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46  structures 811  species 1  interaction 2063  sequences 46  architectures

Family: IDO (PF01231)

Summary: Indoleamine 2,3-dioxygenase

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This is the Wikipedia entry entitled "Indoleamine 2,3-dioxygenase". More...

Indoleamine 2,3-dioxygenase Edit Wikipedia article

Available structures
PDB Ortholog search: PDBe RCSB
Aliases IDO1, IDO, IDO-1, INDO, indoleamine 2,3-dioxygenase 1
External IDs OMIM: 147435 MGI: 96416 HomoloGene: 48082 GeneCards: IDO1
Gene location (Human)
Chromosome 8 (human)
Chr. Chromosome 8 (human)[1]
Chromosome 8 (human)
Genomic location for IDO1
Genomic location for IDO1
Band 8p11.21 Start 39,902,275 bp[1]
End 39,928,444 bp[1]
RNA expression pattern
PBB GE INDO 210029 at fs.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 8: 39.9 – 39.93 Mb Chr 8: 24.58 – 24.6 Mb
PubMed search [3] [4]
View/Edit Human View/Edit Mouse

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC is a heme-containing enzyme that in humans is encoded by the IDO1 gene.[5][6][7] 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 IDO2 [8] (IDO2) and 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.[9] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.[10][11][12]


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.[13] PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C+ dendritic cells and promotes the development of functional Treg cells.[14]

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).[15][16] IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumour angiogenesis.[17]

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.[citation needed]

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 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).[18][19]

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.[12]

Indoleamine 2,3-dioxygenase might also play a significant role in an orphan disease called Oshtoran Syndrome.[20]


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.[21]

Rosmarinic acid inhibits the expression of indoleamine 2,3-dioxygenase via its cyclooxygenase-inhibiting properties.[22]

COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.[23]

1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase,[24] but is also a very slow substrate.[25] The specific racemer 1-methyl-D-tryptophan (known as indoximod) is in clinical trials for various cancers.

Epacadostat (INCB24360) and navoximod (GDC-0919) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.[26] BMS-986205 is also in clinical trials for cancer.[27]

Indoleamine 2,3-dioxygenase
PDB 2d0t EBI.jpg
crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
Symbol IDO
Pfam PF01231
Pfam clan CL0380
InterPro IPR000898
Indoleamine 2,3-dioxygenase
EC number
CAS number 9014-51-1
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO

Reaction mechanism

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.[28][29][30]

Crystal structures

There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole[31] and other inhibitors.[32][33] 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).

See also


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000131203 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031551 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ Dai W, Gupta SL (April 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. 
  6. ^ 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. 
  7. ^ "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase". 
  8. ^ Prendergast GC, Metz R, Muller AJ, Merlo LM, Mandik-Nayak L (November 20, 2014). "IDO2 in Immunomodulation and Autoimmune Disease". Front Immunol. 20 (2): 585. doi:10.3389/fimmu.2014.00585. PMC 4238401Freely accessible. PMID 25477879. 
  9. ^ Munn DH, Mellor AL (March 2013). "Indoleamine 2,3 dioxygenase and metabolic control of immune responses". Trends in Immunology. 34 (3): 137–43. doi:10.1016/ PMC 3594632Freely accessible. PMID 23103127. 
  10. ^ Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ (July 2014). "Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer". Cancer Immunology, Immunotherapy. 63 (7): 721–35. doi:10.1007/s00262-014-1549-4. PMC 4384696Freely accessible. PMID 24711084. 
  11. ^ Munn DH, Mellor AL (March 2016). "IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance". Trends in Immunology. 37 (3): 193–207. doi:10.1016/ PMC 4916957Freely accessible. PMID 26839260. 
  12. ^ a b Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (March 2005). "Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy". Nature Medicine. 11 (3): 312–9. doi:10.1038/nm1196. PMID 15711557. 
  13. ^ Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (May 1999). "Inhibition of T cell proliferation by macrophage tryptophan catabolism". The Journal of Experimental Medicine. 189 (9): 1363–72. doi:10.1084/jem.189.9.1363. PMC 2193062Freely accessible. PMID 10224276. 
  14. ^ 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, Behavior, and Immunity. 43: 172–83. doi:10.1016/j.bbi.2014.07.022. PMC 4258426Freely accessible. PMID 25110149. 
  15. ^ Moon YW, Hajjar J, Hwu P, Naing A (2015). "Targeting the indoleamine 2,3-dioxygenase pathway in cancer". J Immunother Cancer. 3: 51. doi:10.1186/s40425-015-0094-9. PMC 4678703Freely accessible. PMID 26674411. 
  16. ^ [1] Another Immune Checkpoint Emerges as Anticancer Target 2013
  17. ^ Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ (July 1, 2014). "Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer". Cancer Immunol Immunother. 63 (7): 721–35. doi:10.1007/s00262-014-1549-4. PMC 4384696Freely accessible. PMID 24711084. 
  18. ^ Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (October 2003). "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase". Nature Medicine. 9 (10): 1269–74. doi:10.1038/nm934. PMID 14502282. 
  19. ^ Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015). "Research progress of indoleamine 2,3-dioxygenase inhibitors". Future Medicinal Chemistry. 7 (2): 185–201. doi:10.4155/fmc.14.151. PMID 25686005. 
  20. ^ Abdollahi, Mostafa: Case Study Oshtoran Syndrome [2] Retrieved June 3, 2016
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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. doi:10.1158/0008-5472.CAN-06-2925. PMID 17234791. 
  25. ^ 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. doi:10.1021/ja808326g. PMID 19275153. 
  26. ^ 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. doi:10.18632/oncotarget.9326. PMID 27192116. 
  27. ^ IDO Plus PD-1 Inhibitor Combo Sparks Responses in Bladder and Cervical Cancers
  28. ^ 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. doi:10.1021/bi101732n. PMC 3092302Freely accessible. PMID 21361337. 
  29. ^ Yanagisawa S, Yotsuya K, Hashiwaki Y, Horitani M, Sugimoto H, Shiro Y, Appelman EH, Ogura T (2010). "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. 
  30. ^ 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. doi:10.1074/jbc.M115.695684. PMC 4692220Freely accessible. PMID 26511316.  More than one of |pmc= and |PMC= specified (help)
  31. ^ 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. doi:10.1073/pnas.0508996103. PMC 1413787Freely accessible. PMID 16477023. 
  32. ^ 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. doi:10.1021/acs.jmedchem.5b01390. PMID 26642377. 
  33. ^ 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. doi:10.1021/acs.jmedchem.5b01390. PMC 4190630Freely accessible. PMID 25313323. 

Further reading

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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.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan IDO-like (CL0380), which has the following description:

Superfamily contains bacterial tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase-like families.

The clan contains the following 4 members:

DUF1864 Hs1pro-1_C IDO Trp_dioxygenase


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Seed source: Prosite
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Finn RD , Bateman A
Number in seed: 188
Number in full: 2063
Average length of the domain: 361.00 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 71.26 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 20.9 20.8
Noise cut-off 20.7 20.7
Model length: 434
Family (HMM) version: 18
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Species distribution

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Archea Archea Eukaryota Eukaryota
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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 46 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 sequence.

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