IDO1 — Indoleamine 2,3-Dioxygenase 1

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IDO1 — Indoleamine 2,3-Dioxygenase 1

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IDO1 — Indoleamine 2,3-Dioxygenase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IDO1 — Indoleamine 2,3-Dioxygenase 1</th>
</tr>
<tr> [@dantzer2008]
<td class="label">Symbol</td> [@platten2019]
<td><strong>IDO1</strong></td> [@lim2017]
</tr> [@campbell2014]
<tr>
<td class="label">Full Name</td>
<td>Indoleamine 2,3-Dioxygenase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>8p11.21</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3620" target="_blank">3620</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131203" target="_blank">ENSG00000131203</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/147435" target="_blank">147435</a></td>
</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">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), [Huntington's Disease](/diseases/huntingtons), Major Depression</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Microglia, [astrocytes](/entities/astrocytes), macrophages, dendritic cells</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Features</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Rate-limiting k

...

IDO1 — Indoleamine 2,3-Dioxygenase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IDO1 — Indoleamine 2,3-Dioxygenase 1</th>
</tr>
<tr> [@dantzer2008]
<td class="label">Symbol</td> [@platten2019]
<td><strong>IDO1</strong></td> [@lim2017]
</tr> [@campbell2014]
<tr>
<td class="label">Full Name</td>
<td>Indoleamine 2,3-Dioxygenase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>8p11.21</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3620" target="_blank">3620</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131203" target="_blank">ENSG00000131203</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/147435" target="_blank">147435</a></td>
</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">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), [Huntington's Disease](/diseases/huntingtons), Major Depression</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Microglia, [astrocytes](/entities/astrocytes), macrophages, dendritic cells</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Features</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Rate-limiting kynurenine pathway enzyme<br>IFN-γ–inducible<br>Produces neurotoxic quinolinic acid<br>Immune checkpoint</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 — Indoleamine 2,3-Dioxygenase 1

Overview

Mermaid diagram (expand to render)

IDO1 (Indoleamine 2,3-Dioxygenase 1) is a gene on chromosome 8p11.21 encoding the rate-limiting enzyme of the kynurenine pathway — the major route of tryptophan catabolism outside the liver. IDO1 catalyzes the oxidative cleavage of the indole ring of L-tryptophan to produce N-formylkynurenine, initiating a metabolic cascade that generates both neuroprotective metabolites (kynurenic acid) and neurotoxic metabolites (quinolinic acid, 3-hydroxykynurenine). In the brain, IDO1 is strongly induced in [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/cell-types/astrocytes) by [IFN-gamma](/proteins/ifn-gamma-protein) and other inflammatory signals, making it a critical link between [neuroinflammation](/mechanisms/neuroinflammation) and neurodegeneration across [Alzheimer's](/diseases/alzheimers-disease), [Parkinson's](/diseases/parkinsons-disease), [Huntington's](/diseases/huntingtons), and [ALS](/diseases/als).

> Key takeaway: IDO1 is the rate-limiting enzyme that diverts tryptophan into the kynurenine pathway during neuroinflammation. The resulting shift from serotonin production to neurotoxic quinolinic acid production drives excitotoxicity, oxidative stress, and neuronal death across multiple neurodegenerative diseases.

Gene Structure and Expression

Genomic Organization

IDO1 spans approximately 15 kb on chromosome 8p11.21, comprising 10 exons encoding a 403-amino acid heme-containing oxidoreductase. IDO1 is located adjacent to IDO2 (which has similar but weaker enzymatic activity). The gene promoter contains multiple interferon-stimulated response elements (ISREs) and GAS elements, reflecting its strong inducibility by interferons.

Brain Expression Pattern

IDO1 expression in the CNS is minimal under basal conditions but dramatically upregulated during inflammation:

[Microglia](/cell-types/microglia-neuroinflammation): Primary source of brain IDO1; produces the neurotoxic branch metabolites (quinolinic acid, 3-OH-kynurenine)
[Astrocytes](/cell-types/astrocytes): Express IDO1 and preferentially produce the neuroprotective metabolite kynurenic acid (via KAT enzymes)
Perivascular macrophages: High IDO1 induction at [blood-brain barrier](/entities/blood-brain-barrier)
[Neurons](/entities/neurons): Low/absent IDO1 expression; neurons are consumers, not producers, of kynurenine metabolites

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=IDO1).

Transcriptional Regulation

IDO1 is one of the most strongly interferon-inducible genes:

IFN-γ (primary inducer): Activates IDO1 transcription via JAK/STAT1 pathway → GAS elements in promoter
IFN-α/β: Type I interferons also induce IDO1 via ISRE elements
[TNF-α](/genes/tnf): Synergizes with IFN-γ for maximal IDO1 induction
[NF-κB](/genes/nfkb1): Inflammatory signaling upregulates IDO1
[TLR4](/genes/tlr4): LPS and DAMPs (including [HMGB1](/genes/hmgb1)) induce IDO1 through TLR signaling
Aryl hydrocarbon receptor (AhR): Kynurenine itself activates AhR, which further upregulates IDO1 (positive feedback loop)

Function

Enzymatic Activity

IDO1 catalyzes the first and rate-limiting step of the kynurenine pathway:

L-Tryptophan + O₂ → N-Formylkynurenine

The enzyme:

Uses molecular oxygen and a heme cofactor
Has a catalytic mechanism involving superoxide radical intermediates
Shows Michaelis-Menten kinetics with Km ~20 μM for L-tryptophan
Is inhibited by 1-methyltryptophan (1-MT), the classic IDO inhibitor

The Kynurenine Pathway in Brain

IDO1 activation diverts tryptophan through the kynurenine pathway, generating metabolites with profoundly different neurological effects:

Neuroprotective branch (astrocytes):

L-Kynurenine → Kynurenic acid (KYNA) (via KAT enzymes)
KYNA is an [NMDA receptor](/entities/nmda-receptor) antagonist and α7-nicotinic receptor antagonist
KYNA is neuroprotective by reducing excitotoxicity

Neurotoxic branch (microglia):

L-Kynurenine → 3-Hydroxykynurenine (3-HK) → 3-Hydroxyanthranilic acid → Quinolinic acid (QUIN)
3-HK generates [reactive oxygen species](/entities/reactive-oxygen-species), causing [oxidative stress](/mechanisms/oxidative-stress)
QUIN is an NMDA receptor agonist that causes [excitotoxicity](/mechanisms/excitotoxicity)
QUIN generates free radicals through Fenton chemistry
QUIN promotes [tau](/proteins/tau) hyperphosphorylation

Immune Modulation

IDO1 also functions as an immune checkpoint:

Depletes tryptophan in the local microenvironment, inhibiting T cell proliferation
Generates kynurenine, which activates AhR on regulatory T cells (Tregs)
Creates an immunosuppressive milieu around inflammatory foci
This immune checkpoint function is exploited by tumors (hence IDO1 inhibitors in oncology)

Disease Associations

Alzheimer's Disease

IDO1 is centrally involved in [AD](/diseases/alzheimers-disease) through multiple mechanisms:

Upregulation: IDO1 expression and activity are markedly increased in AD [hippocampus](/brain-regions/hippocampus), temporal [cortex](/brain-regions/cortex), and frontal cortex compared to age-matched controls
Amyloid-β induction: [Aβ](/proteins/amyloid-beta-protein) oligomers directly induce IDO1 expression in microglia via [TLR4](/genes/tlr4) and IFN-γ signaling
Quinolinic acid accumulation: QUIN levels are elevated in AD brain regions, colocalizing with [neurofibrillary tangles](/mechanisms/neurofibrillary-tangles)
[Tau](/proteins/tau) phosphorylation: QUIN activates NMDA receptors, leading to calcium influx and activation of [GSK3β](/genes/gsk3b) and [CDK5](/genes/cdk5), promoting tau hyperphosphorylation
Serotonin depletion: Tryptophan diversion reduces serotonin synthesis, contributing to depression and behavioral symptoms in AD
KYN/TRP ratio biomarker: Elevated kynurenine-to-tryptophan ratio in CSF and plasma is a biomarker of neuroinflammation-driven tryptophan catabolism in AD

Parkinson's Disease

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

IDO1 is upregulated in [substantia nigra](/brain-regions/substantia-nigra) microglia
Quinolinic acid contributes to dopaminergic neuron excitotoxicity
3-HK generates ROS that exacerbate [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction) in dopaminergic neurons
[α-Synuclein](/proteins/alpha-synuclein) aggregates activate microglia and induce IDO1
IDO1 inhibition is neuroprotective in MPTP and 6-OHDA PD models

Huntington's Disease

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

Quinolinic acid levels are elevated in HD striatum, directly linking excitotoxicity to disease
Intrastriatal injection of QUIN reproduces HD-like striatal neurodegeneration in animal models
3-HK levels increase progressively with HD severity
The QUIN/KYNA ratio is shifted toward neurotoxicity in HD brain
IDO1 inhibition reduces striatal QUIN and improves phenotype in HD mice

ALS

In [amyotrophic lateral sclerosis](/diseases/als):

Kynurenine pathway activation in spinal cord microglia
Elevated QUIN in ALS motor cortex and spinal cord
Tryptophan metabolism alterations detectable in ALS patient plasma
IDO1 inhibition reduces motor neuron loss in SOD1 mouse models

Depression and Neuropsychiatric Symptoms

IDO1 activation directly links inflammation to depression:

Tryptophan depletion reduces serotonin (5-HT) synthesis
IFN-α therapy (for hepatitis C) induces IDO1 and causes depression in ~30% of patients
Depression in AD and PD patients correlates with IDO1 activation markers
This is the molecular basis of "sickness behavior" during infection

Expression

Induction Kinetics

| Stimulus | Cell Type | IDO1 Fold-Induction | Peak Time |
|---|---|---|---|
| IFN-γ | Microglia | 50-200× | 24-48 h |
| IFN-γ + TNF-α | Microglia | 200-500× | 24 h |
| LPS | Microglia | 10-50× | 12-24 h |
| [Aβ](/proteins/amyloid-beta) oligomers | Microglia | 5-20× | 48 h |
| α-Synuclein | Microglia | 5-15× | 48 h |
| IFN-γ | Astrocytes | 20-100× | 24-48 h |

Regional Distribution in Disease

In AD brains, IDO1 immunoreactivity is highest in:

Hippocampus (especially CA1, dentate gyrus)

[Entorhinal cortex](/brain-regions/entorhinal-cortex)

Temporal neocortex

Frontal cortex

Minimal in cerebellum (disease-resistant region)

Therapeutic Targeting

IDO1 Inhibitors

1-Methyltryptophan (1-MT): Classic competitive IDO1 inhibitor; both L- and D-isomers have been studied. Neuroprotective in multiple preclinical models.
Epacadostat (INCB024360): Selective, potent IDO1 inhibitor developed for oncology; being repurposed for neurodegeneration studies
Navoximod (GDC-0919): Another clinical-stage IDO1 inhibitor
BMS-986205 (linrodostat): Irreversible IDO1 inhibitor in clinical trials for cancer
Natural inhibitors: Berberine, curcumin, and certain flavonoids have IDO1 inhibitory activity

Kynurenine Pathway Modulators

KMO inhibitors: Block conversion of kynurenine to 3-HK, reducing both 3-HK and QUIN; Ro 61-8048, GSK180 are lead compounds
Kynurenic acid analogs: Synthetic KYNA derivatives that cross the BBB (KYNA itself has poor BBB penetration)
QPRT enhancers: Increase quinolinic acid phosphoribosyltransferase activity to clear QUIN

Clinical Relevance

IDO1 is a validated drug target in oncology with multiple clinical-stage inhibitors
Repurposing these inhibitors for neurodegenerative diseases is an active area of research
Biomarker-guided treatment (KYN/TRP ratio) could identify patients most likely to benefit
Combination with anti-inflammatory therapies may provide synergistic neuroprotection

External Links

[IDO1 at NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/3620)
[IDO1 at UniProt (P14902)](https://www.uniprot.org/uniprot/P14902)
[IDO1 at OMIM (147435)](https://omim.org/entry/147435)
[IDO1 at GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IDO1)
[Allen Brain Atlas — IDO1](https://human.brain-map.org/microarray/search/show?search_term=IDO1)
[KEGG: Tryptophan Metabolism](https://www.genome.jp/kegg-bin/show_pathway?hsa00380)

References

[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)

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

[Widner et al., Tryptophan degradation and immune activation in Alzheimer's disease (2000) (2000)](https://doi.org/10.1136/jnnp.68.6.778)

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

[Dantzer et al., From inflammation to sickness and depression: when the immune system subjugates the brain (2008) (2008)](https://doi.org/10.1038/nrn2297)

[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)

[Lim et al., Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression (2017) (2017)](https://doi.org/10.1038/s41598-017-12138-y)

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

Pathway Diagram

The following diagram shows the key molecular relationships involving IDO1 — Indoleamine 2,3-Dioxygenase 1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

IDO1

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ido1
kg_node_id	IDO1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-f8aa64c860a4
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ido1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

25

Outgoing

29

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IDO1 — Indoleamine 2,3-Dioxygenase 1

IDO1 — Indoleamine 2,3-Dioxygenase 1

IDO1 — Indoleamine 2,3-Dioxygenase 1

IDO1 — Indoleamine 2,3-Dioxygenase 1

Overview

Gene Structure and Expression

Genomic Organization

Brain Expression Pattern

Transcriptional Regulation

Function

Enzymatic Activity

The Kynurenine Pathway in Brain

Immune Modulation

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

ALS

Depression and Neuropsychiatric Symptoms

Expression

Induction Kinetics

Regional Distribution in Disease

Therapeutic Targeting

IDO1 Inhibitors

Kynurenine Pathway Modulators

Clinical Relevance

See Also

External Links

References

Pathway Diagram

💬 Discussion