Summary: Indoleamine 2,3-dioxygenase
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Indoleamine 2,3-dioxygenase Edit Wikipedia article
|Indoleamine 2,3-dioxygenase 1|
PDB rendering based on 2d0t.
|Symbols||; IDO; IDO-1; INDO|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 22.214.171.124) is an enzyme that in humans is encoded by the IDO1 gene. This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine.
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.
IDO 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).
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. Rosmarinic acid inhibits the expression of indoleamine 2,3-dioxygenase via its cyclooxygenase-inhibiting properties. COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity. Alpha-Methyl-Tryptophan also inhibits indoleamine dioxygenase.
- 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".
- Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. (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.
- 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, et al. (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, et al. (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.
- 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 330282. 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, et 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 (Mar 2001). "The role of L-tryptophan transport in L-tryptophan degradation by indoleamine 2,3-dioxygenase in human placental explants". The Journal of Physiology 531 (Pt 2): 417–23. doi:10.1111/j.1469-7793.2001.0417i.x. PMC 2278460. PMID 11230514.
- Terentis AC, Thomas SR, Takikawa O, Littlejohn TK, Truscott RJ, Armstrong RS, et al. (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, et al. (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 1906325. PMID 11876748.
- Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, et al. (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.
- Indoleamine-Pyrrole 2,3,-Dioxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
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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)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Author:||Finn RD, Bateman A|
|Number in seed:||191|
|Number in full:||693|
|Average length of the domain:||365.40 aa|
|Average identity of full alignment:||27 %|
|Average coverage of the sequence by the domain:||73.55 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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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.
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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 8 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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