Indoleamine 2,3-dioxygenase

Indoleamine 2,3-dioxygenase 1
PDB rendering based on 2d0t.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2D0T​, 2D0U​, 4PK5​, 4PK6​
Identifiers
Symbols	IDO1 ; IDO; IDO-1; INDO
External IDs	OMIM: 147435 MGI: 96416 HomoloGene: 48082 ChEMBL: 4685 GeneCards: IDO1 Gene
EC number	1.13.11.52
Gene ontology Molecular function • tryptophan 2,3-dioxygenase activity • electron carrier activity • heme binding • indoleamine 2,3-dioxygenase activity • metal ion binding Cellular component • cytosol • smooth muscle contractile fiber • stereocilium bundle Biological process • cytokine production involved in inflammatory response • positive regulation of T cell tolerance induction • positive regulation of chronic inflammatory response • positive regulation of type 2 immune response • tryptophan catabolic process • female pregnancy • tryptophan catabolic process to kynurenine • response to lipopolysaccharide • negative regulation of interleukin-10 production • positive regulation of interleukin-12 production • multicellular organismal response to stress • kynurenic acid biosynthetic process • cellular nitrogen compound metabolic process • swimming behavior • negative regulation of T cell proliferation • small molecule metabolic process • regulation of activated T cell proliferation • oxidation-reduction process • negative regulation of T cell apoptotic process • positive regulation of T cell apoptotic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3620	15930
Ensembl	ENSG00000131203	ENSMUSG00000031551
UniProt	P14902	P28776
RefSeq (mRNA)	NM_002164	NM_001293690
RefSeq (protein)	NP_002155	NP_001280619
Location (UCSC)	Chr 8: 39.9 – 39.93 Mb	Chr 8: 24.58 – 24.6 Mb
PubMed search

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is a heme-containing enzyme that in humans is encoded by the IDO1 gene.^[1][2] This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine^[3] using the superoxide anion as an oxygen donor.

Function

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.^[4] PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C(+) dendritic cells and promotes the development of functional Treg cells.^[5]

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.

Clinical significance

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).^[6][7]

Inhibitors

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.^[8]

Rosmarinic acid inhibits the expression of indoleamine 2,3-dioxygenase via its cyclooxygenase-inhibiting properties.^[9]

COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.^[10]

Alpha-methyl-tryptophan also inhibits indoleamine dioxygenase.^[11]

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 PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Indoleamine 2,3-dioxygenase Identifiers EC number 1.13.11.52 CAS number 9014-51-1 Databases IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures RCSB PDB PDBe PDBsum Gene Ontology AmiGO / EGO Search PMC articles PubMed articles NCBI proteins

See also

• 1-Methyltryptophan
• Tryptophan 2,3-dioxygenase

References

1. 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.
2. 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.
3. "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase".
4. 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 4258426. PMID 10224276.
5. 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 4258426. PMID 25110149.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.

Further reading

• 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, 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 (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, 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 1906325. 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.

External links

• Indoleamine-Pyrrole 2,3,-Dioxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)