IMPDH2 Protein

IMPDH2 Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IMPDH2 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>IMPDH2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Inosine Monophosphate Dehydrogenase 2</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P12282</td>
</tr>
<tr>
<td class="label">PDB Structures</td>
<td>1ME7, 1B8O, 3L1N</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>55,640 Da</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, Nucleus</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>IMPDH family</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Mycophenolate mofetil</td>
<td>Non-competitive inhibition</td>
</tr>
<tr>
<td class="label">Ribavirin</td>
<td>NAD+ analog</td>
</tr>
<tr>
<td class="label">Tiazofurin</td>
<td>Competitive inhibition</td>
</tr>
<tr>
<td class="label">Mizoribine</td>
<td>Competitive inhibition</td>
</tr>
</table>

IMPDH2 (Inosine Monophosphate Dehydrogenase 2) is a rate-limiting enzyme in de novo purine nucleotide synthesis. It catalyzes the NAD-dependent oxidation of IMP to XMP, the committed step in GTP biosynthesis. IMPDH2 is essential for proliferating cells, including immune cells and neurons under stress [@brown2000].

IMPDH2 Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IMPDH2 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>IMPDH2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Inosine Monophosphate Dehydrogenase 2</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P12282</td>
</tr>
<tr>
<td class="label">PDB Structures</td>
<td>1ME7, 1B8O, 3L1N</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>55,640 Da</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, Nucleus</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>IMPDH family</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Mycophenolate mofetil</td>
<td>Non-competitive inhibition</td>
</tr>
<tr>
<td class="label">Ribavirin</td>
<td>NAD+ analog</td>
</tr>
<tr>
<td class="label">Tiazofurin</td>
<td>Competitive inhibition</td>
</tr>
<tr>
<td class="label">Mizoribine</td>
<td>Competitive inhibition</td>
</tr>
</table>

IMPDH2 (Inosine Monophosphate Dehydrogenase 2) is a rate-limiting enzyme in de novo purine nucleotide synthesis. It catalyzes the NAD-dependent oxidation of IMP to XMP, the committed step in GTP biosynthesis. IMPDH2 is essential for proliferating cells, including immune cells and neurons under stress [@brown2000].

The protein forms tetramers and is a key target for immunosuppressant and antiviral drugs. Recent research links IMPDH2 dysregulation to several neurodegenerative disorders, including [Alzheimer disease](/diseases/alzheimers-disease), [Parkinson disease](/diseases/parkinsons-disease), and retinitis pigmentosa.

Overview

IMPDH2 is a 514-amino acid enzyme that catalyzes the rate-limiting step in GTP synthesis. The enzyme is essential for cell proliferation and is particularly important in cells with high metabolic demand, including [neurons](/entities/neurons), immune cells, and photoreceptor cells.

Dysregulation of IMPDH2 contributes to neurodegenerative diseases through impaired purine metabolism, leading to nucleotide depletion and altered GTP-dependent signaling [@stolte2020].

Basic Information

Structure and Function

Molecular Architecture

IMPDH2 forms a tetrameric enzyme complex (approximately 220 kDa). Each monomer contains:

The enzyme undergoes conformational changes during catalysis, transitioning between active and inactive states based on GTP levels [@hedstrom2009].

Catalytic Mechanism

IMPDH2 catalyzes the two-step oxidation of IMP to XMP:

Tissue Distribution

• Brain: Moderate expression in cortex, hippocampus
• Retina: High expression in photoreceptors
• Immune system: High expression in proliferating immune cells
• Cellular localization: Cytoplasm

Role in Neurodegeneration

Retinitis Pigmentosa

IMPDH1/2 mutations cause autosomal dominant retinitis pigmentosa. Photoreceptor cells are particularly vulnerable to nucleotide imbalance due to their high metabolic demand for phototransduction [@bowne2002].

• Mechanism: Mutant IMPDH forms abnormal tetramers
• Phenotype: Progressive photoreceptor degeneration
• Onset: Adolescence to early adulthood

Alzheimer Disease

Impaired purine metabolism is increasingly recognized in [Alzheimer disease](/diseases/alzheimers-disease). Studies show altered IMPDH activity in AD brains, correlating with neurofibrillary tangle formation [@pietzsch2022]:

• GTP depletion: Affects tau phosphorylation through altered kinase activity
• Nucleotide imbalance: Impairs DNA repair
• Energy failure: Reduced GTP for mitochondrial function

Parkinson Disease

In [Parkinson disease](/diseases/parkinsons-disease), IMPDH dysregulation affects dopaminergic neurons:

• 6-OHDA models: Show IMPDH inhibition
• Nucleotide depletion: Contributes to neuronal vulnerability
• NAD+ metabolism: Linked to sirtuin activity

ALS and Motor Neuron Disease

Altered purine metabolism in motor neurons:

• IMPDH2 expression: Changes in ALS models
• Ribavirin trials: Tested in ALS (Phase 2 showed some benefit) [@siddle2018]
• Mycophenolate: Tested but not beneficial in Phase 3

Therapeutic Targeting

IMPDH Inhibitors

Several IMPDH inhibitors have been developed:

Clinical Trials in Neurodegeneration

• Ribavirin in ALS: Phase 2 trials showed some benefit but was discontinued [@siddle2018]
• Mycophenolate in ALS: Phase 3 showed no benefit
• Gene therapy: AAV-IMPDH for retinitis pigmentosa under development

Molecular Pathways

Research Gaps and Future Directions

Cross-References

• [IMPDH2 Gene](/genes/impdh2) - Gene page
• [Purine Metabolism](/mechanisms/purine-metabolism) - Related pathway
• [Retinitis Pigmentosa](/diseases/retinitis-pigmentosa) - Associated disease
• [Alzheimer Disease](/diseases/alzheimers-disease) - Related disease
• [Parkinson Disease](/diseases/parkinsons-disease) - Related disease
• [GTPase Signaling](/mechanisms/gtpase-signaling) - Downstream pathway
• [Tau Protein](/proteins/tau) - GTP-dependent phosphorylation

Key Publications

External Links

• [UniProt](https://www.uniprot.org/uniprot/P12282) - Protein database
• [PDB](https://www.rcsb.org/) - Structural data
• [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=IMPDH2+neurodegeneration) - Literature
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html) - Pathway database