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{{Infobox_gene}}
{{Infobox_gene}}
'''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]].<ref name="pmid2109605">{{cite journal | vauthors = Dai W, Gupta SL | title = Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA | journal = Biochemical and Biophysical Research Communications | volume = 168 | issue = 1 | pages = 1–8 | date = April 1990 | pmid = 2109605 | doi = 10.1016/0006-291X(90)91666-G }}</ref><ref name="pmid8404046">{{cite journal | vauthors = Najfeld V, Menninger J, Muhleman D, Comings DE, Gupta SL | title = Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-->p11 by fluorescent in situ hybridization | journal = Cytogenetics and Cell Genetics | volume = 64 | issue = 3-4 | pages = 231–2 | year = 1993 | pmid = 8404046 | doi = 10.1159/000133584 }}</ref><ref>{{cite web | title = Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3620| accessdate = }}</ref> It is one of two enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O<sub>2</sub>-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.<ref name="pmid23103127">{{cite journal | vauthors = Munn DH, Mellor AL | title = Indoleamine 2,3 dioxygenase and metabolic control of immune responses | journal = Trends in Immunology | volume = 34 | issue = 3 | pages = 137–43 | date = March 2013 | pmid = 23103127 | doi = 10.1016/j.it.2012.10.001 }}</ref> Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.<ref name="pmid24711084">{{cite journal | vauthors = Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ | title = Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer | journal = Cancer Immunology, Immunotherapy | volume = 63 | issue = 7 | pages = 721–35 | date = July 2014 | pmid = 24711084 | doi = 10.1007/s00262-014-1549-4 }}</ref><ref name="pmid26839260">{{cite journal | vauthors = Munn DH, Mellor AL | title = IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance | journal = Trends in Immunology | volume = 37 | issue = 3 | pages = 193–207 | date = March 2016 | pmid = 26839260 | doi = 10.1016/j.it.2016.01.002 }}</ref><ref name="pmid15711557">{{cite journal | vauthors = Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC | title = Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy | journal = Nature Medicine | volume = 11 | issue = 3 | pages = 312–9 | date = March 2005 | pmid = 15711557 | doi = 10.1038/nm1196 }}</ref>
== Function ==
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 cell]]s.<ref name="pmid10224276">{{cite journal | vauthors = Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL | title = Inhibition of T cell proliferation by macrophage tryptophan catabolism | journal = The Journal of Experimental Medicine | volume = 189 | issue = 9 | pages = 1363–72 | date = May 1999 | pmid = 10224276 | pmc = 2193062 | doi = 10.1084/jem.189.9.1363 }}</ref> [[PGE2]] is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C(+) [[dendritic cell]]s and promotes the development of functional [[Treg cell]]s.<ref name="pmid25110149">{{cite journal | vauthors = Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, Wang J | title = Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system | journal = Brain, Behavior, and Immunity | volume = 43 | pages = 172–83 | date = January 2015 | pmid = 25110149 | pmc = 4258426 | doi = 10.1016/j.bbi.2014.07.022 }}</ref>
IDO is an [[immune checkpoint]] molecule in the sense that it is an [[immunomodulator]]y enzyme produced by some [[alternatively activated macrophage]]s and other immunoregulatory cells (also used as an immune subversion strategy by many tumors and chronic infectious viruses).<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678703/ ''Targeting the indoleamine 2,3-dioxygenase pathway in cancer'' 2013]</ref><ref>[http://www.onclive.com/publications/oncology-live/2013/september-2013/exploring-ido-inhibitors-another-immune-checkpoint-emerges-as-anticancer-target ]
''Another Immune Checkpoint Emerges as Anticancer Target'' 2013</ref> IDO is known to suppress T and [[NK cell]]s, generate and activate [[Treg]]s and [[myeloid-derived suppressor cell]]s, and promote tumour angiogenesis.<ref name=Prendergast2014>{{cite journal |vauthors=Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ |title=Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer  |journal=Cancer Immunol Immunother  |volume=63  |issue=7  |pages=721–35  |date=July 1, 2014  |doi= 10.1007/s00262-014-1549-4  |pmid=24711084  |pmc=4384696 }}</ref>
[[Interferon-gamma]] has an antiproliferative effect on many tumor cells and inhibits intracellular pathogens such as ''[[Toxoplasma gondii|Toxoplasma]]'' and ''[[Chlamydia (bacterium)|Chlamydia]]'', at least partly because of the induction of indoleamine 2,3-dioxygenase. {{citation needed|reason=no citation|date=September 2015}}
== Clinical significance ==
It has been shown that IDO permits tumor cells to escape the immune system by depletion of L-Trp in the [[Tumor microenvironment|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).<ref name="pmid14502282">{{cite journal | vauthors = Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ | title = Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase | journal = Nature Medicine | volume = 9 | issue = 10 | pages = 1269–74 | date = October 2003 | pmid = 14502282 | doi = 10.1038/nm934 }}</ref><ref name="pmid25686005">{{cite journal | vauthors = Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z | title = Research progress of indoleamine 2,3-dioxygenase inhibitors | journal = Future Medicinal Chemistry | volume = 7 | issue = 2 | pages = 185–201 | year = 2015 | pmid = 25686005 | doi = 10.4155/fmc.14.151 }}</ref>
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.<ref name="pmid15711557"/>
Indoleamine 2,3-dioxygenase might also play a significant role in an [[orphan disease]] called [[Oshtoran Syndrome]].<ref>Abdollahi, Mostafa: Case Study Oshtoran Syndrome [http://issuu.com/mostafaabdollahi/docs/oshtoran_case_study] Retrieved June 3, 2016</ref>
== 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]].<ref name="pmid10947071">{{cite journal | vauthors = Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F | title = Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages | journal = Journal of Leukocyte Biology | volume = 68 | issue = 2 | pages = 260–6 | date = August 2000 | pmid = 10947071 | doi =  | url = http://www.jleukbio.org/content/68/2/260.long }}</ref>
[[Rosmarinic acid]] inhibits the expression of indoleamine 2,3-dioxygenase via its [[cyclooxygenase]]-inhibiting properties.<ref name="pmid17229401">{{cite journal | vauthors = Lee HJ, Jeong YI, Lee TH, Jung ID, Lee JS, Lee CM, Kim JI, Joo H, Lee JD, Park YM | title = Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells | journal = Biochemical Pharmacology | volume = 73 | issue = 9 | pages = 1412–21 | date = May 2007 | pmid = 17229401 | doi = 10.1016/j.bcp.2006.12.018 }}</ref>
[[COX-2 inhibitors]] down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in [[kynurenine]] levels as well as reducing proinflammatory cytokine activity.<ref name="pmid21517752">{{cite journal | vauthors = Cesario A, Rocca B, Rutella S | title = The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer | journal = Current Medicinal Chemistry | volume = 18 | issue = 15 | pages = 2263–71 | year = 2011 | pmid = 21517752 | doi = 10.2174/092986711795656063 }}</ref>
[[1-Methyltryptophan]] is a [[Racemic mixture|racemic compound]] that weakly inhibits indoleamine dioxygenase,<ref name="pmid17234791">{{cite journal | vauthors = Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH | title = Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses | journal = Cancer Research | volume = 67 | issue = 2 | pages = 792–801 | date = January 2007 | pmid = 17234791 | doi = 10.1158/0008-5472.CAN-06-2925 }}</ref> but is also a very slow substrate.<ref>{{cite journal | vauthors = Chauhan N, Thackray SJ, Rafice SA, Eaton G, Lee M, Efimov I, Basran J, Jenkins PR, Mowat CG, Chapman SK, Raven EL | title = Reassessment of the reaction mechanism in the heme dioxygenases | journal = Journal of the American Chemical Society | volume = 131 | issue = 12 | pages = 4186–7 | date = April 2009 | pmid = 19275153 | doi = 10.1021/ja808326g | url = http://pubs.acs.org/doi/pdf/10.1021/ja808326g }}</ref> 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.<ref name="pmid27192116">{{cite journal | vauthors = 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 | title = The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells | journal = Oncotarget | volume = 7 | issue = 25 | pages = 37762–37772 | date = June 2016 | pmid = 27192116 | doi = 10.18632/oncotarget.9326 }}</ref> [[BMS-986205]] is also in clinical trials for cancer.<ref>[http://www.onclive.com/web-exclusives/ido-plus-pd1-inhibitor-combo-sparks-responses-in-bladder-and-cervical-cancers ''IDO Plus PD-1 Inhibitor Combo Sparks Responses in Bladder and Cervical Cancers'']</ref>
{{Infobox protein family
{{Infobox protein family
| Symbol = IDO
| Symbol = IDO
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| caption =  
| caption =  
}}
}}
'''Indoleamine-pyrrole 2,3-dioxygenase''' ('''IDO''' or '''INDO''' {{EC number|1.13.11.52}}) is a heme-containing [[enzyme]] that in humans is encoded by the ''IDO1'' [[gene]].<ref>{{cite web | title = Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3620| accessdate = }}</ref> It is one of three enzymes that catalyze the first and rate-limiting step in the [[kynurenine pathway]], the O<sub>2</sub>-dependent oxidation of [[L-tryptophan]] to [[N-formylkynurenine]], the others being [[Indoleamine 2,3-dioxygenase 2|IDO2]] and [[tryptophan 2,3-dioxygenase]] (TDO).
IDO has been implicated in [[immune system|immune]] modulation through its ability to limit [[T-cell]] function and engage mechanisms of [[immune tolerance]].<ref name="pmid23103127">{{cite journal | vauthors = Munn DH, Mellor AL | title = Indoleamine 2,3 dioxygenase and metabolic control of immune responses | journal = Trends in Immunology | volume = 34 | issue = 3 | pages = 137–43 | date = March 2013 | pmid = 23103127 | doi = 10.1016/j.it.2012.10.001 | pmc=3594632}}</ref> Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.<ref name=Prendergast2014/><ref name="pmid26839260">{{cite journal | vauthors = Munn DH, Mellor AL | title = IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance | journal = Trends in Immunology | volume = 37 | issue = 3 | pages = 193–207 | date = March 2016 | pmid = 26839260 | doi = 10.1016/j.it.2016.01.002 | pmc=4916957}}</ref>
==Protein==
There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole<ref>{{cite journal | vauthors = Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y | title = Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 8 | pages = 2611–6 | date = February 2006 | pmid = 16477023 | doi = 10.1073/pnas.0508996103 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413787/pdf/pnas-0508996103.pdf | pmc=1413787}}</ref> and other inhibitors.<ref>{{cite journal | vauthors = 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 | title = Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1 | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 1 | pages = 282–93 | date = January 2016 | pmid = 26642377 | doi = 10.1021/acs.jmedchem.5b01390 | url = http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01390 }}</ref><ref>{{cite journal | vauthors = Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y | title = Crystal Structures and Structure-Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors | journal = ACS Medicinal Chemistry Letters | volume = 5 | issue = 10 | pages = 1119–23 | date = October 2014 | pmid = 25313323 | doi = 10.1021/acs.jmedchem.5b01390 | url = http://pubs.acs.org/doi/pdf/10.1021/ml500247w | pmc=4190630}}</ref>
==Species, tissue, and subcellular distribution==
== Function ==
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 [[Integrin alpha X|CD11C]]<sup>+</sup> [[dendritic cell]]s and promotes the development of functional [[T-regulatory cell]]s (Treg cells), which inhibit T-cell activity.
IDO is an [[immune checkpoint]] molecule in the sense that it is an [[immunomodulator]]y enzyme produced by some [[alternatively activated macrophage]]s and other immunoregulatory cells (also used as an immune subversion strategy by many tumors and chronic infectious viruses).<ref>{{cite journal| pmc=4678703 | pmid=26674411 | doi=10.1186/s40425-015-0094-9 | volume=3 | title=Targeting the indoleamine 2,3-dioxygenase pathway in cancer | year=2015 | author=Moon YW, Hajjar J, Hwu P, Naing A | journal=J Immunother Cancer | page=51}}</ref> IDO is known to suppress T and [[NK cell]]s, generate and activate [[Treg]]s and [[myeloid-derived suppressor cell]]s, and promote the growth of new blood cells to feed the tumor ([[angiogenesis]]).<ref name=Prendergast2014>{{cite journal |vauthors=Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ |title=Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer  |journal=Cancer Immunol Immunother  |volume=63  |issue=7  |pages=721–35  |date=July 1, 2014  |doi= 10.1007/s00262-014-1549-4  |pmid=24711084  |pmc=4384696 }}</ref>  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).<ref name="pmid25686005">{{cite journal | vauthors = Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z | title = Research progress of indoleamine 2,3-dioxygenase inhibitors | journal = Future Medicinal Chemistry | volume = 7 | issue = 2 | pages = 185–201 | year = 2015 | pmid = 25686005 | doi = 10.4155/fmc.14.151 }}</ref>
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.<ref>{{cite journal | vauthors = Efimov I, Basran J, Thackray SJ, Handa S, Mowat CG, Raven EL | title = Structure and reaction mechanism in the heme dioxygenases | journal = Biochemistry | volume = 50 | issue = 14 | pages = 2717–24 | date = April 2011 | pmid = 21361337 | doi = 10.1021/bi101732n | url = http://pubs.acs.org/doi/pdf/10.1021/bi101732n | pmc=3092302}}</ref>
==Interactions==
[[Interferon-gamma]] has an antiproliferative effect on many tumor cells and inhibits intracellular pathogens such as ''[[Toxoplasma gondii|Toxoplasma]]'' and ''[[Chlamydia (bacterium)|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.<ref name=Yu2018>{{cite journal | vauthors = Yu CP, Fu SF, Chen X, Ye J, Ye Y, Kong LD, Zhu Z | title = The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis | journal = Cellular Physiology and Biochemistry | volume = 49 | issue = 1 | pages = 134–143 | date = 2018 | pmid = 30134237 | doi = 10.1159/000492849 }}</ref>
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,<ref name="pmid25686005"/> as well as efforts to understand if it could be used as a [[biomarker]] for prognosis.<ref name=Yu2018/> 
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.<ref name=Yu2018/>  A 2018 meta-analysis found that it correlated with worse outcomes in all cancers, but the results were weak.<ref name=Yu2018/>


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


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.<ref>{{cite journal | vauthors = Efimov I, Basran J, Thackray SJ, Handa S, Mowat CG, Raven EL | title = Structure and reaction mechanism in the heme dioxygenases | journal = Biochemistry | volume = 50 | issue = 14 | pages = 2717–24 | date = April 2011 | pmid = 21361337 | doi = 10.1021/bi101732n | url = http://pubs.acs.org/doi/pdf/10.1021/bi101732n }}</ref><ref>{{cite journal | vauthors = Yanagisawa S, Yotsuya K, Hashiwaki Y, Horitani M, Sugimoto H, Shiro Y, Appelman EH, Ogura T | title = Identification of the Fe-O<sub>2</sub> and the Fe=O heme species for indoleamine 2,3-dioxygenase during catalytic turnover | journal = Chem Lett | volume = 39 | pages = 36–37 | doi = 10.1246/cl.2010.36 | url = https://www.researchgate.net/publication/244732938_Identification_of_the_Fe-O2_and_the_FeO_Heme_Species_for_Indoleamine_23Dioxygenase_during_Catalytic_Turnover}}</ref><ref>{{cite journal | vauthors = Booth ES, Basran J, Lee M, Handa S, Raven EL | title = Substrate Oxidation by Indoleamine 2,3-Dioxygenase: EVIDENCE FOR A COMMON REACTION MECHANISM | journal = The Journal of Biological Chemistry | volume = 290 | issue = 52 | pages = 30924–30 | date = December 2015 | pmid = 26511316 | doi = 10.1074/jbc.M115.695684 | url = http://www.jbc.org/content/290/52/30924.full.pdf | PMC = 4692220 }}</ref>
[[1-Methyltryptophan]] is a [[Racemic mixture|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 structures ==
[[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.


There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole<ref>{{cite journal | vauthors = Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y | title = Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 8 | pages = 2611–6 | date = February 2006 | pmid = 16477023 | doi = 10.1073/pnas.0508996103 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413787/pdf/pnas-0508996103.pdf }}</ref> and other inhibitors.<ref>{{cite journal | vauthors = 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 | title = Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1 | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 1 | pages = 282–93 | date = January 2016 | pmid = 26642377 | doi = 10.1021/acs.jmedchem.5b01390 | url = http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01390 }}</ref><ref>{{cite journal | vauthors = Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y | title = Crystal Structures and Structure-Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors | journal = ACS Medicinal Chemistry Letters | volume = 5 | issue = 10 | pages = 1119–23 | date = October 2014 | pmid = 25313323 | doi = 10.1021/acs.jmedchem.5b01390 | url = http://pubs.acs.org/doi/pdf/10.1021/ml500247w }}</ref> 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]]).
==History==


== See also ==
== See also ==
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== References ==
== References ==
{{reflist|33em}}
{{reflist|33em}}
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Grohmann U, Fallarino F, Puccetti P | title = Tolerance, DCs and tryptophan: much ado about IDO | journal = Trends in Immunology | volume = 24 | issue = 5 | pages = 242–8 | date = May 2003 | pmid = 12738417 | doi = 10.1016/S1471-4906(03)00072-3 }}
* {{cite journal | vauthors = Takikawa O | title = Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism | journal = Biochemical and Biophysical Research Communications | volume = 338 | issue = 1 | pages = 12–9 | date = December 2005 | pmid = 16176799 | doi = 10.1016/j.bbrc.2005.09.032 }}
* {{cite journal | vauthors = Puccetti P | title = On watching the watchers: IDO and type I/II IFN | journal = European Journal of Immunology | volume = 37 | issue = 4 | pages = 876–9 | date = April 2007 | pmid = 17393386 | doi = 10.1002/eji.200737184 }}
* {{cite journal | vauthors = Kadoya A, Tone S, Maeda H, Minatogawa Y, Kido R | title = Gene structure of human indoleamine 2,3-dioxygenase | journal = Biochemical and Biophysical Research Communications | volume = 189 | issue = 1 | pages = 530–6 | date = November 1992 | pmid = 1449503 | doi = 10.1016/0006-291X(92)91590-M }}
* {{cite journal | vauthors = Kamimura S, Eguchi K, Yonezawa M, Sekiba K | title = Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta | journal = Acta Medica Okayama | volume = 45 | issue = 3 | pages = 135–9 | date = June 1991 | pmid = 1716396 | doi =  }}
* {{cite journal | vauthors = Tone S, Takikawa O, Habara-Ohkubo A, Kadoya A, Yoshida R, Kido R | title = Primary structure of human indoleamine 2,3-dioxygenase deduced from the nucleotide sequence of its cDNA | journal = Nucleic Acids Research | volume = 18 | issue = 2 | pages = 367 | date = January 1990 | pmid = 2326172 | pmc = 330282 | doi = 10.1093/nar/18.2.367 }}
* {{cite journal | vauthors = Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H | title = Tumour necrosis factor-alpha and lipopolysaccharide enhance interferon-induced tryptophan degradation and pteridine synthesis in human cells | journal = Biological Chemistry Hoppe-Seyler | volume = 370 | issue = 9 | pages = 1063–9 | date = September 1989 | pmid = 2482041 | doi = 10.1515/bchm3.1989.370.2.1063 }}
* {{cite journal | vauthors = Carlin JM, Borden EC, Byrne GI | title = Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages | journal = Journal of Interferon Research | volume = 9 | issue = 3 | pages = 329–37 | date = June 1989 | pmid = 2501398 | doi = 10.1089/jir.1989.9.329 }}
* {{cite journal | vauthors = Kobayashi K, Hayashi K, Sono M | title = Effects of tryptophan and pH on the kinetics of superoxide radical binding to indoleamine 2,3-dioxygenase studied by pulse radiolysis | journal = The Journal of Biological Chemistry | volume = 264 | issue = 26 | pages = 15280–3 | date = September 1989 | pmid = 2549057 | doi =  }}
* {{cite journal | vauthors = Daley-Yates PT, Powell AP, Smith LL | title = Pulmonary indoleamine 2,3-dioxygenase activity and its significance in the response of rats, mice, and rabbits to oxidative stress | journal = Toxicology and Applied Pharmacology | volume = 96 | issue = 2 | pages = 222–32 | date = November 1988 | pmid = 2848333 | doi = 10.1016/0041-008X(88)90082-8 }}
* {{cite journal | vauthors = Burkin DJ, Kimbro KS, Barr BL, Jones C, Taylor MW, Gupta SL | title = Localization of the human indoleamine 2,3-dioxygenase (IDO) gene to the pericentromeric region of human chromosome 8 | journal = Genomics | volume = 17 | issue = 1 | pages = 262–3 | date = July 1993 | pmid = 8406467 | doi = 10.1006/geno.1993.1319 }}
* {{cite journal | vauthors = Malina HZ, Martin XD | title = Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye | journal = Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie | volume = 234 | issue = 7 | pages = 457–62 | date = July 1996 | pmid = 8817290 | doi = 10.1007/BF02539413 }}
* {{cite journal | vauthors = Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL | title = Prevention of allogeneic fetal rejection by tryptophan catabolism | journal = Science | volume = 281 | issue = 5380 | pages = 1191–3 | date = August 1998 | pmid = 9712583 | doi = 10.1126/science.281.5380.1191 }}
* {{cite journal | vauthors = Takikawa O, Littlejohn TK, Truscott RJ | title = Indoleamine 2,3-dioxygenase in the human lens, the first enzyme in the synthesis of UV filters | journal = Experimental Eye Research | volume = 72 | issue = 3 | pages = 271–7 | date = March 2001 | pmid = 11180976 | doi = 10.1006/exer.2000.0951 }}
* {{cite journal | vauthors = Kudo Y, Boyd CA | title = The role of L-tryptophan transport in L-tryptophan degradation by indoleamine 2,3-dioxygenase in human placental explants | journal = The Journal of Physiology | volume = 531 | issue = Pt 2 | pages = 417–23 | date = March 2001 | pmid = 11230514 | pmc = 2278460 | doi = 10.1111/j.1469-7793.2001.0417i.x }}
* {{cite journal | vauthors = Papadopoulou ND, Mewies M, McLean KJ, Seward HE, Svistunenko DA, Munro AW, Raven EL | title = Redox and spectroscopic properties of human indoleamine 2,3-dioxygenase and a His303Ala variant: implications for catalysis | journal = Biochemistry | volume = 44 | issue = 43 | pages = 14318–28 | date = November 2005 | pmid = 16245948 | doi = 10.1021/bi0513958 }}
* {{cite journal | vauthors = Terentis AC, Thomas SR, Takikawa O, Littlejohn TK, Truscott RJ, Armstrong RS, Yeh SR, Stocker R | title = The heme environment of recombinant human indoleamine 2,3-dioxygenase. Structural properties and substrate-ligand interactions | journal = The Journal of Biological Chemistry | volume = 277 | issue = 18 | pages = 15788–94 | date = May 2002 | pmid = 11867636 | doi = 10.1074/jbc.M200457200 }}
* {{cite journal | vauthors = Kvirkvelia N, Vojnovic I, Warner TD, Athie-Morales V, Free P, Rayment N, Chain BM, Rademacher TW, Lund T, Roitt IM, Delves PJ | title = Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL-2-dependent proliferation of CTLL-2 T cells | journal = Clinical and Experimental Immunology | volume = 127 | issue = 2 | pages = 263–9 | date = February 2002 | pmid = 11876748 | pmc = 1906325 | doi = 10.1046/j.1365-2249.2002.01718.x }}
* {{cite journal | vauthors = Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, Walcher W, Reich O, Takikawa O, Dohr G | title = Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta | journal = Molecular Human Reproduction | volume = 8 | issue = 4 | pages = 385–91 | date = April 2002 | pmid = 11912287 | doi = 10.1093/molehr/8.4.385 }}
* {{cite journal | vauthors = Basran J, Efimov I, Chauhan N, Thackray SJ, Krupa JL, Eaton G, Griffith GA, Mowat CG, Handa S, Raven EL | title = The mechanism of formation of N-formylkynurenine by heme dioxygenases | journal = Journal of the American Chemical Society | volume = 133 | issue = 40 | pages = 16251–7 | date = October 2011 | pmid = 21892828 | doi = 10.1021/ja207066z }}
{{refend}}


== External links ==
== External links ==

Latest revision as of 08:38, 10 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
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
Identifiers
SymbolIDO
PfamPF01231
Pfam clanCL0380
InterProIPR000898
PROSITEPDOC00684
Indoleamine 2,3-dioxygenase
Identifiers
EC number1.13.11.52
CAS number9014-51-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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] 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]

Protein

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

Function

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]

Interactions

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]

Inhibitors

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.

History

See also

References

  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/j.it.2012.10.001. 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/j.it.2016.01.002. 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.

External links

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