ID IOD1_HUMAN Reviewed; 249 AA. AC P49895; Q1RN02; Q3KNP8; Q6Q4C1; Q6Q4C2; Q6Q4C3; Q6Q4C4; Q6Q4C5; Q6Q4C6; AC Q6Q4C7; Q6Q4C9; Q8WWC6; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 26-FEB-2008, sequence version 3. DT 27-MAR-2024, entry version 197. DE RecName: Full=Type I iodothyronine deiodinase; DE EC=1.21.99.4 {ECO:0000269|PubMed:32718224}; DE AltName: Full=5DI; DE AltName: Full=DIOI; DE AltName: Full=Type 1 DI; DE AltName: Full=Type-I 5'-deiodinase; GN Name=DIO1; Synonyms=ITDI1, TXDI1; 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] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=1400883; DOI=10.1210/jcem.75.4.1400883; RA Mandel S.J., Berry M.J., Kieffer J.D., Harney J.W., Warne R.L., RA Larsen P.R.; RT "Cloning and in vitro expression of the human selenoprotein, type I RT iodothyronine deiodinase."; RL J. Clin. Endocrinol. Metab. 75:1133-1139(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4; 5; 6; 7; 8 AND 9). RC TISSUE=Liver; RA Wassen F.J.W.S., Kuiper G.G.J.M., Visser T.J.; RT "Type I iodothyronine deiodinase splice variants in human liver."; RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5). RC TISSUE=Kidney; 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 [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-25. RX PubMed=7651427; DOI=10.1128/mcb.15.9.5100; RA Toyoda N., Zavacki A.M., Maia A.L., Harney J.W., Larsen P.R.; RT "A novel retinoid X receptor-independent thyroid hormone response element RT is present in the human type 1 deiodinase gene."; RL Mol. Cell. Biol. 15:5100-5112(1995). RN [6] RP INVOLVEMENT IN THMA2, VARIANTS THMA2 LYS-94 AND ILE-201, FUNCTION, RP BIOPHYSICOCHEMICAL PROPERTIES, AND CATALYTIC ACTIVITY. RX PubMed=32718224; DOI=10.1089/thy.2020.0253; RA Franca M.M., German A., Fernandes G.W., Liao X.H., Bianco A.C., RA Refetoff S., Dumitrescu A.M.; RT "Human Type 1 Iodothyronine Deiodinase (DIO1) Mutations Cause Abnormal RT Thyroid Hormone Metabolism."; RL Thyroid 31:202-207(2021). CC -!- FUNCTION: Responsible for the deiodination of T4 (3,5,3',5'- CC tetraiodothyronine) into T3 (3,5,3'-triiodothyronine) and of T3 into T2 CC (3,3'-diiodothyronine). Plays a role in providing a source of plasma T3 CC by deiodination of T4 in peripheral tissues such as liver and kidney. CC {ECO:0000269|PubMed:32718224}. CC -!- CATALYTIC ACTIVITY: CC Reaction=3,3',5-triiodo-L-thyronine + A + H(+) + iodide = AH2 + L- CC thyroxine; Xref=Rhea:RHEA:19745, ChEBI:CHEBI:13193, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16382, ChEBI:CHEBI:17499, CC ChEBI:CHEBI:58448, ChEBI:CHEBI:533015; EC=1.21.99.4; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10107, CC ECO:0000269|PubMed:32718224}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19747; CC Evidence={ECO:0000269|PubMed:32718224}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=10 uM for L-thyroxine {ECO:0000269|PubMed:32718224}; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000250}; CC Single-pass membrane protein {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=9; CC Name=1; Synonyms=a; CC IsoId=P49895-1; Sequence=Displayed; CC Name=2; Synonyms=b; CC IsoId=P49895-2; Sequence=VSP_012774; CC Name=3; Synonyms=c/f; CC IsoId=P49895-3; Sequence=VSP_012777, VSP_012778; CC Name=4; Synonyms=d; CC IsoId=P49895-4; Sequence=VSP_012781; CC Name=5; Synonyms=e; CC IsoId=P49895-5; Sequence=VSP_012783, VSP_012784; CC Name=6; Synonyms=k; CC IsoId=P49895-6; Sequence=VSP_012772, VSP_012773; CC Name=7; Synonyms=l; CC IsoId=P49895-7; Sequence=VSP_012782; CC Name=8; Synonyms=m; CC IsoId=P49895-8; Sequence=VSP_012775, VSP_012776; CC Name=9; Synonyms=s; CC IsoId=P49895-9; Sequence=VSP_012779, VSP_012780; CC -!- DISEASE: Thyroid hormone metabolism, abnormal, 2 (THMA2) [MIM:619855]: CC An autosomal dominant disorder characterized by slightly increased CC thyroid-stimulating hormone levels, and elevated serum reverse CC triiodothyronine (rT3) levels and rT3/T3 ratios. CC {ECO:0000269|PubMed:32718224}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 3]: The UGA codon in position 83 may either CC function as a selenocysteine codon or a translation termination codon. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 6]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. The UGA codon in position 34 may either function as a CC selenocysteine codon or a translation termination codon. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 8]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. The UGA codon in position 59 may either function as a CC selenocysteine codon or a translation termination codon. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 9]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. The UGA codon in position 59 may either function as a CC selenocysteine codon or a translation termination codon. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the iodothyronine deiodinase family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Deiodinase entry; CC URL="https://en.wikipedia.org/wiki/Deiodinase"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; S48220; AAB23670.2; -; mRNA. DR EMBL; AY560374; AAT02480.1; -; mRNA. DR EMBL; AY560375; AAT02481.1; -; mRNA. DR EMBL; AY560376; AAT02482.1; -; mRNA. DR EMBL; AY560377; AAT02483.1; -; mRNA. DR EMBL; AY560378; AAT02484.1; -; mRNA. DR EMBL; AY560379; AAT02485.1; -; mRNA. DR EMBL; AY560380; AAT02486.1; -; mRNA. DR EMBL; AY560381; AAT02487.1; -; mRNA. DR EMBL; AY560382; AAT02488.1; -; mRNA. DR EMBL; AY560383; AAT02489.1; -; mRNA. DR EMBL; AL031427; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC017955; AAH17955.2; -; mRNA. DR EMBL; BC107170; AAI07171.1; -; mRNA. DR EMBL; BC107171; AAI07172.1; -; mRNA. DR EMBL; S79349; AAB35380.2; -; Genomic_DNA. DR CCDS; CCDS30722.1; -. [P49895-4] DR CCDS; CCDS41339.1; -. [P49895-1] DR CCDS; CCDS41340.1; -. [P49895-5] DR CCDS; CCDS53320.1; -. [P49895-2] DR CCDS; CCDS81328.1; -. [P49895-7] DR RefSeq; NP_000783.2; NM_000792.6. [P49895-1] DR RefSeq; NP_001034804.1; NM_001039715.2. [P49895-4] DR RefSeq; NP_001034805.1; NM_001039716.2. [P49895-5] DR RefSeq; NP_001311245.1; NM_001324316.1. [P49895-7] DR RefSeq; NP_998758.1; NM_213593.4. [P49895-2] DR BioGRID; 108077; 1. DR STRING; 9606.ENSP00000354643; -. DR ChEMBL; CHEMBL2019; -. DR DrugBank; DB09100; Thyroid, porcine. DR DrugCentral; P49895; -. DR iPTMnet; P49895; -. DR PhosphoSitePlus; P49895; -. DR BioMuta; DIO1; -. DR DMDM; 182702125; -. DR EPD; P49895; -. DR MassIVE; P49895; -. DR PaxDb; 9606-ENSP00000354643; -. DR PeptideAtlas; P49895; -. DR ProteomicsDB; 56164; -. [P49895-1] DR ProteomicsDB; 56165; -. [P49895-2] DR ProteomicsDB; 56166; -. [P49895-3] DR ProteomicsDB; 56167; -. [P49895-4] DR ProteomicsDB; 56168; -. [P49895-5] DR ProteomicsDB; 56170; -. [P49895-7] DR ProteomicsDB; 56171; -. [P49895-8] DR ProteomicsDB; 56172; -. [P49895-9] DR Antibodypedia; 33120; 127 antibodies from 25 providers. DR DNASU; 1733; -. DR Ensembl; ENST00000322679.10; ENSP00000323198.6; ENSG00000211452.12. [P49895-5] DR Ensembl; ENST00000361921.8; ENSP00000354643.4; ENSG00000211452.12. [P49895-1] DR Ensembl; ENST00000388876.3; ENSP00000373528.3; ENSG00000211452.12. [P49895-4] DR Ensembl; ENST00000525202.5; ENSP00000435725.1; ENSG00000211452.12. [P49895-2] DR Ensembl; ENST00000532493.5; ENSP00000434758.1; ENSG00000211452.12. [P49895-7] DR GeneID; 1733; -. DR KEGG; hsa:1733; -. DR MANE-Select; ENST00000361921.8; ENSP00000354643.4; NM_000792.7; NP_000783.2. DR UCSC; uc001cwb.4; human. [P49895-1] DR AGR; HGNC:2883; -. DR CTD; 1733; -. DR DisGeNET; 1733; -. DR GeneCards; DIO1; -. DR HGNC; HGNC:2883; DIO1. DR HPA; ENSG00000211452; Group enriched (kidney, liver, thyroid gland). DR MalaCards; DIO1; -. DR MIM; 147892; gene. DR MIM; 619855; phenotype. DR neXtProt; NX_P49895; -. DR OpenTargets; ENSG00000211452; -. DR PharmGKB; PA27337; -. DR VEuPathDB; HostDB:ENSG00000211452; -. DR eggNOG; ENOG502QUGZ; Eukaryota. DR GeneTree; ENSGT00940000154482; -. DR HOGENOM; CLU_089345_2_0_1; -. DR InParanoid; P49895; -. DR OMA; PPFMYKL; -. DR OrthoDB; 5405869at2759; -. DR PhylomeDB; P49895; -. DR TreeFam; TF329721; -. DR BRENDA; 1.21.99.4; 2681. DR PathwayCommons; P49895; -. DR Reactome; R-HSA-350864; Regulation of thyroid hormone activity. DR SABIO-RK; P49895; -. DR SIGNOR; P49895; -. DR BioGRID-ORCS; 1733; 10 hits in 1143 CRISPR screens. DR ChiTaRS; DIO1; human. DR GenomeRNAi; 1733; -. DR Pharos; P49895; Tclin. DR PRO; PR:P49895; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P49895; Protein. DR Bgee; ENSG00000211452; Expressed in right lobe of thyroid gland and 108 other cell types or tissues. DR ExpressionAtlas; P49895; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0008430; F:selenium binding; TAS:ProtInc. DR GO; GO:0004800; F:thyroxine 5'-deiodinase activity; IBA:GO_Central. DR GO; GO:0006520; P:amino acid metabolic process; IGI:ARUK-UCL. DR GO; GO:0042446; P:hormone biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0006590; P:thyroid hormone generation; TAS:ProtInc. DR GO; GO:0042403; P:thyroid hormone metabolic process; IBA:GO_Central. DR Gene3D; 3.40.30.10; Glutaredoxin; 1. DR InterPro; IPR000643; Iodothyronine_deiodinase. DR InterPro; IPR008261; Iodothyronine_deiodinase_AS. DR InterPro; IPR027252; Iodothyronine_deiodinase_I/III. DR InterPro; IPR036249; Thioredoxin-like_sf. DR PANTHER; PTHR11781; IODOTHYRONINE DEIODINASE; 1. DR PANTHER; PTHR11781:SF23; TYPE I IODOTHYRONINE DEIODINASE; 1. DR Pfam; PF00837; T4_deiodinase; 1. DR PIRSF; PIRSF001330; IOD; 1. DR PIRSF; PIRSF500144; IODI_III; 1. DR SUPFAM; SSF52833; Thioredoxin-like; 1. DR PROSITE; PS01205; T4_DEIODINASE; 1. DR Genevisible; P49895; HS. PE 1: Evidence at protein level; KW Alternative splicing; Disease variant; Endoplasmic reticulum; Membrane; KW Oxidoreductase; Reference proteome; Selenocysteine; KW Thyroid hormones biosynthesis; Transmembrane; Transmembrane helix. FT CHAIN 1..249 FT /note="Type I iodothyronine deiodinase" FT /id="PRO_0000154311" FT TRANSMEM 13..33 FT /note="Helical" FT /evidence="ECO:0000255" FT ACT_SITE 126 FT NON_STD 126 FT /note="Selenocysteine" FT VAR_SEQ 26..40 FT /note="GKVLLILFPDRVKRN -> APSISGSSURSVGSD (in isoform 6)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012772" FT VAR_SEQ 41..249 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012773" FT VAR_SEQ 50..113 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012774" FT VAR_SEQ 50..89 FT /note="MTRNPHFSHDNWIPTFFSTQYFWFVLKVRWQRLEDTTELG -> PLAATRGH FT DUARGSGPKLPGGPPLRTEVQHLGVYARWLGF (in isoform 9)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012779" FT VAR_SEQ 50..85 FT /note="MTRNPHFSHDNWIPTFFSTQYFWFVLKVRWQRLEDT -> PLAATRGHDUAR FT GSGPKLPGGPPLRTEVQHLGVYAR (in isoform 8)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012775" FT VAR_SEQ 78..109 FT /note="RWQRLEDTTELGGLAPNCPVVRLSGQRCNIWE -> IGHWCUILEVVPDLHL FT CSNLTSSRGLLKTLVP (in isoform 3)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012777" FT VAR_SEQ 86..249 FT /note="Missing (in isoform 8)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012776" FT VAR_SEQ 90..249 FT /note="Missing (in isoform 9)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012780" FT VAR_SEQ 110..249 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012778" FT VAR_SEQ 113..160 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012781" FT VAR_SEQ 114..249 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_012782" FT VAR_SEQ 161 FT /note="D -> G (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.2" FT /id="VSP_012783" FT VAR_SEQ 162..249 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.2" FT /id="VSP_012784" FT VARIANT 94 FT /note="N -> K (in THMA2; reduced catalytic activity, due to FT a 2-fold reduction in T4 substrate affinity; FT dbSNP:rs754694815)" FT /evidence="ECO:0000269|PubMed:32718224" FT /id="VAR_087106" FT VARIANT 201 FT /note="M -> I (in THMA2; reduced catalytic activity, due to FT a 3-fold reduction in T4 substrate affinity; FT dbSNP:rs201420507)" FT /evidence="ECO:0000269|PubMed:32718224" FT /id="VAR_087107" SQ SEQUENCE 249 AA; 28924 MW; 2D8BBFBA54B5A927 CRC64; MGLPQPGLWL KRLWVLLEVA VHVVVGKVLL ILFPDRVKRN ILAMGEKTGM TRNPHFSHDN WIPTFFSTQY FWFVLKVRWQ RLEDTTELGG LAPNCPVVRL SGQRCNIWEF MQGNRPLVLN FGSCTUPSFM FKFDQFKRLI EDFSSIADFL VIYIEEAHAS DGWAFKNNMD IRNHQNLQDR LQAAHLLLAR SPQCPVVVDT MQNQSSQLYA ALPERLYIIQ EGRILYKGKS GPWNYNPEEV RAVLEKLHS //