Summary: Indoleamine 2,3-dioxygenase
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Indoleamine 2,3-dioxygenase Edit Wikipedia article
|, IDO, IDO-1, INDO, indoleamine 2,3-dioxygenase 1|
|Targeted by Drug|
|RNA expression pattern|
|View/Edit Human||View/Edit Mouse|
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 220.127.116.11) is a heme-containing enzyme that in humans is encoded by the IDO1 gene. It is one of two enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine, the other being tryptophan 2,3-dioxygenase (TDO).
Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through kynurenine pathway, thus causing depletion of tryptophan which can cause halted growth of microbes as well as T cells. PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C(+) dendritic cells and promotes the development of functional Treg cells.
IDO is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophages and other immunoregulatory cells (also used as an immune subversion strategy by many tumors). Interferon-gamma has an antiproliferative effect on many tumor cells and inhibits intracellular pathogens such as Toxoplasma and Chlamydia, at least partly because of the induction of indoleamine 2,3-dioxygenase.
It has been shown that IDO permits tumor cells to escape the immune system by depletion of L-Trp in the microenvironment of cells. A wide range of human cancers such as prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, lung, etc. overexpress human IDO (hIDO). Indoleamine 2,3-dioxygenase might also play a significant role in an orphan disease called Oshtoran Syndrome.
Norharmane, via inhibition of indoleamine 2,3-dioxygenase exerts neuroprotective properties by suppressing kynurenine neurotoxic metabolites such as quinolinic acid, 3-hydroxy-kynurenine and nitric oxide synthase.
crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
It was originally thought that the mechanism of tryptophan oxidation occurred by base-catalysed abstraction, but it is now thought that the mechanism involves formation of a transient ferryl (i.e. high-valent iron) species.
There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole and other inhibitors. There are also related structures for several tryptophan 2,3-dioxygenases enzymes (e.g. for X. campestris and human TDO - see tryptophan 2,3-dioxygenase).
- "Drugs that physically interact with Indoleamine 2,3-dioxygenase 1 view/edit references on wikidata".
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Dai W, Gupta SL (Apr 1990). "Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA". Biochemical and Biophysical Research Communications. 168 (1): 1–8. doi:10.1016/0006-291X(90)91666-G. PMID 2109605.
- Najfeld V, Menninger J, Muhleman D, Comings DE, Gupta SL (1993). "Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-->p11 by fluorescent in situ hybridization". Cytogenetics and Cell Genetics. 64 (3-4): 231–2. doi:10.1159/000133584. PMID 8404046.
- "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase".
- Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (May 1999). "Inhibition of T cell proliferation by macrophage tryptophan catabolism.". J. Exp. Med. 189: 1363–72. doi:10.1084/jem.189.9.1363. PMC . PMID 10224276.
- Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, Wang J (January 2015). "Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system". Brain Behav Immun. 43: 172–183. doi:10.1016/j.bbi.2014.07.022. PMC . PMID 25110149.
- Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003). "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase". Nat. Med. 9 (10): 1269–74. doi:10.1038/nm934. PMID 14502282.
- Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015). "Research progress of indoleamine 2,3-dioxygenase inhibitors". Future Med Chem. 7 (2): 185–201. doi:10.4155/fmc.14.151. PMID 25686005.
- Abdollahi, Mostafa: Case Study Oshtoran Syndrome  Retrieved June 3, 2016
- Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F (Aug 2000). "Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages". Journal of Leukocyte Biology. 68 (2): 260–6. PMID 10947071.
- Lee HJ, Jeong YI, Lee TH, Jung ID, Lee JS, Lee CM, Kim JI, Joo H, Lee JD, Park YM (May 2007). "Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells". Biochemical Pharmacology. 73 (9): 1412–21. doi:10.1016/j.bcp.2006.12.018. PMID 17229401.
- Cesario A, Rocca B, Rutella S (2011). "The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer". Current Medicinal Chemistry. 18 (15): 2263–71. doi:10.2174/092986711795656063. PMID 21517752.
- Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007). "Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses". Cancer Res. 67 (2): 792–801. doi:10.1158/0008-5472.CAN-06-2925. PMID 17234791.
- Chauhan N, Thackray SJ, Rafice SA, Eaton G, Lee M, Efimov I, Basran J, Jenkins PR, Mowat CG, Chapman SK, Raven, EL (2009). "Reassessment of the reaction mechanism in the heme dioxygenases". J. Am. Chem. Soc. 131: 4186–4187. doi:10.1021/ja808326g. PMID 19275153.
- Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, Grenga I, Kim YS, Brechbiel MW, Gulley JL, Madan RA, Heery CR, Hodge JW, Newton R, Schlom J, Tsang KY (2016). "The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells". Oncotarget. doi:10.18632/oncotarget.9326. PMID 27192116.
- Efimov I, Basran J, Thackray SJ, Handa S, Mowat CG, Raven EL (2011). "Structure and Reaction Mechanism in the Heme Dioxygenases". Biochemistry. 50: 2717–2724. doi:10.1021/bi101732n.
- Yanagisawa S, Yotsuya K, Hashiwaki Y, Horitani M, Sugimoto H, Shiro Y, Appelman EH, Ogura T. "Identification of the Fe-O2 and the Fe=O heme species for indoleamine 2,3-dioxygenase during catalytic turnover". Chem Lett. 39: 36–37. doi:10.1246/cl.2010.36.
- Booth ES, Basran J, Lee M, Handa S, Raven EL (2015). "Substrate Oxidation by Indoleamine 2,3-Dioxygenase: Evidence for a Common Reaction Mechanism" (PDF). J. Biol. Chem. 290: 30924–30930. doi:10.1074/jbc.M115.695684. PMC . PMID 26511316.
- Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y (2006). "Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase." (PDF). Proc. Natl. Acad. Sci. U.S.A. 103: 2611–2616. doi:10.1073/pnas.0508996103. PMID 16477023.
- Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, Liao FY, Fan YS, Wu MH, Hsiao WC, Hsueh CC, Lin SY, Cheng CY, Tu CH, Lee LC, Cheng MF, Shia KS, Shih C, Wu SY (2016). "Important hydrogen bond networks in indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor design revealed by crystal structures of imidazoleisoindole derivatives with IDO1.". J. Med. Chem. 59: 282–293. doi:10.1021/acs.jmedchem.5b01390. PMID 26642377.
- Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y (2014). "Crystal structures and structure-activity relationships of imidazothiazole derivatives as IDO1 inhibitors.". ACS Med. Chem. Lett. 4: 1119–1123. doi:10.1021/acs.jmedchem.5b01390. PMID 25313323.
- Grohmann U, Fallarino F, Puccetti P (May 2003). "Tolerance, DCs and tryptophan: much ado about IDO". Trends in Immunology. 24 (5): 242–8. doi:10.1016/S1471-4906(03)00072-3. PMID 12738417.
- Takikawa O (Dec 2005). "Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism". Biochemical and Biophysical Research Communications. 338 (1): 12–9. doi:10.1016/j.bbrc.2005.09.032. PMID 16176799.
- Puccetti P (Apr 2007). "On watching the watchers: IDO and type I/II IFN". European Journal of Immunology. 37 (4): 876–9. doi:10.1002/eji.200737184. PMID 17393386.
- Kadoya A, Tone S, Maeda H, Minatogawa Y, Kido R (Nov 1992). "Gene structure of human indoleamine 2,3-dioxygenase". Biochemical and Biophysical Research Communications. 189 (1): 530–6. doi:10.1016/0006-291X(92)91590-M. PMID 1449503.
- Kamimura S, Eguchi K, Yonezawa M, Sekiba K (Jun 1991). "Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta". Acta Medica Okayama. 45 (3): 135–9. PMID 1716396.
- Tone S, Takikawa O, Habara-Ohkubo A, Kadoya A, Yoshida R, Kido R (Jan 1990). "Primary structure of human indoleamine 2,3-dioxygenase deduced from the nucleotide sequence of its cDNA". Nucleic Acids Research. 18 (2): 367. doi:10.1093/nar/18.2.367. PMC . PMID 2326172.
- Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H (Sep 1989). "Tumour necrosis factor-alpha and lipopolysaccharide enhance interferon-induced tryptophan degradation and pteridine synthesis in human cells". Biological Chemistry Hoppe-Seyler. 370 (9): 1063–9. doi:10.1515/bchm3.1989.370.2.1063. PMID 2482041.
- Carlin JM, Borden EC, Byrne GI (Jun 1989). "Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages". Journal of Interferon Research. 9 (3): 329–37. doi:10.1089/jir.1989.9.329. PMID 2501398.
- Kobayashi K, Hayashi K, Sono M (Sep 1989). "Effects of tryptophan and pH on the kinetics of superoxide radical binding to indoleamine 2,3-dioxygenase studied by pulse radiolysis". The Journal of Biological Chemistry. 264 (26): 15280–3. PMID 2549057.
- Daley-Yates PT, Powell AP, Smith LL (Nov 1988). "Pulmonary indoleamine 2,3-dioxygenase activity and its significance in the response of rats, mice, and rabbits to oxidative stress". Toxicology and Applied Pharmacology. 96 (2): 222–32. doi:10.1016/0041-008X(88)90082-8. PMID 2848333.
- Burkin DJ, Kimbro KS, Barr BL, Jones C, Taylor MW, Gupta SL (Jul 1993). "Localization of the human indoleamine 2,3-dioxygenase (IDO) gene to the pericentromeric region of human chromosome 8". Genomics. 17 (1): 262–3. doi:10.1006/geno.1993.1319. PMID 8406467.
- Malina HZ, Martin XD (Jul 1996). "Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye". Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht von Graefes Archiv für Klinische und Experimentelle Ophthalmologie. 234 (7): 457–62. doi:10.1007/BF02539413. PMID 8817290.
- Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (Aug 1998). "Prevention of allogeneic fetal rejection by tryptophan catabolism". Science. 281 (5380): 1191–3. doi:10.1126/science.281.5380.1191. PMID 9712583.
- Takikawa O, Littlejohn TK, Truscott RJ (Mar 2001). "Indoleamine 2,3-dioxygenase in the human lens, the first enzyme in the synthesis of UV filters". Experimental Eye Research. 72 (3): 271–7. doi:10.1006/exer.2000.0951. PMID 11180976.
- Kudo Y, Boyd CA (2005). "The role of L-tryptophan transport in L-tryptophan degradation by indoleamine 2,3-dioxygenase in human placental explants". The Journal of Physiology. 531: 417–23. doi:10.1111/j.1469-7793.2001.0417i.x. PMC . PMID 11230514.
- Papadopoulou ND, Mewies M, McLean KJ, Seward HE, Svistunenko DA, Munro AW, Raven EL (2011). "Redox and spectroscopic properties of human indoleamine 2,3-dioxygenase and a His303Ala variant: implications for catalysis.". Biochemistry. 44: 14318–14328. doi:10.1021/bi0513958. PMID 16245948.
- Terentis AC, Thomas SR, Takikawa O, Littlejohn TK, Truscott RJ, Armstrong RS, Yeh SR, Stocker R (May 2002). "The heme environment of recombinant human indoleamine 2,3-dioxygenase. Structural properties and substrate-ligand interactions". The Journal of Biological Chemistry. 277 (18): 15788–94. doi:10.1074/jbc.M200457200. PMID 11867636.
- Kvirkvelia N, Vojnovic I, Warner TD, Athie-Morales V, Free P, Rayment N, Chain BM, Rademacher TW, Lund T, Roitt IM, Delves PJ (Feb 2002). "Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL-2-dependent proliferation of CTLL-2 T cells". Clinical and Experimental Immunology. 127 (2): 263–9. doi:10.1046/j.1365-2249.2002.01718.x. PMC . PMID 11876748.
- Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, Walcher W, Reich O, Takikawa O, Dohr G (Apr 2002). "Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta". Molecular Human Reproduction. 8 (4): 385–91. doi:10.1093/molehr/8.4.385. PMID 11912287.
- Basran J, Efimov I, Chauhan N, Thackray SJ, Krupa JL, Eaton G, Griffith GA, Mowat CG, Handa S, Raven EL (2011). "The mechanism of formation of N-formylkynurenine by heme dioxygenases.". J. Am. Chem. Soc. 133: 16251–16257. doi:10.1021/ja207066z. PMID 21892828.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Indoleamine 2,3-dioxygenase Provide feedback
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Internal database links
|Similarity to PfamA using HHSearch:||DUF1864|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000898
Indoleamine 2,3-dioxgyenase (IDO, EC) [PUBMED:1907934] is a cytosolic haem protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyzes the conversion of tryptophan and other indole derivatives to kynurenines. The physiological role of IDO is not fully understood but is of great interest, because IDO is widely distributed in human tissues, can be up-regulated via cytokines such as interferon-gamma, and can thereby modulate the levels of tryptophan, which is vital for cell growth. The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. IDO is a haem-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 (SWISSPROT) to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to haem directly as the distal ligand or is essential in maintaining the conformation of the haem pocket [PUBMED:12766158].
Other proteins that are evolutionarily related to IDO include yeast hypothetical protein YJR078w; and myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor [PUBMED:8011076, PUBMED:12711393]. These unusual globins lack enzymatic activity but have kept the haem group.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||heme binding (GO:0020037)|
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|Author:||Finn RD, Bateman A|
|Number in seed:||189|
|Number in full:||1502|
|Average length of the domain:||359.90 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||70.41 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IDO domain has been found. There are 20 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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