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| A: Structure of human IDO2 gene and transcripts. Complete coding region is 1260 bps encoding a 420 aa polypeptide. Alternate splice isoforms lacking the exons indicated are noted. Hatch boxes represent a frameshift in the coding region to an alternate reading frame leading to termination. Black boxes represent 3' untranslated regions. Nucleotide numbers, intron sizes, and positioning are based on IDO sequence files NW_923907.1 and GI:89028628 in the Genbank database. |
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Description | The human IDO2 gene is encoded by 10 exons spanning 81,437 bps at chromosome 8p11.21 (nucleotides 39,911,631-39,993,067). The murine IDO2 gene is similarly sized but localized to a syntenic locus on mouse chromosome 8A2. The IDO1 and IDO2 genes are present tandemly in a tail-to-head arrangment on chromosome 8 in humans and mice. In lower vertebrates such as zebrafish and toads only a single IDO gene may be present that may be more IDO2-like in structure. This closer relationship to IDO2 suggests that IDO2 may actually be the ancestor of the better characterized IDO1 gene, and that IDO1 might have been generated by gene duplication of IDO2 before the origin of tetrapods in mammalian evolutionary history. Two single nucleotide polymorphisms (SNPs) that occur commonly in the coding region human IDO2 gene have been characterized. These SNPs are discussed further below in the Protein Function section. |
Transcription | Transcription of IDO2 gene produces multiple mRNA messages of which the first characterized was 1,260 bp in length. At least two transcripts are expressed with alternate 5' exons, suggesting that the IDO2 gene may have multiple promoter regions. Exon 1A of the IDO2 genes contain the start codon for a full-length protein; the transcript(s) containing exon 1B do not have an in-frame start codon at a similar position. On the other hand, transcripts containing exon 1B have a more widespread expression pattern than those containing exon 1A that encode full-length proteins. Start codons in exon 3 exist that have a Kozak consensus sequence that are conserved in an alignment of all vertebrate IDO proteins, thus, these codons may potentially be used to generate NH2 terminally-truncated IDO2 proteins. The IDO2 gene encodes least 4 alternatively spliced transcripts that lack various patterns of exons (exons 3, 4, 5, 6, and 8) from within the full-length coding sequence. The IDO2 promoter contains a prominent binding site for IRF7, a master regulator of dendritic cell differentiation. |
Pseudogene | None known. |
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| B: Amino acid alignment of IDO and IDO2. Amino acids determined by mutagenesis and the crystal structure of IDO that are critical for catalytic activity are positioned below the human IDO sequence. Two commonly occurring SNPs identified in the coding region of human IDO2 are shown above the sequence which alter a critical amino acid (R248W) or introduce a premature termination codon (Y359stop). |
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Description | Full-length IDO2 encodes a protein of 420 amino acids with an approximately calculated molecular weight of 45 kDa. The size of this IDO2 protein is slightly larger than full-length IDO1 protein. |
Expression | IDO2 is expressed in a variety of antigen-presenting cell types consistent with the notion that it functions as an immunomodulatory gene like IDO1. Human IDO2 mRNA is detected in liver, small intestine, spleen, placenta, thymus, lung, brain, kidney, and colon. In mice, IDO2 is predominantly expressed in the kidney, followed by epididymis, testis, liver, ovary, uteris, and placenta. In mouse epididymis, IDO2 is expressed in the tails of spermatozoa while IDO1 is expressed in the principal and apical cells of the caput epididymis. In mouse kidney, IDO2 is expressed only in the tubules while IDO1 is expressed primarily in blood vessels. The expression patterns of IDO1 and IDO2 suggest the possibility of functional non-redundance. |
Localisation | Indirect immunofluorescence studies suggest that IDO2 protein has a predominantly cytoplasmic localization. Biochemical studies suggest there may be some differences in localization compared to the cytoplasmic IDO1 protein, based on the greater ease of extracting IDO1 compared to IDO2 from cells. |
Function | IDO2 is a presumptive immunomodulatory gene based on its close structural relationship to IDO1 and its expression in a variety of antigen-presenting cell types. Both IDO1 and IDO2 will catabolize tryptophan to kynurenine. Biochemical studies indicate that both enzymes are similarly robust in catabolic activity, although the in vitro conditions required for IDO2 to manifest the same level of activity differ somewhat from IDO1. However, whether IDO2 is active as a tryptophan catabolizing enzyme in human dendritic cells has been disputed. Further work is needed to conclusively determine that IDO1 and IDO2 are similar in their preference for substrates and reaction pathways to generate product. A non-redundant function for IDO2 relative to IDO1 is suggested by their rather distinct expression patterns and response to extracellular stimuli. For example, IDO1 is strongly induced by interferon-gamma (IFNG) but it is less clear this is the case for IDO2. Additionally, whereas IDO1 is induced in endothelial cells during malaria infection in mice, IDO2 is induced in kidney, downregulated in liver, and unlike IDO1 independent of the presence IFN-g. Both IDO and IDO2 catabolize tryptophan, trigger phosphorylation of the translation initiating factor eIF2a, and mobilize translation of LIP, an inhibitory form of the immune regulatory transcription factor NF-IL6/CEBPb that is upregulated by amino acid deprivation. However, whereas tryptophan restoration switches off the LIP induction pathway when it is activated by IDO1, LIP induction is not switched off when it is activated by IDO2. Together, this information suggests that IDO1 and IDO2 produce somewhat distinct signaling pathways, suggesting distinct functions in immunomodulation. Two single nucleotide polymorphisms (SNP) that produce non-conservative changes in the coding region have been characterized that abolish catalytic activity. One SNP is a C-T transition that causes the amino acid change R248W. Based on knowledge of the related IDO protein, the R248W change is predicted to abolish a critical contact in the catalytic site that contacts the indole ring of tryptophan, the presumptive substrate. Experimental data confirm that this SNP abolishes tryptophan catabolic activity. The other SNP is a T-A transversion that produces the premature stop codon Y359STOP. Experimental data confirm that this SNP also abolishes tryptophan catabolic activity. The R248W alteration is highly represented in individuals of European descent. The Y359STOP alteration is highly represented in individuals of Asian descent. Neither SNP is as prevalent in individuals of African descent. Individuals with one of these inactivating alleles might display alterned immune function relative to individuals with a wild-type allelic configuration. In biochemical assays, IDO2 exhibits preferences distinct from IDO1 for inhibition by the well-studied IDO inhibitor 1-methyl-D,L-tryptophan (1MT). Specifically, the levo stereoisoform L-1MT preferentially inhibits IDO1 activity whereas the dextro stereoisoform D-1MT preferentially inhibits IDO2. Interestingly, in preclinical models D-1MT has been observed to exhibit greater antitumor activity compared to L-1MT, prompting the hypothesis that IDO2 may contribute to tumoral immune escape like IDO1. However, since IDO is genetically required for the activity of D-1MT the biochemical mechanisms underlying 1MT action are likely to be complex. Nevertheless, results of in vitro biochemical experiments suggest that L-1MT preferentially blocks IDO1, with little effect on IDO2, whereas D-1MT preferentially the IDO2, with little effect on IDO1. |
Homology | Human IDO has 62% identities (77% similarities) with mouse IDO, and 44% identities (64% similarities) with mouse IDO2. Human IDO2 has 72% identities (84% similarities) with mouse IDO2 and 45% identities (65% similarities) with mouse IDO. Human IDO has 44% identities (63% similarities) with human IDO2 and mouse IDO has 44% identities (64% similarities) with mouse IDO2. |
Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. |
Ball HJ, Sanchez-Perez A, Weiser S, Austin CJ, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH. |
Gene. 2007 Jul 1;396(1):203-13. Epub 2007 Apr 18. |
PMID 17499941 |
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Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. |
Ball HJ, Yuasa HJ, Austin CJ, Weiser S, Hunt NH. |
Int J Biochem Cell Biol. 2009 Mar;41(3):467-71. Epub 2008 Jan 11. |
PMID 18282734 |
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IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. |
Lob S, Konigsrainer A, Zieker D, Brucher BL, Rammensee HG, Opelz G, Terness P. |
Cancer Immunol Immunother. 2009 Jan;58(1):153-7. Epub 2008 Apr 17. |
PMID 18418598 |
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Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. |
Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. |
Cancer Res. 2007 Aug 1;67(15):7082-7. |
PMID 17671174 |
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Immune escape as a fundamental trait of cancer: focus on IDO. |
Prendergast GC. |
Oncogene. 2008 Jun 26;27(28):3889-900. Epub 2008 Mar 3. Review |
PMID 18317452 |
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| Nomenclature |
HGNC (Hugo) | IDO2 27269 |
| Cards |
Atlas | IDO2ID44387ch8p11 |
Entrez_Gene (NCBI) | IDO2 169355 indoleamine 2,3-dioxygenase 2 |
Aliases | INDOL1 |
GeneCards (Weizmann) | IDO2 |
Ensembl hg19 (Hinxton) | ENSG00000188676 [Gene_View] |
Ensembl hg38 (Hinxton) | ENSG00000188676 [Gene_View]  ENSG00000188676 [Sequence] chr8:39934955-40016391 [Contig_View] IDO2 [Vega] |
ICGC DataPortal | ENSG00000188676 |
TCGA cBioPortal | IDO2 |
AceView (NCBI) | IDO2 |
Genatlas (Paris) | IDO2 |
WikiGenes | 169355 |
SOURCE (Princeton) | IDO2 |
Genetics Home Reference (NIH) | IDO2 |
| Genomic and cartography |
GoldenPath hg38 (UCSC) | IDO2 - chr8:39934955-40016391 + 8p11.21 [Description] (hg38-Dec_2013) |
GoldenPath hg19 (UCSC) | IDO2 - 8p11.21 [Description] (hg19-Feb_2009) |
GoldenPath | IDO2 - 8p11.21 [CytoView hg19] IDO2 - 8p11.21 [CytoView hg38] |
ImmunoBase | ENSG00000188676 |
Mapping of homologs : NCBI | IDO2 [Mapview hg19] IDO2 [Mapview hg38] |
OMIM | 612129 |
| Gene and transcription |
Genbank (Entrez) | AK092502 AK128691 BC031685 BC113496 BC113498 |
RefSeq transcript (Entrez) | NM_194294 |
RefSeq genomic (Entrez) | |
Consensus coding sequences : CCDS (NCBI) | IDO2 |
Cluster EST : Unigene | Hs.676257 [ NCBI ] |
CGAP (NCI) | Hs.676257 |
Alternative Splicing Gallery | ENSG00000188676 |
Gene Expression | IDO2 [ NCBI-GEO ] IDO2 [ EBI - ARRAY_EXPRESS ]
IDO2 [ SEEK ] IDO2 [ MEM ] |
Gene Expression Viewer (FireBrowse) | IDO2 [ Firebrowse - Broad ] |
SOURCE (Princeton) | Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60] |
Genevestigator | Expression in : [tissues]  [cell-lines]  [cancer]  [perturbations]   |
BioGPS (Tissue expression) | 169355 |
GTEX Portal (Tissue expression) | IDO2 |
Human Protein Atlas | ENSG00000188676-IDO2 [pathology] [cell] [tissue] |
| Protein : pattern, domain, 3D structure |
UniProt/SwissProt | Q6ZQW0 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction] |
NextProt | Q6ZQW0 [Sequence] [Exons] [Medical] [Publications] |
With graphics : InterPro | Q6ZQW0 |
Splice isoforms : SwissVar | Q6ZQW0 |
PhosPhoSitePlus | Q6ZQW0 |
Domains : Interpro (EBI) | Indolamine_dOase Trp/Indoleamine_2_3_dOase-like |
Domain families : Pfam (Sanger) | IDO (PF01231) |
Domain families : Pfam (NCBI) | pfam01231 |
Conserved Domain (NCBI) | IDO2 |
DMDM Disease mutations | 169355 |
Blocks (Seattle) | IDO2 |
Superfamily | Q6ZQW0 |
Human Protein Atlas [tissue] | ENSG00000188676-IDO2 [tissue] |
Peptide Atlas | Q6ZQW0 |
HPRD | 14113 |
IPI | IPI00375581 IPI00847197 |
| Protein Interaction databases |
DIP (DOE-UCLA) | Q6ZQW0 |
IntAct (EBI) | Q6ZQW0 |
FunCoup | ENSG00000188676 |
BioGRID | IDO2 |
STRING (EMBL) | IDO2 |
ZODIAC | IDO2 |
| Ontologies - Pathways |
QuickGO | Q6ZQW0 |
Ontology : AmiGO | immune system process tryptophan 2,3-dioxygenase activity cytoplasm cytoplasm cytosol tryptophan catabolic process tryptophan catabolic process to kynurenine tryptophan catabolic process to kynurenine tryptophan catabolic process to kynurenine tryptophan catabolic process to kynurenine heme binding indoleamine 2,3-dioxygenase activity indoleamine 2,3-dioxygenase activity indoleamine 2,3-dioxygenase activity 'de novo' NAD biosynthetic process from tryptophan metal ion binding oxidation-reduction process |
Ontology : EGO-EBI | immune system process tryptophan 2,3-dioxygenase activity cytoplasm cytoplasm cytosol tryptophan catabolic process tryptophan catabolic process to kynurenine tryptophan catabolic process to kynurenine tryptophan catabolic process to kynurenine tryptophan catabolic process to kynurenine heme binding indoleamine 2,3-dioxygenase activity indoleamine 2,3-dioxygenase activity indoleamine 2,3-dioxygenase activity 'de novo' NAD biosynthetic process from tryptophan metal ion binding oxidation-reduction process |
Pathways : KEGG | Tryptophan metabolism African trypanosomiasis |
REACTOME | Q6ZQW0 [protein] |
REACTOME Pathways | R-HSA-71240 [pathway] |
NDEx Network | IDO2 |
Atlas of Cancer Signalling Network | IDO2 |
Wikipedia pathways | IDO2 |
| Orthology - Evolution |
OrthoDB | 169355 |
GeneTree (enSembl) | ENSG00000188676 |
Phylogenetic Trees/Animal Genes : TreeFam | IDO2 |
HOGENOM | Q6ZQW0 |
Homologs : HomoloGene | IDO2 |
Homology/Alignments : Family Browser (UCSC) | IDO2 |
| Gene fusions - Rearrangements |
Fusion : FusionGDB | 27570 30767 31409 36966 38215 |
Fusion : Fusion_Hub | AQPEP--IDO2 FBXO16--IDO2 PLEKHA2--IDO2 RBM47--IDO2 SYS1--IDO2 TM2D2--IDO2 |
Fusion : Quiver | IDO2 |
| Polymorphisms : SNP and Copy number variants |
NCBI Variation Viewer | IDO2 [hg38] |
dbSNP Single Nucleotide Polymorphism (NCBI) | IDO2 |
dbVar | IDO2 |
ClinVar | IDO2 |
1000_Genomes | IDO2 |
Exome Variant Server | IDO2 |
ExAC (Exome Aggregation Consortium) | ENSG00000188676 |
GNOMAD Browser | ENSG00000188676 |
Varsome Browser | IDO2 |
Genetic variants : HAPMAP | 169355 |
Genomic Variants (DGV) | IDO2 [DGVbeta] |
DECIPHER | IDO2 [patients] [syndromes] [variants] [genes] |
CONAN: Copy Number Analysis | IDO2 |
| Mutations |
ICGC Data Portal | IDO2 |
TCGA Data Portal | IDO2 |
Broad Tumor Portal | IDO2 |
OASIS Portal | IDO2 [ Somatic mutations - Copy number] |
Somatic Mutations in Cancer : COSMIC | IDO2 [overview] [genome browser] [tissue] [distribution] |
Somatic Mutations in Cancer : COSMIC3D | IDO2 |
Mutations and Diseases : HGMD | IDO2 |
LOVD (Leiden Open Variation Database) | Whole genome datasets |
LOVD (Leiden Open Variation Database) | LOVD - Leiden Open Variation Database |
LOVD (Leiden Open Variation Database) | LOVD 3.0 shared installation |
BioMuta | search IDO2 |
DgiDB (Drug Gene Interaction Database) | IDO2 |
DoCM (Curated mutations) | IDO2 (select the gene name) |
CIViC (Clinical Interpretations of Variants in Cancer) | IDO2 (select a term) |
intoGen | IDO2 |
NCG5 (London) | IDO2 |
Cancer3D | IDO2(select the gene name) |
Impact of mutations | [PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser] |
| Diseases |
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OMIM | 612129 |
Orphanet | |
DisGeNET | IDO2 |
Medgen | IDO2 |
Genetic Testing Registry | IDO2
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NextProt | Q6ZQW0 [Medical] |
TSGene | 169355 |
GENETests | IDO2 |
Target Validation | IDO2 |
Huge Navigator |
IDO2 [HugePedia] |
snp3D : Map Gene to Disease | 169355 |
BioCentury BCIQ | IDO2 |
ClinGen | IDO2 |
| Clinical trials, drugs, therapy |
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Chemical/Protein Interactions : CTD | 169355 |
Chemical/Pharm GKB Gene | PA164720782 |
Clinical trial | IDO2 |
| Miscellaneous |
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canSAR (ICR) | IDO2 (select the gene name) |
DataMed Index | IDO2 |
| Probes |
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| Litterature |
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PubMed | 25 Pubmed reference(s) in Entrez |
GeneRIFs | Gene References Into Functions (Entrez) |
CoreMine | IDO2 |
EVEX | IDO2 |
GoPubMed | IDO2 |
iHOP | IDO2 |