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|
|RNA expression pattern|
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 184.108.40.206) 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). IDO has been implicated in immune modulation through its ability to limit T cell function and engage mechanisms of immune tolerance. Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.
Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the 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 and chronic infectious viruses). 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 and by production of the catabolic product kynurenine, which selectively impairs the growth and survival of T cells. A wide range of human cancers such as prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, lung, etc. overexpress human IDO (hIDO). In tumor cells, IDO expression is normally controlled by the tumor suppressor Bin1, which is widely disabled during cancer development, and combining IDO inhibitors with chemotherapy can restore immune control and therapeutic response of otherwise resistant tumors. 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.
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.
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).
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
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- Abdollahi, Mostafa: Case Study Oshtoran Syndrome  Retrieved June 3, 2016
- Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F (August 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. PMID 17229401. doi:10.1016/j.bcp.2006.12.018.
- 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. PMID 21517752. doi:10.2174/092986711795656063.
- Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (January 2007). "Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses". Cancer Research. 67 (2): 792–801. PMID 17234791. doi:10.1158/0008-5472.CAN-06-2925.
- Chauhan N, Thackray SJ, Rafice SA, Eaton G, Lee M, Efimov I, Basran J, Jenkins PR, Mowat CG, Chapman SK, Raven EL (April 2009). "Reassessment of the reaction mechanism in the heme dioxygenases". Journal of the American Chemical Society. 131 (12): 4186–7. PMID 19275153. doi:10.1021/ja808326g.
- 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 (June 2016). "The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells". Oncotarget. 7 (25): 37762–37772. PMID 27192116. doi:10.18632/oncotarget.9326.
- Efimov I, Basran J, Thackray SJ, Handa S, Mowat CG, Raven EL (April 2011). "Structure and reaction mechanism in the heme dioxygenases". Biochemistry. 50 (14): 2717–24. PMID 21361337. 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 (December 2015). "Substrate Oxidation by Indoleamine 2,3-Dioxygenase: EVIDENCE FOR A COMMON REACTION MECHANISM" (PDF). The Journal of Biological Chemistry. 290 (52): 30924–30. PMC . PMID 26511316. doi:10.1074/jbc.M115.695684.
- Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y (February 2006). "Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 103 (8): 2611–6. PMID 16477023. doi:10.1073/pnas.0508996103.
- 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 (January 2016). "Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1". Journal of Medicinal Chemistry. 59 (1): 282–93. PMID 26642377. doi:10.1021/acs.jmedchem.5b01390.
- Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y (October 2014). "Crystal Structures and Structure-Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors". ACS Medicinal Chemistry Letters. 5 (10): 1119–23. PMID 25313323. doi:10.1021/acs.jmedchem.5b01390.
- Grohmann U, Fallarino F, Puccetti P (May 2003). "Tolerance, DCs and tryptophan: much ado about IDO". Trends in Immunology. 24 (5): 242–8. PMID 12738417. doi:10.1016/S1471-4906(03)00072-3.
- Takikawa O (December 2005). "Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism". Biochemical and Biophysical Research Communications. 338 (1): 12–9. PMID 16176799. doi:10.1016/j.bbrc.2005.09.032.
- Puccetti P (April 2007). "On watching the watchers: IDO and type I/II IFN". European Journal of Immunology. 37 (4): 876–9. PMID 17393386. doi:10.1002/eji.200737184.
- Kadoya A, Tone S, Maeda H, Minatogawa Y, Kido R (November 1992). "Gene structure of human indoleamine 2,3-dioxygenase". Biochemical and Biophysical Research Communications. 189 (1): 530–6. PMID 1449503. doi:10.1016/0006-291X(92)91590-M.
- Kamimura S, Eguchi K, Yonezawa M, Sekiba K (June 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 (January 1990). "Primary structure of human indoleamine 2,3-dioxygenase deduced from the nucleotide sequence of its cDNA". Nucleic Acids Research. 18 (2): 367. PMC . PMID 2326172. doi:10.1093/nar/18.2.367.
- Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H (September 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. PMID 2482041. doi:10.1515/bchm3.1989.370.2.1063.
- Carlin JM, Borden EC, Byrne GI (June 1989). "Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages". Journal of Interferon Research. 9 (3): 329–37. PMID 2501398. doi:10.1089/jir.1989.9.329.
- Kobayashi K, Hayashi K, Sono M (September 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 (November 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. PMID 2848333. doi:10.1016/0041-008X(88)90082-8.
- Burkin DJ, Kimbro KS, Barr BL, Jones C, Taylor MW, Gupta SL (July 1993). "Localization of the human indoleamine 2,3-dioxygenase (IDO) gene to the pericentromeric region of human chromosome 8". Genomics. 17 (1): 262–3. PMID 8406467. doi:10.1006/geno.1993.1319.
- Malina HZ, Martin XD (July 1996). "Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye". Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. 234 (7): 457–62. PMID 8817290. doi:10.1007/BF02539413.
- Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (August 1998). "Prevention of allogeneic fetal rejection by tryptophan catabolism". Science. 281 (5380): 1191–3. PMID 9712583. doi:10.1126/science.281.5380.1191.
- Takikawa O, Littlejohn TK, Truscott RJ (March 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. PMID 11180976. doi:10.1006/exer.2000.0951.
- Kudo Y, Boyd CA (March 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. PMC . PMID 11230514. doi:10.1111/j.1469-7793.2001.0417i.x.
- Papadopoulou ND, Mewies M, McLean KJ, Seward HE, Svistunenko DA, Munro AW, Raven EL (November 2005). "Redox and spectroscopic properties of human indoleamine 2,3-dioxygenase and a His303Ala variant: implications for catalysis". Biochemistry. 44 (43): 14318–28. PMID 16245948. doi:10.1021/bi0513958.
- 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. PMID 11867636. doi:10.1074/jbc.M200457200.
- Kvirkvelia N, Vojnovic I, Warner TD, Athie-Morales V, Free P, Rayment N, Chain BM, Rademacher TW, Lund T, Roitt IM, Delves PJ (February 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. PMC . PMID 11876748. doi:10.1046/j.1365-2249.2002.01718.x.
- Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, Walcher W, Reich O, Takikawa O, Dohr G (April 2002). "Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta". Molecular Human Reproduction. 8 (4): 385–91. PMID 11912287. doi:10.1093/molehr/8.4.385.
- Basran J, Efimov I, Chauhan N, Thackray SJ, Krupa JL, Eaton G, Griffith GA, Mowat CG, Handa S, Raven EL (October 2011). "The mechanism of formation of N-formylkynurenine by heme dioxygenases". Journal of the American Chemical Society. 133 (40): 16251–7. PMID 21892828. doi:10.1021/ja207066z.
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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|Similarity to PfamA using HHSearch:||DUF1864|
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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 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
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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.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
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.
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.
Loading structure mapping...