGeNET; 114112; -.
DR   GeneCards; TXNRD3; -.
DR   HGNC; HGNC:20667; TXNRD3.
DR   HPA; ENSG00000197763; Tissue enhanced (testis).
DR   MIM; 606235; gene.
DR   neXtProt; NX_Q86VQ6; -.
DR   OpenTargets; ENSG00000197763; -.
DR   PharmGKB; PA134920642; -.
DR   VEuPathDB; HostDB:ENSG00000197763; -.
DR   GeneTree; ENSGT00940000159178; -.
DR   InParanoid; Q86VQ6; -.
DR   OMA; HPTCGEI; -.
DR   OrthoDB; 5473641at2759; -.
DR   BRENDA; 1.8.1.9; 2681.
DR   PathwayCommons; Q86VQ6; -.
DR   SignaLink; Q86VQ6; -.
DR   BioGRID-ORCS; 114112; 14 hits in 404 CRISPR screens.
DR   ChiTaRS; TXNRD3; human.
DR   EvolutionaryTrace; Q86VQ6; -.
DR   GenomeRNAi; 114112; -.
DR   Pharos; Q86VQ6; Tbio.
DR   PRO; PR:Q86VQ6; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; Q86VQ6; Protein.
DR   Bgee; ENSG00000197763; Expressed in right testis and 127 other cell types or tissues.
DR   ExpressionAtlas; Q86VQ6; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR   GO; GO:0004791; F:thioredoxin-disulfide reductase (NADP) activity; IBA:GO_Central.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0045454; P:cell redox homeostasis; IBA:GO_Central.
DR   GO; GO:0007283; P:spermatogenesis; IEA:UniProtKB-KW.
DR   CDD; cd03419; GRX_GRXh_1_2_like; 1.
DR   Gene3D; 3.30.390.30; -; 1.
DR   Gene3D; 3.50.50.60; FAD/NAD(P)-binding domain; 2.
DR   Gene3D; 3.40.30.10; Glutaredoxin; 1.
DR   InterPro; IPR036188; FAD/NAD-bd_sf.
DR   InterPro; IPR023753; FAD/NAD-binding_dom.
DR   InterPro; IPR016156; FAD/NAD-linked_Rdtase_dimer_sf.
DR   InterPro; IPR002109; Glutaredoxin.
DR   InterPro; IPR011899; Glutaredoxin_euk/vir.
DR   InterPro; IPR046952; GSHR/TRXR-like.
DR   InterPro; IPR004099; Pyr_nucl-diS_OxRdtase_dimer.
DR   InterPro; IPR012999; Pyr_OxRdtase_I_AS.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   InterPro; IPR006338; Thioredoxin/glutathione_Rdtase.
DR   NCBIfam; TIGR02180; GRX_euk; 1.
DR   NCBIfam; TIGR01438; TGR; 1.
DR   PANTHER; PTHR42737; GLUTATHIONE REDUCTASE; 1.
DR   PANTHER; PTHR42737:SF7; THIOREDOXIN REDUCTASE 3; 1.
DR   Pfam; PF00462; Glutaredoxin; 1.
DR   Pfam; PF07992; Pyr_redox_2; 1.
DR   Pfam; PF02852; Pyr_redox_dim; 1.
DR   PRINTS; PR00368; FADPNR.
DR   PRINTS; PR00411; PNDRDTASEI.
DR   SUPFAM; SSF51905; FAD/NAD(P)-binding domain; 1.
DR   SUPFAM; SSF55424; FAD/NAD-linked reductases, dimerisation (C-terminal) domain; 1.
DR   SUPFAM; SSF52833; Thioredoxin-like; 1.
DR   PROSITE; PS51354; GLUTAREDOXIN_2; 1.
DR   PROSITE; PS00076; PYRIDINE_REDOX_1; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Cytoplasm; Developmental protein; Differentiation;
KW   Disulfide bond; Electron transport; Endoplasmic reticulum; FAD;
KW   Flavoprotein; Methylation; Microsome; NADP; Nucleus; Oxidoreductase;
KW   Phosphoprotein; Redox-active center; Reference proteome; Selenocysteine;
KW   Spermatogenesis; Transport.
FT   CHAIN           1..643
FT                   /note="Thioredoxin reductase 3"
FT                   /id="PRO_0000320695"
FT   DOMAIN          56..156
FT                   /note="Glutaredoxin"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00686"
FT   REGION          1..53
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        616
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   BINDING         158..187
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   NON_STD         642
FT                   /note="Selenocysteine"
FT   MOD_RES         26
FT                   /note="Asymmetric dimethylarginine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q99MD6"
FT   MOD_RES         26
FT                   /note="Omega-N-methylarginine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q99MD6"
FT   MOD_RES         41
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         42
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         379
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q99MD6"
FT   DISULFID        203..208
FT                   /note="Redox-active"
FT                   /evidence="ECO:0000250"
FT   CROSSLNK        641..642
FT                   /note="Cysteinyl-selenocysteine (Cys-Sec)"
FT                   /evidence="ECO:0000250"
FT   CONFLICT        65..66
FT                   /note="RS -> AE (in Ref. 3; AAD51325)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        246
FT                   /note="T -> I (in Ref. 2; AAH30028)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        337
FT                   /note="T -> P (in Ref. 4; AAD39929)"
FT                   /evidence="ECO:0000305"
FT   HELIX           53..65
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   STRAND          67..72
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   HELIX           77..88
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   STRAND          94..97
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   TURN            98..100
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   HELIX           104..115
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   STRAND          122..125
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   STRAND          128..132
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   HELIX           133..142
FT                   /evidence="ECO:0007829|PDB:3H8Q"
FT   HELIX           144..150
FT                   /evidence="ECO:0007829|PDB:3H8Q"
SQ   SEQUENCE   643 AA;  70683 MW;  6FB04128943A4017 CRC64;
     MERSPPQSPG PGKAGDAPNR RSGHVRGARV LSPPGRRARL SSPGPSRSSE AREELRRHLV
     GLIERSRVVI FSKSYCPHST RVKELFSSLG VECNVLELDQ VDDGARVQEV LSEITNQKTV
     PNIFVNKVHV GGCDQTFQAY QSGLLQKLLQ EDLAYDYDLI IIGGGSGGLS CAKEAAILGK
     KVMVLDFVVP SPQGTSWGLG GTCVNVGCIP KKLMHQAALL GQALCDSRKF GWEYNQQVRH
     NWETMTKAIQ NHISSLNWGY RLSLREKAVA YVNSYGEFVE HHKIKATNKK GQETYYTAAQ
     FVIATGERPR YLGIQGDKEY CITSDDLFSL PYCPGKTLVV GASYVALECA GFLAGFGLDV
     TVMVRSILLR GFDQEMAEKV GSYMEQHGVK FLRKFIPVMV QQLEKGSPGK LKVLAKSTEG
     TETIEGVYNT VLLAIGRDSC TRKIGLEKIG VKINEKSGKI PVNDVEQTNV PYVYAVGDIL
     EDKPELTPVA IQSGKLLAQR LFGASLEKCD YINVPTTVFT PLEYGCCGLS EEKAIEVYKK
     ENLEIYHTLF WPLEWTVAGR ENNTCYAKII CNKFDHDRVI GFHILGPNAG EVTQGFAAAM
     KCGLTKQLLD DTIGIHPTCG EVFTTLEITK SSGLDITQKG CUG
//