ID   I23O2_HUMAN             Reviewed;         407 AA.
AC   Q6ZQW0; A4UD41; F5H5G0;
DT   01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT   13-SEP-2023, sequence version 5.
DT   27-MAR-2024, entry version 136.
DE   RecName: Full=Indoleamine 2,3-dioxygenase 2 {ECO:0000305|PubMed:17671174};
DE            Short=IDO-2 {ECO:0000303|PubMed:17671174};
DE            EC=1.13.11.- {ECO:0000269|PubMed:17671174};
DE   AltName: Full=Indoleamine 2,3-dioxygenase-like protein 1 {ECO:0000303|PubMed:17499941};
DE   AltName: Full=Indoleamine-pyrrole 2,3-dioxygenase-like protein 1 {ECO:0000312|HGNC:HGNC:27269};
GN   Name=IDO2 {ECO:0000312|HGNC:HGNC:27269};
GN   Synonyms=INDOL1 {ECO:0000303|PubMed:17499941};
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=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   [2]
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   [3]
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   [4]
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   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, ALTERNATIVE SPLICING, ACTIVITY REGULATION,
RP   TISSUE SPECIFICITY, AND VARIANTS TRP-235 AND 346-TYR--GLY-407 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   -!- SEQUENCE CAUTION:
CC       Sequence=AAI13497.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAI13499.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC       Sequence=BAC87573.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/44387/IDO2";
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DR   EMBL; EF052681; ABM69260.1; -; mRNA.
DR   EMBL; AK128691; BAC87573.1; ALT_INIT; mRNA.
DR   EMBL; AC007991; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC087518; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC113496; AAI13497.1; ALT_INIT; mRNA.
DR   EMBL; BC113498; AAI13499.1; ALT_INIT; mRNA.
DR   CCDS; CCDS6114.3; -. [Q6ZQW0-1]
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   PaxDb; 9606-ENSP00000443432; -.
DR   Antibodypedia; 42276; 553 antibodies from 34 providers.
DR   DNASU; 169355; -.
DR   Ensembl; ENST00000502986.4; ENSP00000443432.2; ENSG00000188676.15. [Q6ZQW0-1]
DR   GeneID; 169355; -.
DR   KEGG; hsa:169355; -.
DR   MANE-Select; ENST00000502986.4; ENSP00000443432.2; NM_194294.5; NP_919270.3.
DR   UCSC; uc010lwy.1; human.
DR   UCSC; uc064mgi.1; human. [Q6ZQW0-1]
DR   AGR; HGNC:27269; -.
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   OpenTargets; ENSG00000188676; -.
DR   PharmGKB; PA164720782; -.
DR   VEuPathDB; HostDB:ENSG00000188676; -.
DR   eggNOG; ENOG502QT99; Eukaryota.
DR   GeneTree; ENSGT00940000161813; -.
DR   HOGENOM; CLU_010089_1_0_1; -.
DR   InParanoid; Q6ZQW0; -.
DR   OMA; CMPKGLV; -.
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 315 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 57 other cell types or 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   Gene3D; 1.20.58.480; -; 1.
DR   InterPro; IPR000898; Indolamine_dOase.
DR   InterPro; IPR037217; Trp/Indoleamine_2_3_dOase-like.
DR   PANTHER; PTHR28657; INDOLEAMINE 2,3-DIOXYGENASE; 1.
DR   PANTHER; PTHR28657:SF4; INDOLEAMINE 2,3-DIOXYGENASE 2; 1.
DR   Pfam; PF01231; IDO; 1.
DR   SUPFAM; SSF140959; Indolic compounds 2,3-dioxygenase-like; 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..407
FT                   /note="Indoleamine 2,3-dioxygenase 2"
FT                   /id="PRO_0000285262"
FT   BINDING         347
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         146..159
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         160..407
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:15489334"
FT                   /id="VSP_024859"
FT   VARIANT         235
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         346..407
FT                   /note="Missing (loss of indoleamine 2,3-dioxygenase
FT                   activity)"
FT                   /evidence="ECO:0000269|PubMed:17671174"
FT                   /id="VAR_073727"
SQ   SEQUENCE   407 AA;  45424 MW;  975E8257B5EC3730 CRC64;
     MEPHRPNVKT AVPLSLESYH ISEEYGFLLP DSLKELPDHY RPWMEIANKL PQLIDAHQLQ
     AHVDKMPLLS CQFLKGHREQ RLAHLVLSFL TMGYVWQEGE AQPAEVLPRN LALPFVEVSR
     NLGLPPILVH SDLVLTNWTK KDPDGFLEIG NLETIISFPG GESLHGFILV TALVEKEAVP
     GIKALVQATN AILQPNQEAL LQALQRLRLS IQDITKTLGQ MHDYVDPDIF YAGIRIFLSG
     WKDNPAMPAG LMYEGVSQEP LKYSGGSAAQ STVLHAFDEF LGIRHSKESG DFLYRMRDYM
     PPSHKAFIED IHSAPSLRDY ILSSGQDHLL TAYNQCVQAL AELRSYHITM VTKYLITAAA
     KAKHGKPNHL PGPPQALKDR GTGGTAVMSF LKSVRDKTLE SILHPRG
//