indoleamine 2,3-dioxygenase 1

Target id: 2829

Nomenclature: indoleamine 2,3-dioxygenase 1

Abbreviated Name: IDO1

Family: 1.13.11.- Dioxygenases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     indoleamine 2,3-dioxygenase 1 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 403 8p12-p11 IDO1 indoleamine 2,3-dioxygenase 1 2,9
Mouse - 407 8 A2 Ido1 indoleamine 2,3-dioxygenase 1
Rat - 407 16q12.5 Ido1 indoleamine 2,3-dioxygenase 1
Gene and Protein Information Comments
Two isoforms of mouse Ido1 have been identified. We list the longer of the two, isoform 1 in the table above. The shorter isoform has only 316 amino acids.
Previous and Unofficial Names
INDO | indoleamine-pyrrole 2,3 dioxygenase | IDO-1 | IDO | indoleamine 2
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with Amg-1.
PDB Id:  4PK5
Ligand:  amg-1
Resolution:  2.79Å
Species:  Human
References:  11
Enzyme Reaction
EC Number: 1.13.11.52

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
NLG919 Hs Inhibition 8.1 pKi 6
pKi 8.1 (Ki 7x10-9 M) [6]
compound 5i [PMID: 24099220] Hs Inhibition 7.3 pKi 13
pKi 7.3 (Ki 5.4x10-8 M) [13]
tryptanthrin Hs Inhibition 5.3 pKi 13
pKi 5.3 (Ki 4.81x10-6 M) [13]
1-methyl-L-tryptophan Hs Inhibition 4.4 pKi 13
pKi 4.4 (Ki 4.23x10-5 M) [13]
beta-carboline Hs Inhibition 0.9 pKi 3
pKi 0.9 (Ki 1.2x10-1 M) [3]
epacadostat Hs Inhibition 7.2 pIC50 14
pIC50 7.2 (IC50 6.7x10-8 M) [14]
PF-06840003 Hs Inhibition 6.8 pIC50 1
pIC50 6.8 (IC50 1.5x10-7 M) [1]
Description: Measuring inhibition of IDO1-induced kynurenine production in vitro.
amg-1 Hs Inhibition 5.5 pIC50 7
pIC50 5.5 (IC50 3x10-6 M) [7]
Immunopharmacology Comments
Accumulating evidence indicates that the IDO1-aryl hydrocarbon receptor (AhR, a receptor for l-kynurenine, a product of IDO1 catalysis; AHR; P35869) pathway contributes to immune homeostasis by promoting modulation of innate and adaptive immune responses. IDO1 expression can be increased by IFN-γ and IL-6 [5] (the latter in the presence of a histone deacetylase inhibitor). It is proposed that upregulating IDO1 via HDAC inhibition may be a therapeutic approach for the acute lethal idiopathic pulmonary syndrome that is a complication following allogeneic hematopoietic stem cell transplantation [5].

Depletion of tryptophan (catalyzed by IDO1) promotes Treg cell differentiation, suppresses the immune response and decreases DC function, creating a tolerogenic environment. IDO1 inhibitors reverse this response. ID01 has emerged as a promising molecular target for the development of novel agents as cancer immunotherapeutics, and for the treatment of other diseases characterized by the reduction of local tryptophan levels. The applicability of ID01 inhibition has been shown in preclinical models of many diseases, including arthritis, ischemia-reperfusion injury, endotoxin shock, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, airway inflammation, and cancer [4,12].
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process ID:  4
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  negative regulation of T cell proliferation (GO:0042130) IEA
negative regulation of T cell apoptotic process (GO:0070233) IEA
positive regulation of T cell apoptotic process (GO:0070234) IMP
References: 
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  cytokine production involved in inflammatory response (GO:0002534) IEA
positive regulation of chronic inflammatory response (GO:0002678) IEA
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  positive regulation of T cell tolerance induction (GO:0002666) IEA
positive regulation of chronic inflammatory response (GO:0002678) IEA
positive regulation of type 2 immune response (GO:0002830) IEA
negative regulation of T cell proliferation (GO:0042130) IEA
References: 
Immuno Process:  Immune system development
Immuno Process ID:  8
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  positive regulation of T cell tolerance induction (GO:0002666) IEA
References: 
Immuno Process:  Cytokine production & signalling
Immuno Process ID:  9
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  cytokine production involved in inflammatory response (GO:0002534) IEA
negative regulation of interleukin-10 production (GO:0032693) IEA
positive regulation of interleukin-12 production (GO:0032735) IEA
References: 
Immuno Process:  Chemotaxis & migration
Immuno Process ID:  10
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of T cell proliferation (GO:0042130) IEA
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of T cell proliferation (GO:0042130) IEA
References: 
Physiological Functions
Indoleamine 2,3-dioxygenase 1 catalyzes the degradation of L-tryptophan via the reaction L-tryptophan + O2 <=> N-formyl-L-kynurenine. L-tryptophan has an immunosuppressive effect.
Species:  Human
Tissue:  Macrophages
References:  8
IDO expression at the maternal–fetal interface depletes L-tryptophan, an effect which inhibits activation of maternal T-cells in resopnse to fetal alloantigens, thereby preventing rejection of the fetus.
Species:  Mouse
Tissue:  Decidua, placenta
References:  8
IDO expression by tumour cells, depletes L-tryptophan in the tumour microenvironment blocks T-cell proliferation thereby allowing tumour cells to evade the immune response.
Species:  Human
Tissue:  Melanoma cells, pancreatic cancer cells, non-small cell lung cancer cells, laryngeal carcinoma cells, pharyngeal squamous-cell carcinoma cells.
References:  12
General Comments
IDO1 is a rate-limiting enzyme of tryptophan catabolism along the kynurenine pathway. IDO1 catabolises both the L- and D- enantiomers of tryptophan, but shows preference for L-tryptophan. Additional IDO1 substrates include indoleamines such as serotonin, melatonin, and tryptamine [10].
IDO1 is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism.

References

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1. Crosignani S, Cauwenberghs S, Driessens G, Deroose F. (2015) Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as ido1 inhibitors. Patent number: WO2015173764. Assignee: Iteos Therapeutics. Priority date: 15/05/2014. Publication date: 19/11/2015.

2. Dai W, Gupta SL. (1990) Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA. Biochem. Biophys. Res. Commun.168 (1): 1-8. [PMID:2109605]

3. Dolušić E, Larrieu P, Blanc S, Sapunaric F, Norberg B, Moineaux L, Colette D, Stroobant V, Pilotte L, Colau D et al.. (2011) Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. Bioorg. Med. Chem.19 (4): 1550-61. [PMID:21269836]

4. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. (2013) Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med.210 (7): 1389-402. [PMID:23752227]

5. Lee SM, Park HY, Suh YS, Yoon EH, Kim J, Jang WH, Lee WS, Park SG, Choi IW, Choi I et al.. (2017) Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway. Proc. Natl. Acad. Sci. U.S.A.114 (29): E5881-E5890. [PMID:28673995]

6. Mautino MR, Jaipuri FA, Waldo J, Kumar S, Adams J, Van Allen C, Marcinowicz-Flick A, Munn D, Vahanian N, Link CJ. Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Accessed on 09/02/2016. Modified on 09/02/2016. aacrjournals.org, http://cancerres.aacrjournals.org/content/73/8_Supplement/491. DOI: 10.1158/1538-7445

7. Meininger D, Zalameda L, Liu Y, Stepan LP, Borges L, McCarter JD, Sutherland CL. (2011) Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors. Biochim. Biophys. Acta1814 (12): 1947-54. [PMID:21835273]

8. Mellor AL, Munn DH. (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation?. Immunol. Today20 (10): 469-73. [PMID:10500295]

9. 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. Cytogenet. Cell Genet.64 (3-4): 231-2. [PMID:8404046]

10. Shimizu T, Nomiyama S, Hirata F, Hayaishi O. (1978) Indoleamine 2,3-dioxygenase. Purification and some properties. J. Biol. Chem.253 (13): 4700-6. [PMID:26687]

11. 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 Lett5 (10): 1119-23. [PMID:25313323]

12. 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. [PMID:14502282]

13. Yang S, Li X, Hu F, Li Y, Yang Y, Yan J, Kuang C, Yang Q. (2013) Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in Lewis lung cancer (LLC) tumor-bearing mice. J. Med. Chem.56 (21): 8321-31. [PMID:24099220]

14. Yue EW, Douty B, Wayland B, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Liu C et al.. (2009) Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J. Med. Chem.52 (23): 7364-7. [PMID:19507862]

How to cite this page

1.13.11.- Dioxygenases: indoleamine 2,3-dioxygenase 1. Last modified on 25/07/2017. Accessed on 18/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2829.