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IDO2 (indoleamine 2,3-dioxygenase 2)

Written2009-03Mee Young Chang, Richard Metz, Alexander J Muller, George C Prendergast
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood PA 19096, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesINDOL1
indoleamine-pyrrole 2
Other aliasINDO2
Proto-IDO
HGNC (Hugo) IDO2
LocusID (NCBI) 169355
Atlas_Id 44387
Location 8p11.21  [Link to chromosome band 8p11]
Location_base_pair Starts at 39934955 and ends at 40016391 bp from pter ( according to hg19-Feb_2009)  [Mapping IDO2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
LVRN (5q23.1) / IDO2 (8p11.21)

DNA/RNA

 
  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.
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.

Protein

 
  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).
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.

Mutations

Note None known.

Implicated in

Note
  
Entity Cancer
Note While limited information exists as yet, two lines of information have suggested a possible link between IDO2 and cancer. First, recent work has identified IDO2 expression in human tumors, including gastric, colon, renal, and pancreatic tumors. Immunohistochemical analysis performed in pancreatic tumors reveals IDO2 expression both at the level of the tumor cell as well as immune cells in tumor-draining lymph nodes. However, IDO2 expression and tryptophan catabolizing activity in human tumor cells and antigen-presenting cells has been disputed. Second, the apparent selectivity of IDO2 for inhibition by the D stereoisomer of 1MT, which tends to be more active in a variety of biological assays for IDO function, including in antitumor assays, suggests that IDO2 may be important to sustain immune escape and growth of tumors. Knockout mice that have become available recently will be important for establishing the these suggested roles for IDO2 in cancer.
  

Bibliography

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
 
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
 
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
 
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
 
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
 

Citation

This paper should be referenced as such :
Chang, MY ; Metz, R ; Muller, AJ ; Prendergast, GC
IDO2 (indoleamine 2,3-dioxygenase 2)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(2):149-152.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IDO2ID44387ch8p11.html


External links

Nomenclature
HGNC (Hugo)IDO2   27269
Cards
AtlasIDO2ID44387ch8p11
Entrez_Gene (NCBI)IDO2  169355  indoleamine 2,3-dioxygenase 2
AliasesINDOL1
GeneCards (Weizmann)IDO2
Ensembl hg19 (Hinxton)ENSG00000188676 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000188676 [Gene_View]  chr8:39934955-40016391 [Contig_View]  IDO2 [Vega]
ICGC DataPortalENSG00000188676
TCGA cBioPortalIDO2
AceView (NCBI)IDO2
Genatlas (Paris)IDO2
WikiGenes169355
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)
EnsemblIDO2 - 8p11.21 [CytoView hg19]  IDO2 - 8p11.21 [CytoView hg38]
Mapping of homologs : NCBIIDO2 [Mapview hg19]  IDO2 [Mapview hg38]
OMIM612129   
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 : UnigeneHs.676257 [ NCBI ]
CGAP (NCI)Hs.676257
Alternative Splicing GalleryENSG00000188676
Gene ExpressionIDO2 [ 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]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)169355
GTEX Portal (Tissue expression)IDO2
Human Protein AtlasENSG00000188676-IDO2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6ZQW0   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6ZQW0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6ZQW0
Splice isoforms : SwissVarQ6ZQW0
PhosPhoSitePlusQ6ZQW0
Domains : Interpro (EBI)Indolamine_dOase   
Domain families : Pfam (Sanger)IDO (PF01231)   
Domain families : Pfam (NCBI)pfam01231   
Conserved Domain (NCBI)IDO2
DMDM Disease mutations169355
Blocks (Seattle)IDO2
SuperfamilyQ6ZQW0
Human Protein Atlas [tissue]ENSG00000188676-IDO2 [tissue]
Peptide AtlasQ6ZQW0
HPRD14113
IPIIPI00375581   IPI00847197   
Protein Interaction databases
DIP (DOE-UCLA)Q6ZQW0
IntAct (EBI)Q6ZQW0
FunCoupENSG00000188676
BioGRIDIDO2
STRING (EMBL)IDO2
ZODIACIDO2
Ontologies - Pathways
QuickGOQ6ZQW0
Ontology : AmiGOimmune system process  tryptophan 2,3-dioxygenase activity  cytoplasm  cytosol  tryptophan catabolic process  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  metal ion binding  oxidation-reduction process  
Ontology : EGO-EBIimmune system process  tryptophan 2,3-dioxygenase activity  cytoplasm  cytosol  tryptophan catabolic process  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  metal ion binding  oxidation-reduction process  
Pathways : KEGGTryptophan metabolism    African trypanosomiasis   
REACTOMEQ6ZQW0 [protein]
REACTOME PathwaysR-HSA-71240 [pathway]   
NDEx NetworkIDO2
Atlas of Cancer Signalling NetworkIDO2
Wikipedia pathwaysIDO2
Orthology - Evolution
OrthoDB169355
GeneTree (enSembl)ENSG00000188676
Phylogenetic Trees/Animal Genes : TreeFamIDO2
HOVERGENQ6ZQW0
HOGENOMQ6ZQW0
Homologs : HomoloGeneIDO2
Homology/Alignments : Family Browser (UCSC)IDO2
Gene fusions - Rearrangements
Tumor Fusion PortalIDO2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIDO2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IDO2
dbVarIDO2
ClinVarIDO2
1000_GenomesIDO2 
Exome Variant ServerIDO2
ExAC (Exome Aggregation Consortium)ENSG00000188676
GNOMAD BrowserENSG00000188676
Genetic variants : HAPMAP169355
Genomic Variants (DGV)IDO2 [DGVbeta]
DECIPHERIDO2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIDO2 
Mutations
ICGC Data PortalIDO2 
TCGA Data PortalIDO2 
Broad Tumor PortalIDO2
OASIS PortalIDO2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIDO2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIDO2
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
BioMutasearch 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)
intoGenIDO2
NCG5 (London)IDO2
Cancer3DIDO2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM612129   
Orphanet
DisGeNETIDO2
MedgenIDO2
Genetic Testing Registry IDO2
NextProtQ6ZQW0 [Medical]
TSGene169355
GENETestsIDO2
Target ValidationIDO2
Huge Navigator IDO2 [HugePedia]
snp3D : Map Gene to Disease169355
BioCentury BCIQIDO2
ClinGenIDO2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD169355
Chemical/Pharm GKB GenePA164720782
Clinical trialIDO2
Miscellaneous
canSAR (ICR)IDO2 (select the gene name)
Probes
Litterature
PubMed21 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIDO2
EVEXIDO2
GoPubMedIDO2
iHOPIDO2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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