IDO1 Protein

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IDO1 Protein

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IDO1 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IDO1 Protein</th>
</tr>
<tr> [@dantzer2008]
<td class="label">Gene</td> [@campbell2014]
<td>[IDO1](/genes/ido1)</td> [@maddison2016]
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P14902" target="_blank">P14902</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2D0T" target="_blank">2D0T</a>, <a href="https://www.rcsb.org/structure/5WMU" target="_blank">5WMU</a></td>
</tr>
<tr>
<td class="label">Mol.

...

IDO1 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IDO1 Protein</th>
</tr>
<tr> [@dantzer2008]
<td class="label">Gene</td> [@campbell2014]
<td>[IDO1](/genes/ido1)</td> [@maddison2016]
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P14902" target="_blank">P14902</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2D0T" target="_blank">2D0T</a>, <a href="https://www.rcsb.org/structure/5WMU" target="_blank">5WMU</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~45 kDa (403 aa)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Indoleamine 2,3-dioxygenase family (heme-containing oxidoreductase)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), [Huntington's Disease](/diseases/huntingtons)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/depression" style="color:#ef9a9a">Depression</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">54 edges</a></td>
</tr>
</table>

IDO1 Protein

Overview

IDO1 (Indoleamine 2,3-Dioxygenase 1) is a 45 kDa heme-containing cytoplasmic enzyme encoded by the [IDO1](/genes/ido1) gene. It catalyzes the rate-limiting step of the kynurenine pathway by cleaving the 2,3-double bond of the indole ring of L-tryptophan, converting it to N-formylkynurenine. IDO1 is the primary enzyme driving tryptophan catabolism in the brain during neuroinflammation, as its expression in [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/cell-types/astrocytes) is massively upregulated by inflammatory cytokines, particularly IFN-γ. The resulting metabolic shift generates neurotoxic metabolites (quinolinic acid, 3-hydroxykynurenine) that drive [excitotoxicity](/mechanisms/excitotoxicity) and [oxidative stress](/mechanisms/oxidative-stress) in neurodegenerative diseases.

Structure

Overall Architecture

Crystal structures (PDB: 2D0T, 5WMU) reveal IDO1 as a monomeric α-helical enzyme:

Large domain (residues 1-250): Contains the active site with the heme cofactor coordinated by proximal His346. This domain forms a deep substrate-binding pocket.

Small domain (residues 251-403): Connected to the large domain by a flexible loop; participates in substrate access and product release.

Active site pocket: A deep, hydrophobic channel leading to the heme iron center. The pocket is divided into pocket A (where tryptophan binds) and pocket B (secondary binding site for inhibitors).

Heme-Binding Site

The catalytic center features:

Heme prosthetic group: Iron(II) protoporphyrin IX, the catalytic center
Proximal histidine (His346): Axial ligand to the heme iron
Distal pocket: Contains Ser167, Phe226, and Arg231, which position the substrate and oxygen for catalysis
The heme must be in the Fe(II) state for catalytic activity; oxidation to Fe(III) inactivates the enzyme

Substrate Binding

L-Tryptophan binding in the active site involves:

Indole ring stacking with Phe226 and Phe163
Carboxylate group interaction with Arg231
Amino group hydrogen bonding with Ser167
The C2-C3 bond of the indole ring is positioned directly over the heme iron for dioxygen-mediated cleavage

Inhibitor Binding Sites

IDO1 has been extensively characterized for drug discovery:

Active site (pocket A): Competitive inhibitors like 1-methyltryptophan bind here
Extended pocket (pocket B): Non-competitive inhibitors occupy this secondary site
Apo-IDO1 conformation: Heme-displacing inhibitors (e.g., BMS-986205/linrodostat) bind the apo form and prevent heme incorporation

Catalytic Mechanism

Reaction

L-Tryptophan + O₂ → N-Formylkynurenine

Mechanism Steps

Substrate binding: L-Tryptophan enters the active site and positions its indole C2=C3 bond above the heme Fe(II)

Oxygen activation: Molecular O₂ binds to heme Fe(II), forming a Fe(II)-O₂ complex (ferrous-oxy intermediate)

Electrophilic addition: The activated oxygen attacks the C3 position of the indole ring, forming a C3-peroxo intermediate

Dioxetane intermediate: Ring closure creates a dioxetane intermediate bridging C2 and C3

Ring opening: Homolytic O-O bond cleavage and C2-C3 bond scission opens the indole ring

Product release: N-Formylkynurenine is released, and the enzyme returns to the resting Fe(II) state

Kinetic Properties

Km (L-Trp): ~20 μM (comparable to physiological tryptophan concentration)
kcat: ~2 s⁻¹
Substrate specificity: L-Trp >> D-Trp, 5-HO-Trp, serotonin, melatonin
Cofactor requirement: Fe(II) heme; ascorbate or methylene blue can serve as reducing agents

Function in Kynurenine Pathway

Downstream Metabolites

IDO1 initiates a metabolic cascade with divergent neurological outcomes:

Neuroprotective metabolite (astrocytic branch):

Kynurenine → Kynurenic acid (KYNA) via kynurenine aminotransferases (KATs)
KYNA: [NMDA receptor](/entities/nmda-receptor) antagonist at glycine site, α7-nAChR antagonist
Protects against excitotoxicity; anti-convulsant properties

Neurotoxic metabolites (microglial branch):

Kynurenine → 3-Hydroxykynurenine (3-HK) via kynurenine 3-monooxygenase (KMO)
3-HK → 3-Hydroxyanthranilic acid (3-HAA) → Quinolinic acid (QUIN) via 3-HAO and ACMSD
3-HK: Generates free radicals, causes oxidative DNA damage
QUIN: Potent NMDA receptor agonist at NR2A/NR2B subunits, promotes [excitotoxicity](/mechanisms/excitotoxicity)
QUIN also: chelates Fe(II) generating hydroxyl radicals, promotes lipid peroxidation, promotes [tau](/proteins/tau) phosphorylation

Tryptophan Depletion Effects

IDO1-mediated tryptophan depletion has additional consequences:

Serotonin reduction: Less tryptophan available for tryptophan hydroxylase (rate-limiting for serotonin synthesis)
Melatonin reduction: Reduced serotonin leads to reduced pineal melatonin production
T cell suppression: Tryptophan depletion activates GCN2 kinase in T cells, inducing anergy and [apoptosis](/entities/apoptosis)
Protein synthesis effects: Reduced amino acid availability activates the integrated stress response ([eIF2α](/genes/eif2ak3) phosphorylation)

Role in Neurodegenerative Diseases

Alzheimer's Disease

IDO1 protein is a key mediator of AD neuroinflammation-neurodegeneration coupling:

IDO1 immunoreactivity colocalizes with [senile plaques](/mechanisms/amyloid-pathology) and microglial clusters in AD [cortex](/brain-regions/cortex)
Quinolinic acid accumulates in [neurofibrillary tangles](/mechanisms/neurofibrillary-tangles)
The KYN/TRP ratio in CSF correlates with [amyloid-β](/proteins/amyloid-beta-protein) 42 levels and cognitive decline
IDO1 knockout or inhibition reduces amyloid pathology and improves cognition in [APP](/entities/app-protein)/PS1 mice
Quinolinic acid promotes [tau](/proteins/tau) phosphorylation at AD-relevant epitopes (Thr231, Ser396) via NMDA-Ca²⁺-[GSK3β](/genes/gsk3b) cascade

Parkinson's Disease

In [PD](/diseases/parkinsons-disease):

IDO1 upregulation in nigral microglia following [α-synuclein](/proteins/alpha-synuclein)-mediated activation
QUIN contributes to dopaminergic neurotoxicity via NMDA receptor activation on nigrostriatal [neurons](/entities/neurons)
3-HK-generated oxidative stress exacerbates mitochondrial complex I deficiency
KYN/TRP ratio elevated in PD patient CSF, correlating with motor severity and non-motor symptoms (depression, cognitive impairment)

Huntington's Disease

The kynurenine pathway is severely dysregulated in [HD](/diseases/huntingtons):

QUIN levels are elevated 3-5× in HD striatum
3-HK levels increase progressively through disease stages
KYNA levels are decreased (shifted balance toward neurotoxicity)
KMO inhibition (blocking 3-HK and QUIN production) is neuroprotective in HD models
The striatal medium spiny neurons most vulnerable in HD express high levels of NMDA receptors containing NR2B subunits, making them exquisitely sensitive to QUIN excitotoxicity

Protein-Protein Interactions and Regulation

| Regulator/Partner | Effect | Mechanism |
|---|---|---|
| IFN-γ / [STAT1](/genes/stat1) | Transcriptional induction | GAS element activation |
| SOCS3 | Negative regulation | STAT1 signaling suppression |
| Nitric oxide (NO) | Enzyme inhibition | Binds heme iron (Fe-NO) |
| Superoxide | Enzyme inactivation | Oxidizes heme to Fe(III) |
| [CTLA-4](/proteins/ctla4-protein) | Signaling inducer | Reverse signaling in DCs |
| [TGF-β](/genes/tgfb1) | Expression modulator | Context-dependent regulation |
| AhR | Positive feedback | Kynurenine activates AhR → more IDO1 |

External Links

[IDO1 at UniProt (P14902)](https://www.uniprot.org/uniprot/P14902)
[IDO1 at PDB (2D0T)](https://www.rcsb.org/structure/2D0T)
[IDO1 at Human Protein Atlas](https://www.proteinatlas.org/ENSG00000131203-IDO1)
[IDO1 at KEGG (hsa:3620)](https://www.genome.jp/dbget-bin/www_bget?hsa:3620)
[Kynurenine Pathway at KEGG](https://www.genome.jp/kegg-bin/show_pathway?hsa00380)

References

[Schwarcz et al., Kynurenines in the mammalian brain: when physiology meets pathology (2012) (2012)](https://doi.org/10.1038/nrn3257)

[Sugimoto et al., Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase (2006) (2006)](https://doi.org/10.1073/pnas.0508996103)

[Platten et al., Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond (2019) (2019)](https://doi.org/10.1038/s41573-019-0016-5)

[Guillemin et al., Quinolinic acid in the pathogenesis of Alzheimer's disease (2005) (2005)](https://doi.org/10.1007/978-0-387-30172-1_11)

[Dantzer et al., From inflammation to sickness and depression (2008) (2008)](https://doi.org/10.1038/nrn2297)

[Campbell et al., Kynurenines in CNS disease: regulation by inflammatory cytokines (2014) (2014)](https://doi.org/10.3389/fnins.2014.00012)

[Unknown, Maddison & Bhatt, Kynurenine pathway metabolism and neurodegeneration (2016) (2016)](https://doi.org/10.1016/B978-0-12-802472-3.00006-5)

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Related Entities

IDO1PROTEIN

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slug	proteins-ido1-protein
kg_node_id	IDO1PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c6f09f9a94a4
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-ido1-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

23

Outgoing

24

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IDO1 Protein

IDO1 Protein

IDO1 Protein

IDO1 Protein

Overview

Structure

Overall Architecture

Heme-Binding Site

Substrate Binding

Inhibitor Binding Sites

Catalytic Mechanism

Reaction

Mechanism Steps

Kinetic Properties

Function in Kynurenine Pathway

Downstream Metabolites

Tryptophan Depletion Effects

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Protein-Protein Interactions and Regulation

See Also

External Links

References

💬 Discussion