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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
{{Infobox protein family
| update_page = yes
| Symbol = IDO
| require_manual_inspection = no
| Name = Indoleamine 2,3-dioxygenase
| update_protein_box = yes
| image = PDB 2d0t EBI.jpg
| update_summary = yes
| width =
| update_citations = yes
| caption = crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
| Pfam = PF01231
| Pfam_clan = CL0380
| InterPro = IPR000898
| SMART =
| PROSITE = PDOC00684
| MEROPS =
| SCOP =
| TCDB =  
| OPM family =  
| OPM protein =  
| CAZy =  
| CDD =  
}}
}}
{{infobox enzyme
| Name = Indoleamine 2,3-dioxygenase
| EC_number = 1.13.11.52
| CAS_number = 9014-51-1
| IUBMB_EC_number = 1/13/11/52
| GO_code = 0033754
| image =
| width =
| 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).


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
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>
{{GNF_Protein_box
 
| image = PBB_Protein_INDO_image.jpg
==Protein==
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2d0t.
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>
| PDB = {{PDB2|2d0t}}, {{PDB2|2d0u}}
 
| Name = Indoleamine-pyrrole 2,3 dioxygenase
==Species, tissue, and subcellular distribution==
| HGNCid = 6059
 
| Symbol = INDO
== Function ==
| AltSymbols =; CD107B; IDO
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.
| OMIM = 147435
 
| ECnumber = 1.13.11.42
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>
| Homologene = 48082
 
| MGIid = 96416
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>
| GeneAtlas_image1 = PBB_GE_INDO_210029_at_tn.png
 
| Function = {{GNF_GO|id=GO:0004426 |text = tryptophan 2,3-dioxygenase activity}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0009055 |text = electron carrier activity}} {{GNF_GO|id=GO:0020037 |text = heme binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
==Interactions==
  | Component =  
[[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.
  | Process = {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0007565 |text = female pregnancy}} {{GNF_GO|id=GO:0019441 |text = tryptophan catabolic process to kynurenine}}
 
| Orthologs = {{GNF_Ortholog_box
In tumor cells, IDO expression is normally controlled by the [[tumor suppressor]] [[Bin1]], which is widely disabled during cancer development.
    | Hs_EntrezGene = 3620
 
    | Hs_Ensembl = ENSG00000131203
== Clinical significance ==
    | Hs_RefseqProtein = NP_002155
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>
    | Hs_RefseqmRNA = NM_002164
 
    | Hs_GenLoc_db =
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/> 
    | Hs_GenLoc_chr = 8
 
    | Hs_GenLoc_start = 39890545
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/>
    | Hs_GenLoc_end = 39905120
    | Hs_Uniprot = P14902
    | Mm_EntrezGene = 15930
    | Mm_Ensembl = ENSMUSG00000031551
    | Mm_RefseqmRNA = NM_008324
    | Mm_RefseqProtein = NP_032350
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 8
    | Mm_GenLoc_start = 26049686
    | Mm_GenLoc_end = 26062554
    | Mm_Uniprot = P28776
  }}
}}


'''Indoleamine-pyrrole 2,3-dioxygenase''' (IDO or INDO EC 1.13.11.42) is an [[immunomodulator|immunomodulatory]] enzyme secreted by some alternatively activated macrophages and other immunoregulatory cells (also used as an immune subversion strategy by many tumors).  
=== Inhibitors ===
[[COX-2 inhibitors]] down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in [[kynurenine]] levels as well as reducing proinflammatory cytokine activity.


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
[[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.
{{PBB_Summary
| section_title =
| summary_text = Gamma-interferon (IFNG; MIM 147570) 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 (INDO; EC 1.13.11.42). This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine.[supplied by OMIM]<ref>{{cite web | title = Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3620| accessdate = }}</ref>
}}


[[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.


IDO 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.
==History==


It catalyzes conversion of [[L-tryptophan]] to [[N-formylkynurenine]].
== See also ==
* [[1-Methyltryptophan]]  
* [[Tryptophan 2,3-dioxygenase]]


==References==
== References ==
{{reflist|2}}
{{reflist|33em}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Grohmann U, Fallarino F, Puccetti P |title=Tolerance, DCs and tryptophan: much ado about IDO. |journal=Trends Immunol. |volume=24 |issue= 5 |pages= 242-8 |year= 2004 |pmid= 12738417 |doi=  }}
*{{cite journal  | author=Takikawa O |title=Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism. |journal=Biochem. Biophys. Res. Commun. |volume=338 |issue= 1 |pages= 12-9 |year= 2005 |pmid= 16176799 |doi= 10.1016/j.bbrc.2005.09.032 }}
*{{cite journal  | author=Puccetti P |title=On watching the watchers: IDO and type I/II IFN. |journal=Eur. J. Immunol. |volume=37 |issue= 4 |pages= 876-9 |year= 2007 |pmid= 17393386 |doi= 10.1002/eji.200737184 }}
*{{cite journal  | author=Kadoya A, Tone S, Maeda H, ''et al.'' |title=Gene structure of human indoleamine 2,3-dioxygenase. |journal=Biochem. Biophys. Res. Commun. |volume=189 |issue= 1 |pages= 530-6 |year= 1992 |pmid= 1449503 |doi=  }}
*{{cite journal  | author=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 Med. Okayama |volume=45 |issue= 3 |pages= 135-9 |year= 1991 |pmid= 1716396 |doi=  }}
*{{cite journal  | author=Dai W, Gupta SL |title=Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA. |journal=Biochem. Biophys. Res. Commun. |volume=168 |issue= 1 |pages= 1-8 |year= 1990 |pmid= 2109605 |doi=  }}
*{{cite journal  | author=Tone S, Takikawa O, Habara-Ohkubo A, ''et al.'' |title=Primary structure of human indoleamine 2,3-dioxygenase deduced from the nucleotide sequence of its cDNA. |journal=Nucleic Acids Res. |volume=18 |issue= 2 |pages= 367 |year= 1990 |pmid= 2326172 |doi=  }}
*{{cite journal  | author=Werner-Felmayer G, Werner ER, Fuchs D, ''et al.'' |title=Tumour necrosis factor-alpha and lipopolysaccharide enhance interferon-induced tryptophan degradation and pteridine synthesis in human cells. |journal=Biol. Chem. Hoppe-Seyler |volume=370 |issue= 9 |pages= 1063-9 |year= 1990 |pmid= 2482041 |doi=  }}
*{{cite journal  | author=Carlin JM, Borden EC, Byrne GI |title=Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages. |journal=J. Interferon Res. |volume=9 |issue= 3 |pages= 329-37 |year= 1989 |pmid= 2501398 |doi=  }}
*{{cite journal  | author=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=J. Biol. Chem. |volume=264 |issue= 26 |pages= 15280-3 |year= 1989 |pmid= 2549057 |doi=  }}
*{{cite journal  | author=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=Toxicol. Appl. Pharmacol. |volume=96 |issue= 2 |pages= 222-32 |year= 1989 |pmid= 2848333 |doi=  }}
*{{cite journal  | author=Najfeld V, Menninger J, Muhleman D, ''et al.'' |title=Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-->p11 by fluorescent in situ hybridization. |journal=Cytogenet. Cell Genet. |volume=64 |issue= 3-4 |pages= 231-2 |year= 1993 |pmid= 8404046 |doi=  }}
*{{cite journal  | author=Burkin DJ, Kimbro KS, Barr BL, ''et al.'' |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 |year= 1993 |pmid= 8406467 |doi=  }}
*{{cite journal  | author=Malina HZ, Martin XD |title=Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye. |journal=Graefes Arch. Clin. Exp. Ophthalmol. |volume=234 |issue= 7 |pages= 457-62 |year= 1996 |pmid= 8817290 |doi=  }}
*{{cite journal  | author=Munn DH, Zhou M, Attwood JT, ''et al.'' |title=Prevention of allogeneic fetal rejection by tryptophan catabolism. |journal=Science |volume=281 |issue= 5380 |pages= 1191-3 |year= 1998 |pmid= 9712583 |doi=  }}
*{{cite journal  | author=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=Exp. Eye Res. |volume=72 |issue= 3 |pages= 271-7 |year= 2001 |pmid= 11180976 |doi= 10.1006/exer.2000.0951 }}
*{{cite journal  | author=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=J. Physiol. (Lond.) |volume=531 |issue= Pt 2 |pages= 417-23 |year= 2001 |pmid= 11230514 |doi=  }}
*{{cite journal  | author=Terentis AC, Thomas SR, Takikawa O, ''et al.'' |title=The heme environment of recombinant human indoleamine 2,3-dioxygenase. Structural properties and substrate-ligand interactions. |journal=J. Biol. Chem. |volume=277 |issue= 18 |pages= 15788-94 |year= 2002 |pmid= 11867636 |doi= 10.1074/jbc.M200457200 }}
*{{cite journal  | author=Kvirkvelia N, Vojnovic I, Warner TD, ''et al.'' |title=Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL-2-dependent proliferation of CTLL-2 T cells. |journal=Clin. Exp. Immunol. |volume=127 |issue= 2 |pages= 263-9 |year= 2002 |pmid= 11876748 |doi=  }}
*{{cite journal  | author=Sedlmayr P, Blaschitz A, Wintersteiger R, ''et al.'' |title=Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. |journal=Mol. Hum. Reprod. |volume=8 |issue= 4 |pages= 385-91 |year= 2002 |pmid= 11912287 |doi=  }}
}}
{{refend}}


==External links==
== External links ==
* {{MeshName|Indoleamine-Pyrrole+2,3,-Dioxygenase}}
* {{MeshName|Indoleamine-Pyrrole+2,3,-Dioxygenase}}


[[Category:enzymes]]
{{PDB Gallery|geneid=3620}}
{{Amino acid metabolism enzymes}}
{{Monooxygenases}}
{{Enzymes}}
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[[Category:EC 1.13.11]]
[[Category:Immune system]]
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{{Monooxygenases}}
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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.

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