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) stateKinetic 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
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 |
See Also
- [IDO1 Gene](/genes/ido1) — Encoding gene
- [Excitotoxicity](/mechanisms/excitotoxicity) — QUIN-mediated toxicity
- [Neuroinflammation](/mechanisms/neuroinflammation) — IDO1 induction context
- [Oxidative Stress](/mechanisms/oxidative-stress) — 3-HK-mediated damage
- [Tryptophan Metabolism](/mechanisms/tryptophan-metabolism) — Metabolic pathway
- [Microglial Activation](/cell-types/microglia-neuroinflammation) — Primary IDO1 source
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)