Indoleamine 2,3-dioxygenase: Difference between revisions

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'''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).
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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>
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== Function ==
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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
| Symbol = IDO
| Name = Indoleamine 2,3-dioxygenase
| image = PDB 2d0t EBI.jpg
| width =
| 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 =  
}}
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Reaction mechanism ==
{{GNF_Protein_box
| image = PBB_Protein_INDO_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2d0t.
| PDB = {{PDB2|2d0t}}, {{PDB2|2d0u}}
| Name = Indoleamine-pyrrole 2,3 dioxygenase
| HGNCid = 6059
| Symbol = INDO
| AltSymbols =; CD107B; IDO
| OMIM = 147435
| ECnumber =  1.13.11.42
| Homologene = 48082
| MGIid = 96416
| 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}}
| Component =
| 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
    | Hs_EntrezGene = 3620
    | Hs_Ensembl = ENSG00000131203
    | Hs_RefseqProtein = NP_002155
    | Hs_RefseqmRNA = NM_002164
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 8
    | Hs_GenLoc_start = 39890545
    | 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).  
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>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Crystal structures ==
{{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>
}}


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]]).


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.
== See also ==
* [[1-Methyltryptophan]]  
* [[Tryptophan 2,3-dioxygenase]]


It catalyzes conversion of [[L-tryptophan]] to [[N-formylkynurenine]].
== References ==
{{reflist|33em}}


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|33em}}
==Further reading==
* {{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 }}
{{refbegin | 2}}
* {{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 }}
{{PBB_Further_reading
* {{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 }}
| citations =
* {{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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 }}
*{{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}}
{{refend}}


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


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Revision as of 18:57, 25 November 2017

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Identifiers
Aliases
External IDsGeneCards: [3]
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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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][2][3] It is one of two enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-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.[4] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.[5][6][7]

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 cells.[8] PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C(+) dendritic cells and promotes the development of functional Treg cells.[9]

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).[10][11] IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumour angiogenesis.[12]

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).[13][14]

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.[7]

Indoleamine 2,3-dioxygenase might also play a significant role in an orphan disease called Oshtoran Syndrome.[15]

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.[16]

Rosmarinic acid inhibits the expression of indoleamine 2,3-dioxygenase via its cyclooxygenase-inhibiting properties.[17]

COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.[18]

1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase,[19] but is also a very slow substrate.[20] 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.[21] BMS-986205 is also in clinical trials for cancer.[22]

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

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.[23][24][25]

Crystal structures

There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole[26] and other inhibitors.[27][28] 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

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase".
  4. ↑ 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. PMID 23103127.
  5. ↑ 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. PMID 24711084.
  6. ↑ 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. PMID 26839260.
  7. ↑ 7.0 7.1 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.
  8. ↑ 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 2193062. PMID 10224276.
  9. ↑ 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 4258426. PMID 25110149.
  10. ↑ Targeting the indoleamine 2,3-dioxygenase pathway in cancer 2013
  11. ↑ [1] Another Immune Checkpoint Emerges as Anticancer Target 2013
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Abdollahi, Mostafa: Case Study Oshtoran Syndrome [2] Retrieved June 3, 2016
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ IDO Plus PD-1 Inhibitor Combo Sparks Responses in Bladder and Cervical Cancers
  23. ↑ 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. PMID 21361337.
  24. ↑ Yanagisawa S, Yotsuya K, Hashiwaki Y, Horitani M, Sugimoto H, Shiro Y, Appelman EH, Ogura T. "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.
  25. ↑ 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 4692220. PMID 26511316.
  26. ↑ 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. PMID 16477023.
  27. ↑ 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.
  28. ↑ 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. PMID 25313323.

Further reading

External links

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