Indoleamine 2,3-dioxygenase

IDO1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases IDO1, IDO, IDO-1, INDO, indoleamine 2,3-dioxygenase 1
External IDs OMIM: 147435 MGI: 96416 HomoloGene: 48082 GeneCards: IDO1
Targeted by Drug
norharman[1]
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

3620

15930

Ensembl

ENSG00000131203

ENSMUSG00000031551

UniProt

P14902

P28776

RefSeq (mRNA)

NM_002164

NM_008324
NM_001293690

RefSeq (protein)

NP_002155.1

NP_001280619.1
NP_032350.1

Location (UCSC) Chr 8: 39.9 – 39.93 Mb Chr 8: 24.58 – 24.6 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

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.[4][5] This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine[6] using the superoxide anion as an oxygen donor.

Function

Indoleamine 2,3-dioxygenase 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.[7] PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C(+) dendritic cells and promotes the development of functional Treg cells.[8]

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). 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.

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. A wide range of human cancers such as prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, lung, etc. overexpress human IDO (hIDO).[9][10] Indoleamine 2,3-dioxygenase might also play a significant role in an orphan disease called Oshtoran Syndrome.[11]

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.[12]

Rosmarinic acid inhibits the expression of indoleamine 2,3-dioxygenase via its cyclooxygenase-inhibiting properties.[13]

COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.[14]

Alpha-methyl-tryptophan also inhibits indoleamine dioxygenase.[15]

Epacadostat is in clinical trials for various cancers.[16]

Indoleamine 2,3-dioxygenase

crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
Identifiers
Symbol IDO
Pfam PF01231
Pfam clan CL0380
InterPro IPR000898
PROSITE PDOC00684
Indoleamine 2,3-dioxygenase
Identifiers
EC number 1.13.11.52
CAS number 9014-51-1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

See also

References

  1. ↑ "Drugs that physically interact with Indoleamine 2,3-dioxygenase 1 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ Dai W, Gupta SL (Apr 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.
  5. ↑ 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.
  6. ↑ "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase".
  7. ↑ Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (May 1999). "Inhibition of T cell proliferation by macrophage tryptophan catabolism.". J. Exp. Med. 189: 1363–72. doi:10.1084/jem.189.9.1363. PMC 2193062Freely accessible. PMID 10224276.
  8. ↑ 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 Behav Immun. 43: 172–183. doi:10.1016/j.bbi.2014.07.022. PMC 4258426Freely accessible. PMID 25110149.
  9. ↑ Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003). "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase". Nat. Med. 9 (10): 1269–74. doi:10.1038/nm934. PMID 14502282.
  10. ↑ Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015). "Research progress of indoleamine 2,3-dioxygenase inhibitors". Future Med Chem. 7 (2): 185–201. doi:10.4155/fmc.14.151. PMID 25686005.
  11. ↑ Abdollahi, Mostafa: Case Study Oshtoran Syndrome Retrieved June 3, 2016
  12. ↑ Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F (Aug 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007). "Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses". Cancer Res. 67 (2): 792–801. doi:10.1158/0008-5472.CAN-06-2925. PMID 17234791.
  16. ↑ 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 (2016). "The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells". Oncotarget. doi:10.18632/oncotarget.9326. PMID 27192116.

Further reading

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