[^1]
[^2]
[^3]
| Gene | [IDO1](/genes/ido1) |
| UniProt |
P14902 |
| PDB |
2D0T, 5WMU |
| Mol. Weight |
~45 kDa (403 aa) |
| Localization |
Cytoplasm |
| Family |
Indoleamine 2,3-dioxygenase family (heme-containing oxidoreductase) |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), [Huntington's Disease](/diseases/huntingtons) |
IDO1 (Indoleamine 2,3-Dioxygenase 1) is a 45 kDa heme-containing cytoplasmic enzyme encoded by the 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 and astrocytes is massively upregulated by inflammatory cytokines, particularly IFN-γ. The resulting metabolic shift generates neurotoxic metabolites (quinolinic acid, 3-hydroxykynurenine) that drive excitotoxicity and oxidative stress in neurodegenerative diseases.
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).
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
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
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
L-Tryptophan + O₂ → N-Formylkynurenine
- 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
- 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
IDO1 initiates a metabolic cascade with divergent neurological outcomes:
Neuroprotective metabolite (astrocytic branch):
- Kynurenine → Kynurenic acid (KYNA) via kynurenine aminotransferases (KATs)
- KYNA: 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
- QUIN also: chelates Fe(II) generating hydroxyl radicals, promotes lipid peroxidation, promotes tau phosphorylation
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
- Protein synthesis effects: Reduced amino acid availability activates the integrated stress response (eIF2α phosphorylation)
IDO1 protein is a key mediator of AD neuroinflammation-neurodegeneration coupling:
- IDO1 immunoreactivity colocalizes with senile plaques and microglial clusters in AD cortex
- Quinolinic acid accumulates in neurofibrillary tangles
- The KYN/TRP ratio in CSF correlates with amyloid-β 42 levels and cognitive decline
- IDO1 knockout or inhibition reduces amyloid pathology and improves cognition in APP/PS1 mice
- Quinolinic acid promotes tau phosphorylation at AD-relevant epitopes (Thr231, Ser396) via NMDA-Ca²⁺-GSK3β cascade
In PD:
- IDO1 upregulation in nigral microglia following α-synuclein-mediated activation
- QUIN contributes to dopaminergic neurotoxicity via NMDA receptor activation on nigrostriatal 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)
The kynurenine pathway is severely dysregulated in HD:
- 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 |
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 |
Signaling inducer |
Reverse signaling in DCs |
| TGF-β |
Expression modulator |
Context-dependent regulation |
| AhR |
Positive feedback |
Kynurenine activates AhR → more IDO1 |