IDO1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2D0T, 2D0U, 4PK5, 4PK6, 4U72, 4U74, 5EK2, 5EK3, 5EK4, 5ETW
Identifiers
Aliases	IDO1, IDO, IDO-1, INDO, indoleamine 2,3-dioxygenase 1
External IDs	OMIM: 147435 MGI: 96416 HomoloGene: 48082 GeneCards: IDO1
Gene location ( Human) Chr. Chromosome 8 (human) [1] Band 8p11.21 Start 39,902,275 bp [1] End 39,928,790 bp [1]
Gene location ( Mouse) Chr. Chromosome 8 (mouse) [2] Band 8|8 A2 Start 25,074,152 bp [2] End 25,087,025 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in palpebral conjunctiva appendix placenta lymph node endometrium upper lobe of left lung rectum right lung gallbladder jejunal mucosa Top expressed in mucous cell of stomach jejunum duodenum intestinal villus nucleus accumbens Paneth cell globus pallidus submandibular gland plantaris muscle olfactory tubercle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function dioxygenase activity metal ion binding heme binding electron transfer activity oxidoreductase activity indoleamine 2,3-dioxygenase activity tryptophan 2,3-dioxygenase activity Cellular component cytoplasm stereocilium bundle cytosol smooth muscle contractile fiber Biological process negative regulation of interleukin-10 production multicellular organismal response to stress positive regulation of interleukin-12 production immune system process female pregnancy positive regulation of T cell tolerance induction cytokine production involved in inflammatory response positive regulation of chronic inflammatory response negative regulation of T cell apoptotic process regulation of activated T cell proliferation response to lipopolysaccharide negative regulation of T cell proliferation positive regulation of apoptotic process tryptophan catabolic process positive regulation of type 2 immune response inflammatory response kynurenic acid biosynthetic process positive regulation of T cell apoptotic process swimming behavior tryptophan catabolic process to kynurenine electron transport chain 'de novo' NAD biosynthetic process from tryptophan Sources: Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3620 15930 Ensembl ENSG00000131203 ENSMUSG00000031551 UniProt P14902 P28776 RefSeq (mRNA) NM_002164 NM_008324 NM_001293690 RefSeq (protein) NP_002155 NP_001280619 NP_032350 Location (UCSC) Chr 8: 39.9 – 39.93 Mb Chr 8: 25.07 – 25.09 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Indoleamine 2,3-dioxygenase
crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
Identifiers
Symbol	IDO
Pfam	PF01231
Pfam clan	CL0380
InterPro	IPR000898
PROSITE	PDOC00684
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta. ^[5] In humans is encoded by the IDO1 gene. ^[6] IDO is involved in tryptophan metabolism. It is one of three enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O₂-dependent oxidation of L-tryptophan to N-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2) ^[7] and tryptophan 2,3-dioxygenase (TDO). ^[8] IDO is an important part of the immune system and plays a part in natural defense against various pathogens. ^{[9] [10]} It is produced by the cells in response to inflammation and has an immunosuppressive function because of its ability to limit T-cell function and engage mechanisms of immune tolerance. ^[11] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. Expression of IDO has been described in a number of types of cancer, such as acute myeloid leukemia, ovarian cancer or colorectal cancer. IDO is part of the malignant transformation process and plays a key role in suppressing the anti-tumor immune response in the body, so inhibiting it could increase the effect of chemotherapy as well as other immunotherapeutic protocols. ^{[12] [13] [14]} Furthermore, there is data implicating a role for IDO1 in the modulation of vascular tone in conditions of inflammation via a novel pathway involving singlet oxygen. ^[15]

Physiological function

Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway.

IDO is an important molecule in the mechanisms of tolerance and its physiological functions include the suppression of potentially dangerous inflammatory processes in the body. ^[16] IDO also plays a role in natural defense against microorganisms. Expression of IDO is induced by interferon-gamma, which explains why the expression increases during inflammatory diseases or even during tumorigenesis. ^[17] Since tryptophan is essential for the survival of pathogens, the activity of enzyme IDO destroys them. Microorganisms susceptible to tryptophan deficiency include bacteria of genus Streptococcus ^[18] or viruses such as herpes simplex ^[19] or measles. ^[20]

One of the organs with high IDO expression is the placenta. In the 1990s, the immunosuppressive function of this enzyme was first described in mice due to the study of placental tryptophan metabolism. Thus, mammalian placenta, due to intensive tryptophan catabolism has the ability to suppress T cell activity, thereby contributing to its position of immunologically privileged tissue. ^[21]

Clinical significance

IDO is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by alternatively activated macrophages and other immunoregulatory cells. ^[22] IDO is known to suppress T and NK cells, generate Tregs and myeloid-derived suppressor cells, and also supports angiogenesis. ^[12]

These mechanisms are crucial in the process of carcinogenesis. IDO allows tumor cells to escape the immune system by two main mechanisms. The first mechanism is based on tryptophan depletion from the tumor microenvironment. ^[23] The second mechanism is based on the production of catabolic products called kynurenins, that are cytotoxic for T lymphocytes and NK cells. ^[24] Overexpression of human IDO (hIDO) is described in a variety of human tumor cell lineages and is often associated with poor prognosis. ^{[25] [26]} Tumors with increased production of IDO include prostate, ovarian, lung or pancreatic cancer or acute myeloid leukemia. ^{[27] [28]} Expression of IDO is under physiological conditions regulated by the Bin1 gene, which can be damaged by tumor transformation. ^[29]

Emerging clinical studies suggest that combination of IDO inhibitors with classical chemotherapy and radiotherapy could restore immune control and provide a therapeutic response to generally resistant tumors. Enzyme IDO used by tumors to escape immune surveillance is currently in focus of research and drug discovery efforts, ^[30] as well as efforts to understand if it could be used as a biomarker for prognosis. ^[31]

Inhibitors

COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.^{[ citation needed]}

1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl-D-tryptophan (known as indoximod) is in clinical trials for various cancers.

Epacadostat (INCB24360), navoximod (GDC-0919), and linrodostat (BMS-986205) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.

See also

• 1-Methyltryptophan
• Tryptophan 2,3-dioxygenase

References

External links

• Indoleamine-Pyrrole+2,3,-Dioxygenase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Indoleamine 2,3-dioxygenase 1