Indoleamine 2,3-dioxygenase

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External IDsGeneCards: [1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)n/an/a
PubMed searchn/an/a
View/Edit Human
Indoleamine 2,3-dioxygenase
File:PDB 2d0t EBI.jpg
crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
Pfam clanCL0380
Indoleamine 2,3-dioxygenase
EC number1.13.11.52
CAS number9014-51-1
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC is a heme-containing enzyme that in humans is encoded by the IDO1 gene.[1] 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 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.[2] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.[3][4]


There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole[5] and other inhibitors.[6][7]

Species, tissue, and subcellular distribution


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 slow the 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 T-regulatory cells (Treg cells), which inhibit T-cell activity.

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).[8] IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote the growth of new blood cells to feed the tumor (angiogenesis).[3] IDO permits tumor cells to escape the immune system by depletion of L-tryptophan in the tumor microenvironment 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).[9]

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.[10]


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.

In tumor cells, IDO expression is normally controlled by the tumor suppressor Bin1, which is widely disabled during cancer development.

Clinical significance

In mice, IDO has a normal immune checkpoint function in immune tolerance in pregnancy, suppressing the mother's immune system.[11]

By 2018 the function of IDO as a checkpoint used by tumors to escape immune surveillance was a focus of research and drug discovery efforts,[9] as well as efforts to understand if it could be used as a biomarker for prognosis.[11]

As of 2018, it appeared that overexpression of IDO in some tumors, such as ovarian, colorectal, and endometrial, and esophageal cancer, correlated with swifter death, while in kidney and liver cancers it appeared to correlate with better outcomes.[11] A 2018 meta-analysis found that it correlated with worse outcomes in all cancers, but the results were weak.[11]


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

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.

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


See also


  1. "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase".
  2. 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 3594632. PMID 23103127.
  3. 3.0 3.1 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 4384696. PMID 24711084.
  4. 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 4916957. PMID 26839260.
  5. 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 1413787. PMID 16477023.
  6. 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.
  7. 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 4190630. PMID 25313323.
  8. 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 4678703. PMID 26674411.
  9. 9.0 9.1 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.
  10. 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 3092302. PMID 21361337.
  11. 11.0 11.1 11.2 11.3 Yu CP, Fu SF, Chen X, Ye J, Ye Y, Kong LD, Zhu Z (2018). "The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis". Cellular Physiology and Biochemistry. 49 (1): 134–143. doi:10.1159/000492849. PMID 30134237.

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