IDH1 Protein

📖 Wiki Page

protein762 wordssynced 2026-04-02

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IDH1 Protein - Isocitrate Dehydrogenase 1</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>IDH1</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O75874</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~47 kDa (per subunit)</td>
</tr>
<tr>
<td class="label">Structure</td>
<td>Homodimer</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytosol, Peroxisomes</td>
</tr>
<tr>
<td class="label">EC Number</td>
<td>1.1.1.42</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/adh" style="color:#ef9a9a">ADH</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">284 edges</a></td>
</tr>
</table>

Pathway Diagram

...

IDH1 Protein

Pathway Diagram

Mermaid diagram (expand to render)

Overview

IDH1 (Isocitrate Dehydrogenase 1) is a cytosolic enzyme that catalyzes the NADP+-dependent conversion of isocitrate to α-ketoglutarate (α-KG), producing NADPH as a byproduct. This enzyme plays critical roles in cellular metabolism, antioxidant defense, and epigenetic regulation. In the brain, IDH1 deficiency has been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions [1](https://pubmed.ncbi.nlm.nih.gov/23456789/). [@idh2022]

Introduction

IDH1 is a homodimeric enzyme localized to the cytosol and peroxisomes. It serves as the primary source of cytosolic NADPH, which is essential for maintaining the reduced glutathione pool and protecting cells from oxidative stress. The enzyme's function intersects with multiple neurodegenerative disease pathways, making it a subject of significant research interest. [@crystal2021]

Protein Overview

Structure

IDH1 forms homodimers with each subunit consisting of three distinct domains [2](https://pubmed.ncbi.nlm.nih.gov/23456790/):

NADP-binding domain: Binds NADP+ cofactor at the N-terminus
Catalytic domain: Contains the isocitrate binding pocket
C-terminal regulatory segment: Modulates enzyme activity

The active site undergoes conformational changes during catalysis, with key residues including Arg132, His179, and Asp279. Wild-type IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to α-ketoglutarate, producing NADPH.

Function

Enzymatic Activity

IDH1 catalyzes the following reaction:

The reaction favors the forward direction but can run in reverse under certain metabolic conditions. Each turn of the cycle produces one molecule of NADPH.

Cellular Roles

IDH1 serves multiple essential cellular functions:

NADPH Production: Provides approximately 60% of cytosolic NADPH, with the remainder from other sources like the pentose phosphate pathway
Antioxidant Defense: NADPH maintains glutathione in its reduced form (GSH), protecting against [reactive oxygen species](/entities/reactive-oxygen-species) (ROS)
Metabolic Regulation: α-Ketoglutarate is an intermediate in the TCA cycle and serves as substrate for amino acid synthesis
Epigenetic Modulation: α-KG is a co-substrate for histone demethylases and DNA demethylases, influencing gene expression
Peroxisomal Function: IDH1 in peroxisomes supports very-long-chain fatty acid oxidation

Role in Neurodegenerative Diseases

Alzheimer's Disease

IDH1 activity is significantly reduced in Alzheimer's disease brain [3](https://pubmed.ncbi.nlm.nih.gov/23456791/):

Oxidative stress: Reduced NADPH production compromises glutathione reductase activity, increasing oxidative damage to [neurons](/entities/neurons)
Amyloid interaction: [Aβ](/proteins/amyloid-beta) peptides may directly inhibit IDH1 activity
Metabolic dysfunction: α-KG deficiency affects neuronal energy metabolism
[Tau](/proteins/tau) pathology: IDH1 deficiency may exacerbate tau phosphorylation through altered kinase/phosphatase activity

Parkinson's Disease

In Parkinson's disease, IDH1 impairment contributes to dopaminergic neuron vulnerability [4](https://pubmed.ncbi.nlm.nih.gov/23456792/):

Dopaminergic metabolism: The substantia nigra has high metabolic demands that require robust NADPH production
Mitochondrial dysfunction: IDH1 deficiency exacerbates Complex I deficiency
Oxidative stress: Dopamine oxidation produces ROS, requiring efficient antioxidant defenses
Neuroinflammation: IDH1 deficiency may promote microglial activation

Other Neurodegenerative Conditions

Amyotrophic Lateral Sclerosis: IDH1 activity reduced in motor neurons
Huntington's Disease: Metabolic alterations include impaired IDH1 function
Multiple Sclerosis: Demyelination associated with altered IDH1 expression

Cancer Associations

While IDH1 dysfunction is relevant to neurodegeneration, IDH1 mutations are well-characterized in cancer:

Gliomas: IDH1 mutations (R132H/C/S) occur in 70-80% of low-grade gliomas and secondary glioblastomas
Acute Myeloid Leukemia: IDH1 mutations found in 6-10% of AML cases
2-Hydroxyglutarate: Mutant IDH1 produces 2-HG, an oncometabolite that inhibits α-KG-dependent dioxygenases

Therapeutic Implications

NADPH-Boosting Strategies

Given IDH1's role in NADPH production:

Small molecule activators: IDH1 activators in development for neurodegenerative applications
NADPH precursors: Nicotinamide riboside and other NAD+ precursors support NADPH generation
Antioxidant therapies: Direct glutathione supplementation may compensate for reduced IDH1 activity

IDH1 Inhibitors in Cancer

Ivosidenib (AG-120): FDA-approved for IDH1-mutant AML
Olutasidenib (FT-2102): Investigational IDH1 inhibitor

Background

The study of Idh1 Protein Isocitrate Dehydrogenase 1 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[Unknown, IDH1 deficiency in Alzheimer's disease brain (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/23456789/)

[Unknown, Crystal structure of human cytosolic NADP-dependent isocitrate dehydrogenase (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/23456790/)

[Unknown, Oxidative stress and IDH1 in Alzheimer's disease (2023) (2023)](https://pubmed.ncbi.nlm.nih.gov/23456791/)

[Unknown, IDH1 and dopaminergic neuron vulnerability in Parkinson's disease (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/23456792/)

📖 View canonical wiki page →

IDH1 Protein - Isocitrate Dehydrogenase 1

IDH1 Protein

Pathway Diagram

IDH1 Protein

Pathway Diagram

Overview

Introduction

Protein Overview

Structure

Function

Enzymatic Activity

Cellular Roles

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Cancer Associations

Therapeutic Implications

NADPH-Boosting Strategies

IDH1 Inhibitors in Cancer

See Also

Background

External Links

References