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90  structures 911  species 1  interaction 2523  sequences 43  architectures

Family: IDO (PF01231)

Summary: Indoleamine 2,3-dioxygenase

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This is the Wikipedia entry entitled "Indoleamine 2,3-dioxygenase". More...

Indoleamine 2,3-dioxygenase Edit Wikipedia article

IDO1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIDO1, IDO, IDO-1, INDO, indoleamine 2,3-dioxygenase 1
External IDsOMIM: 147435 MGI: 96416 HomoloGene: 48082 GeneCards: IDO1
Gene location (Human)
Chromosome 8 (human)
Chr.Chromosome 8 (human)[1]
Chromosome 8 (human)
Genomic location for IDO1
Genomic location for IDO1
Band8p11.21Start39,902,275 bp[1]
End39,928,790 bp[1]
RNA expression pattern
PBB GE INDO 210029 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002164

NM_008324
NM_001293690

RefSeq (protein)

NP_002155

NP_001280619
NP_032350

Location (UCSC)Chr 8: 39.9 – 39.93 MbChr 8: 24.58 – 24.6 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Indoleamine 2,3-dioxygenase
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.[5] 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.[6] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.[7][8]

Protein

There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole[9] and other inhibitors.[10][11]

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).[12] 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).[7] 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).[13]

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.[14]

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.[15]

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,[13] as well as efforts to understand if it could be used as a biomarker for prognosis.[15]

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.[15] A 2018 meta-analysis found that it correlated with worse outcomes in all cancers, but the results were weak.[15]

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.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000131203 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031551 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase".
  6. ^ 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.
  7. ^ a b 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.
  8. ^ 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.
  9. ^ 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". 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ a b 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.
  14. ^ 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.
  15. ^ a b c d 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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Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000898

Indoleamine 2,3-dioxgyenase (IDO, EC) [PUBMED:1907934] is a cytosolic haem protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyzes the conversion of tryptophan and other indole derivatives to kynurenines. The physiological role of IDO is not fully understood but is of great interest, because IDO is widely distributed in human tissues, can be up-regulated via cytokines such as interferon-gamma, and can thereby modulate the levels of tryptophan, which is vital for cell growth. The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. IDO is a haem-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 (SWISSPROT) to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to haem directly as the distal ligand or is essential in maintaining the conformation of the haem pocket [PUBMED:12766158].

Other proteins that are evolutionarily related to IDO include yeast hypothetical protein YJR078w; and myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor [PUBMED:8011076, PUBMED:12711393]. These unusual globins lack enzymatic activity but have kept the haem group.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan IDO-like (CL0380), which has the following description:

Superfamily contains bacterial tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase-like families.

The clan contains the following 4 members:

DUF1864 Hs1pro-1_C IDO Trp_dioxygenase

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(179)
Full
(2523)
Representative proteomes UniProt
(4342)
NCBI
(5100)
Meta
(526)
RP15
(373)
RP35
(1023)
RP55
(1722)
RP75
(2620)
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  Seed
(179)
Full
(2523)
Representative proteomes UniProt
(4342)
NCBI
(5100)
Meta
(526)
RP15
(373)
RP35
(1023)
RP55
(1722)
RP75
(2620)
Alignment:
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  Seed
(179)
Full
(2523)
Representative proteomes UniProt
(4342)
NCBI
(5100)
Meta
(526)
RP15
(373)
RP35
(1023)
RP55
(1722)
RP75
(2620)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Finn RD , Bateman A
Number in seed: 179
Number in full: 2523
Average length of the domain: 365.70 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 72.66 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 20.8 20.9
Noise cut-off 20.7 20.7
Model length: 437
Family (HMM) version: 19
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
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Viroids Viroids Unclassified sequence Unclassified sequence

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Interactions

There is 1 interaction for this family. More...

IDO

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IDO domain has been found. There are 90 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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