IDO2 (indoleamine 2,3-dioxygenase 2)

	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.

	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.

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