GPX4 Protein - Glutathione Peroxidase 4

GPX4 Protein - Glutathione Peroxidase 4

Introduction

Gpx4 Protein Glutathione Peroxidase 4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

GPX4 Protein - Glutathione Peroxidase 4

Introduction

Gpx4 Protein Glutathione Peroxidase 4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@selenoproteins]
<table> [@ferroptosis]
<tr><th colspan="2" style="background:#f0f0f0;">Glutathione Peroxidase 4 (GPX4)</th></tr> [@lipid]
<tr><td><b>Protein Name</b></td><td>Glutathione Peroxidase 4 (GPX4)</td></tr>
<tr><td><b>Gene</b></td><td><a href="/genes/gpx4">GPX4</a></td></tr>
<tr><td><b>UniProt ID</b></td><td><a href="https://www.uniprot.org/uniprot/P36969">P36969</a></td></tr>
<tr><td><b>Alternative Names</b></td><td>Phospholipid Hydroperoxide GPX, PHGPx</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~19 kDa (monomer)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytosol, mitochondria, nucleus</td></tr>
<tr><td><b>Protein Family</b></td><td>Glutathione peroxidase family (Selenoprotein)</td></tr>
<tr><td><b>Structure</b></td><td>Tetramer of identical subunits</td></tr>
<tr><td><b>Catalytic Residue</b></td><td>Selenocysteine (Sec/U)</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/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1277 edges</a></td>
</tr>
</table>
</div>

Overview

Glutathione Peroxidase 4 (GPX4) is a unique member of the glutathione peroxidase family that catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols. Unlike other GPX enzymes that primarily reduce hydrogen peroxide and simple organic hydroperoxides, GPX4 directly reduces phospholipid and cholesterol hydroperoxides within cellular membranes, making it the central enzyme preventing ferroptosis.

Protein Structure

Quaternary Structure

• Homotetramer: Four identical subunits
• Monomer size: ~19 kDa
• Selenocysteine: Active site contains the 21st amino acid, selenocysteine (Sec)

Active Site

The selenocysteine at position 47 (Sec^47) is essential for catalytic activity:

• Selenol form (SeH) is the active nucleophile
• Higher nucleophilicity than cysteine
• Catalytic efficiency 100-1000x greater than cysteine analogs
• Explained by the "selenol effect" - lower pKa, higher polarizability

Structural Features

• Classic thioredoxin fold: Similar to other GPX family members
• Loop regions: Substrate access and binding
• Dimer interfaces: Critical for tetramer formation

Normal Function

Lipid Peroxide Reduction

GPX4 catalyzes the reduction of lipid hydroperoxides:

Substrate Specificity

GPX4 reduces various lipid peroxides:

• Phosphatidylcholine hydroperoxides (PC-OOH)
• Phosphatidylethanolamine hydroperoxides (PE-OOH)
• Cholesterol hydroperoxides (Chol-OOH)
• Triglyceride hydroperoxides

Cellular Protection

By reducing lipid peroxides, GPX4:

• Prevents membrane damage
• Blocks ferroptotic cell death
• Protects high-lipid cells ([neurons](/entities/neurons), sperm, etc.)
• Maintains redox signaling

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

• Activity reduced: GPX4 activity is decreased in ALS
• Motor neuron vulnerability: High lipid content makes motor neurons dependent on GPX4
• Lipid peroxidation: Elevated in ALS patients and models
• Therapeutic potential: GPX4 activators being explored

Parkinson's Disease

• Substantia nigra vulnerability: High iron + lipid content
• GPX4 decline: Expression decreases with age
• Dopaminergic neurons: Particularly susceptible to ferroptosis
• Iron chelation + GPX4: Combined therapeutic approach

Alzheimer's Disease

• [Aβ](/proteins/amyloid-beta)-induced peroxidation: Amyloid induces lipid peroxidation
• Neuronal loss: [Ferroptosis](/entities/ferroptosis) may contribute
• Age-related decline: GPX4 decreases with age
• Selenium status: Linked to AD risk

Therapeutic Targeting

Direct GPX4 Activators

| Compound | Mechanism | Stage | Notes |
|----------|-----------|-------|-------|
| Ferrostatin-1 | Lipid [ROS](/entities/reactive-oxygen-species) scavenger | Research | Prototype ferroptosis inhibitor |
| Liproxstatin-1 | GPX4 pathway stabilizer | Research | In vivo active |
| SRS | Small molecule activators | Discovery | Novel chemotypes |

Indirect Activation

| Strategy | Approach | Status |
|----------|----------|--------|
| Selenium supplementation | Increase Sec incorporation | Clinical trials |
| GSH precursors | NAC, NACET | Clinical |
| Iron chelation | Deferoxamine, Deferasirox | Approved |
| Vitamin E | Tocopherol supplementation | Supplements |

Protein Interactions

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| GSH | Substrate | Electron donor |
| GSR | Regeneration | GSSG reductase |
| SELENOP | Co-regulation | Selenoprotein synthesis |
| SLC7A11 | Metabolic link | Cystine/GSH axis |

Isoforms

GPX4 has multiple isoforms from alternative splicing:

• Cytosolic GPX4: Most abundant form
• Mitochondrial GPX4: Targeted to mitochondria
• Nuclear GPX4: Involved in transcription regulation

Key Publications

Background

The study of Gpx4 Protein Glutathione Peroxidase 4 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.

Pathway & Interaction Diagram

Interactive diagram showing GPX4's key relationships in the SciDEX knowledge graph (15 connections shown).

See Also

• [GPX4 Gene](/genes/gpx4)
• [SLC7A11 Protein](/genes/c7)
• [Ferroptosis Pathway](/entities/ferroptosis)
• [Oxidative Stress Pathway](/mechanisms/oxidative-stress)
• [ALS Proteins](/content/proteins)
• [Parkinson's Disease Proteins](/content/proteins)
• [Alzheimer's Disease Proteins](/content/proteins)

External Links

• [UniProt: P36969](https://www.uniprot.org/uniprot/P36969)
• [PDB: 2OBI (structure)](https://www.ebi.ac.uk/pdbe/entry/pdb/2obi)
• [AlphaFold Model](https://alphafold.ebi.ac.uk/entry/P36969)
• [GeneCards: GPX4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=GPX4)

References