I23O2_HUMAN
ID I23O2_HUMAN Reviewed; 420 AA.
AC Q6ZQW0; A4UD41; F5H5G0;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 14-OCT-2015, sequence version 4.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=Indoleamine 2,3-dioxygenase 2;
DE Short=IDO-2;
DE EC=1.13.11.- {ECO:0000269|PubMed:17671174};
DE AltName: Full=Indoleamine 2,3-dioxygenase-like protein 1;
DE AltName: Full=Indoleamine-pyrrole 2,3-dioxygenase-like protein 1;
GN Name=IDO2; Synonyms=INDOL1;
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 [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 13-420 (ISOFORM 1).
RX PubMed=17499941; DOI=10.1016/j.gene.2007.04.010;
RA Ball H.J., Sanchez-Perez A., Weiser S., Austin C.J.D., Astelbauer F.,
RA Miu J., McQuillan J.A., Stocker R., Jermiin L.S., Hunt N.H.;
RT "Characterization of an indoleamine 2,3-dioxygenase-like protein found in
RT humans and mice.";
RL Gene 396:203-213(2007).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, ALTERNATIVE SPLICING, ACTIVITY REGULATION,
RP TISSUE SPECIFICITY, AND VARIANTS TRP-248 AND 359-TYR--GLY-420 DEL.
RX PubMed=17671174; DOI=10.1158/0008-5472.can-07-1872;
RA Metz R., Duhadaway J.B., Kamasani U., Laury-Kleintop L., Muller A.J.,
RA Prendergast G.C.;
RT "Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target
RT of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-
RT methyl-tryptophan.";
RL Cancer Res. 67:7082-7087(2007).
RN [6]
RP MISCELLANEOUS, AND DIFFERENCE BETWEEN IDO1 AND IDO2.
RX PubMed=18418598; DOI=10.1007/s00262-008-0513-6;
RA Loeb S., Koenigsrainer A., Zieker D., Bruecher B.L., Rammensee H.G.,
RA Opelz G., Terness P.;
RT "IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl
RT tryptophan inhibits tryptophan catabolism.";
RL Cancer Immunol. Immunother. 58:153-157(2009).
RN [7]
RP POLYMORPHISM, AND DIFFERENCE BETWEEN IDO1 AND IDO2.
RX PubMed=25394548; DOI=10.1038/emm.2014.69;
RA Lee Y.K., Lee H.B., Shin D.M., Kang M.J., Yi E.C., Noh S., Lee J., Lee C.,
RA Min C.K., Choi E.Y.;
RT "Heme-binding-mediated negative regulation of the tryptophan metabolic
RT enzyme indoleamine 2,3-dioxygenase 1 (IDO1) by IDO2.";
RL Exp. Mol. Med. 46:E121-E121(2014).
RN [8]
RP DIFFERENCE BETWEEN IDO1 AND IDO2.
RX PubMed=25950090; DOI=10.1111/febs.13316;
RA Yuasa H.J., Mizuno K., Ball H.J.;
RT "Low efficiency IDO2 enzymes are conserved in lower vertebrates, whereas
RT higher efficiency IDO1 enzymes are dispensable.";
RL FEBS J. 282:2735-2745(2015).
RN [9]
RP REVIEW.
RX PubMed=25477879; DOI=10.3389/fimmu.2014.00585;
RA Prendergast G.C., Metz R., Muller A.J., Merlo L.M., Mandik-Nayak L.;
RT "IDO2 in immunomodulation and autoimmune disease.";
RL Front. Immunol. 5:585-585(2014).
RN [10]
RP REVIEW, AND TISSUE SPECIFICITY.
RX PubMed=25691885; DOI=10.3389/fimmu.2015.00034;
RA van Baren N., Van den Eynde B.J.;
RT "Tryptophan-degrading enzymes in tumoral immune resistance.";
RL Front. Immunol. 6:34-34(2015).
CC -!- FUNCTION: Catalyzes the first and rate limiting step of the catabolism
CC of the essential amino acid tryptophan along the kynurenine pathway
CC (PubMed:17671174). Involved in immune regulation. May not play a
CC significant role in tryptophan-related tumoral resistance
CC (PubMed:25691885). {ECO:0000269|PubMed:17671174,
CC ECO:0000303|PubMed:25691885}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-tryptophan + O2 = N-formyl-L-kynurenine;
CC Xref=Rhea:RHEA:24536, ChEBI:CHEBI:15379, ChEBI:CHEBI:57912,
CC ChEBI:CHEBI:58629; Evidence={ECO:0000269|PubMed:17671174};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P14902};
CC Note=Binds 1 heme group per subunit. {ECO:0000250|UniProtKB:P14902};
CC -!- ACTIVITY REGULATION: Activity is inhibited by D-1MT (1-methyl-D-
CC tryptophan) and MTH-trp (methylthiohydantoin-DL-tryptophan) but not L-
CC 1MT (1-methyl-L-tryptophan). {ECO:0000269|PubMed:17671174}.
CC -!- PATHWAY: Amino-acid degradation; L-tryptophan degradation via
CC kynurenine pathway; L-kynurenine from L-tryptophan: step 1/2.
CC -!- INTERACTION:
CC Q6ZQW0-2; Q8N9N5-2: BANP; NbExp=6; IntAct=EBI-12233645, EBI-11524452;
CC Q6ZQW0-2; Q9Y250: LZTS1; NbExp=3; IntAct=EBI-12233645, EBI-1216080;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=Additional isoforms exist at least in placenta and brain.
CC {ECO:0000269|PubMed:17671174, ECO:0000303|PubMed:25477879};
CC Name=1;
CC IsoId=Q6ZQW0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6ZQW0-2; Sequence=VSP_024858, VSP_024859;
CC -!- TISSUE SPECIFICITY: Detected in liver, small intestine, spleen,
CC placenta, thymus, lung, brain, kidney, and colon (PubMed:17671174).
CC Also expressed at low level in testis and thyroid. Not expressed in the
CC majority of human tumor samples (>99%) (PubMed:25691885).
CC {ECO:0000269|PubMed:17671174, ECO:0000303|PubMed:25691885}.
CC -!- POLYMORPHISM: The variant Trp-248 (p.R248W) drastically reduces the
CC enzymatic activity (PubMed:17671174, PubMed:18418598). The Del359-420
CC variant (p.Y359X) generates a truncated, enzymatically inactive protein
CC (PubMed:17671174). The high prevalence of these polymorphic alleles
CC results in a non-functional IDO2 enzyme in up to 50% of Caucasians
CC (PubMed:18418598). {ECO:0000269|PubMed:17671174,
CC ECO:0000303|PubMed:18418598}.
CC -!- MISCELLANEOUS: IDO1 and IDO2 are 2 distinct enzymes which catalyze the
CC same reaction. IDO2 affinity for tryptophan is much lower than that of
CC IDO1. 50 % of Caucasians harbor polymorphisms which abolish IDO2
CC enzymatic activity. IDO2 is expressed in human tumors in an inactive
CC form: tryptophan degradation is entirely provided by IDO1 in these
CC cells (PubMed:18418598). IDO2 may play a role as a negative regulator
CC of IDO1 by competing for heme-binding with IDO1 (PubMed:25394548). Low
CC efficiency IDO2 enzymes have been conserved throughout vertebrate
CC evolution, whereas higher efficiency IDO1 enzymes are dispensable in
CC many lower vertebrate lineages (PubMed:25950090). IDO1 may have arisen
CC by gene duplication of a more ancient proto-IDO gene before the
CC divergence of marsupial and eutherian (placental) mammals.
CC {ECO:0000269|PubMed:18418598, ECO:0000269|PubMed:25394548,
CC ECO:0000269|PubMed:25950090}.
CC -!- SIMILARITY: Belongs to the indoleamine 2,3-dioxygenase family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/IDO2ID44387ch8p11.html";
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DR EMBL; EF052681; ABM69260.1; -; mRNA.
DR EMBL; AK128691; BAC87573.1; -; mRNA.
DR EMBL; AC007991; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087518; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC113496; AAI13497.1; -; mRNA.
DR EMBL; BC113498; AAI13499.1; -; mRNA.
DR RefSeq; NP_919270.2; NM_194294.2. [Q6ZQW0-1]
DR AlphaFoldDB; Q6ZQW0; -.
DR SMR; Q6ZQW0; -.
DR BioGRID; 127980; 124.
DR IntAct; Q6ZQW0; 11.
DR STRING; 9606.ENSP00000443432; -.
DR BindingDB; Q6ZQW0; -.
DR ChEMBL; CHEMBL3627587; -.
DR GuidetoPHARMACOLOGY; 3019; -.
DR iPTMnet; Q6ZQW0; -.
DR PhosphoSitePlus; Q6ZQW0; -.
DR BioMuta; IDO2; -.
DR DMDM; 215274147; -.
DR MassIVE; Q6ZQW0; -.
DR PaxDb; Q6ZQW0; -.
DR PeptideAtlas; Q6ZQW0; -.
DR PRIDE; Q6ZQW0; -.
DR Antibodypedia; 42276; 469 antibodies from 34 providers.
DR DNASU; 169355; -.
DR Ensembl; ENST00000502986.3; ENSP00000443432.2; ENSG00000188676.14.
DR GeneID; 169355; -.
DR KEGG; hsa:169355; -.
DR UCSC; uc010lwy.1; human.
DR UCSC; uc064mgi.1; human. [Q6ZQW0-1]
DR CTD; 169355; -.
DR DisGeNET; 169355; -.
DR GeneCards; IDO2; -.
DR HGNC; HGNC:27269; IDO2.
DR HPA; ENSG00000188676; Group enriched (liver, placenta).
DR MIM; 612129; gene.
DR neXtProt; NX_Q6ZQW0; -.
DR PharmGKB; PA164720782; -.
DR VEuPathDB; HostDB:ENSG00000188676; -.
DR eggNOG; ENOG502QT99; Eukaryota.
DR HOGENOM; CLU_010089_1_0_1; -.
DR InParanoid; Q6ZQW0; -.
DR OMA; CMPKGLV; -.
DR OrthoDB; 1206249at2759; -.
DR PhylomeDB; Q6ZQW0; -.
DR TreeFam; TF330978; -.
DR BRENDA; 1.13.11.11; 2681.
DR BRENDA; 1.13.11.52; 2681.
DR PathwayCommons; Q6ZQW0; -.
DR Reactome; R-HSA-71240; Tryptophan catabolism.
DR SABIO-RK; Q6ZQW0; -.
DR SignaLink; Q6ZQW0; -.
DR UniPathway; UPA00333; UER00453.
DR BioGRID-ORCS; 169355; 2 hits in 255 CRISPR screens.
DR ChiTaRS; IDO2; human.
DR GenomeRNAi; 169355; -.
DR Pharos; Q6ZQW0; Tchem.
DR PRO; PR:Q6ZQW0; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q6ZQW0; protein.
DR Bgee; ENSG00000188676; Expressed in right lobe of liver and 55 other tissues.
DR ExpressionAtlas; Q6ZQW0; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0033754; F:indoleamine 2,3-dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004833; F:tryptophan 2,3-dioxygenase activity; IBA:GO_Central.
DR GO; GO:0034354; P:'de novo' NAD biosynthetic process from tryptophan; IBA:GO_Central.
DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR GO; GO:0019441; P:tryptophan catabolic process to kynurenine; IDA:UniProtKB.
DR InterPro; IPR000898; Indolamine_dOase.
DR InterPro; IPR037217; Trp/Indoleamine_2_3_dOase-like.
DR PANTHER; PTHR28657; PTHR28657; 1.
DR Pfam; PF01231; IDO; 1.
DR SUPFAM; SSF140959; SSF140959; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Dioxygenase; Heme; Immunity; Iron; Metal-binding;
KW Oxidoreductase; Reference proteome; Tryptophan catabolism.
FT CHAIN 1..420
FT /note="Indoleamine 2,3-dioxygenase 2"
FT /id="PRO_0000285262"
FT BINDING 360
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="proximal binding residue"
FT /evidence="ECO:0000250|UniProtKB:P14902"
FT VAR_SEQ 159..172
FT /note="FLEIGNLETIISFP -> DGVSLCLPGWSAVA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_024858"
FT VAR_SEQ 173..420
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_024859"
FT VARIANT 248
FT /note="R -> W (decreased indoleamine 2,3-dioxygenase
FT activity; dbSNP:rs10109853)"
FT /evidence="ECO:0000269|PubMed:17671174"
FT /id="VAR_032007"
FT VARIANT 359..420
FT /note="Missing (loss of indoleamine 2,3-dioxygenase
FT activity)"
FT /evidence="ECO:0000269|PubMed:17671174"
FT /id="VAR_073727"
FT CONFLICT 1..13
FT /note="Missing (in Ref. 1; ABM69260)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 420 AA; 47075 MW; 28C0CDCD10F933C4 CRC64;
MLHFHYYDTS NKIMEPHRPN VKTAVPLSLE SYHISEEYGF LLPDSLKELP DHYRPWMEIA
NKLPQLIDAH QLQAHVDKMP LLSCQFLKGH REQRLAHLVL SFLTMGYVWQ EGEAQPAEVL
PRNLALPFVE VSRNLGLPPI LVHSDLVLTN WTKKDPDGFL EIGNLETIIS FPGGESLHGF
ILVTALVEKE AVPGIKALVQ ATNAILQPNQ EALLQALQRL RLSIQDITKT LGQMHDYVDP
DIFYAGIRIF LSGWKDNPAM PAGLMYEGVS QEPLKYSGGS AAQSTVLHAF DEFLGIRHSK
ESGDFLYRMR DYMPPSHKAF IEDIHSAPSL RDYILSSGQD HLLTAYNQCV QALAELRSYH
ITMVTKYLIT AAAKAKHGKP NHLPGPPQAL KDRGTGGTAV MSFLKSVRDK TLESILHPRG
