PAHX

PAHX

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PAHX</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PAHX</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Peroxisomal 2-Hydroxyacyl-CoA Lyase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>10p13</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>55627</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000107882</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NXK5</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

PAHX (Peroxisomal 2-Hydroxyacyl-CoA Lyase) is an essential enzyme in peroxisomal fatty acid metabolism, catalyzing the cleavage of 2-hydroxyacyl-CoA intermediates during peroxisomal beta-oxidation of branched-chain fatty acids. This enzyme is crucial for the metabolism of phytanic acid and pristanic acid, dietary branched-chain fatty acids that cannot be processed by mitochondria. PAHX deficiency leads to Refsum disease, a peroxisomal inherited disorder characterized by accumulation of phytanic acid in tissues, causing progressive neurological damage including retinitis pigmentosa, peripheral neuropathy, ataxia, and hearing loss. [@wanders2001]

Gene Information

Function

Enzyme Activity and Substrate Specificity

PAHX

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PAHX</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PAHX</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Peroxisomal 2-Hydroxyacyl-CoA Lyase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>10p13</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>55627</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000107882</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NXK5</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

PAHX (Peroxisomal 2-Hydroxyacyl-CoA Lyase) is an essential enzyme in peroxisomal fatty acid metabolism, catalyzing the cleavage of 2-hydroxyacyl-CoA intermediates during peroxisomal beta-oxidation of branched-chain fatty acids. This enzyme is crucial for the metabolism of phytanic acid and pristanic acid, dietary branched-chain fatty acids that cannot be processed by mitochondria. PAHX deficiency leads to Refsum disease, a peroxisomal inherited disorder characterized by accumulation of phytanic acid in tissues, causing progressive neurological damage including retinitis pigmentosa, peripheral neuropathy, ataxia, and hearing loss. [@wanders2001]

Gene Information

Function

Enzyme Activity and Substrate Specificity

PAHX catalyzes the cleavage of 2-hydroxyacyl-CoA to form aldehydes and acetyl-CoA in the peroxisomal beta-oxidation pathway. This unique lyase activity distinguishes PAHX from other peroxisomal enzymes:

• Substrate specificity: Prefers 2-hydroxy branched-chain fatty acyl-CoA substrates
• Co-factor requirements: Requires CoA as a cofactor and produces acetyl-CoA as a product
• Cellular localization: Exclusively peroxisomal matrix enzyme
• Pathway position: Acts downstream of acyl-CoA oxidase in the beta-oxidation chain

This reaction is essential for completing the peroxisomal beta-oxidation of phytanic acid, which enters the peroxisome as phytanoyl-CoA. [@waterham2017]

Role in Peroxisomal Beta-Oxidation

PAHX plays a critical role in the peroxisomal beta-oxidation system, which handles:

• Branched-chain fatty acids: Phytanic acid, pristanic acid
• Dicarboxylic acids: Succinate derivatives
• Very long-chain fatty acids: C22+ fatty acids
• Bile acid intermediates: C27-bile acid intermediates

Disease Associations

Refsum Disease (PAHX-Related)

PAHX mutations cause autosomal recessive adult Refsum disease, a peroxisomal storage disorder characterized by impaired phytanic acid oxidation:

Clinical Features:

• Retinitis pigmentosa: Progressive retinal degeneration causing tunnel vision and night blindness
• Peripheral neuropathy: Demyelinating sensorimotor neuropathy affecting distal limbs
• Cerebellar ataxia: Truncal ataxia and gait disturbance
• Hearing loss: Progressive sensorineural hearing impairment
• Ichthyosis: Scaly skin appearance, particularly on extremities
• Anosmia: Loss of smell (often an early sign)

Treatment:

• Phytanic acid restriction: Low-phytanic acid diet (avoid dairy, ruminant fat, fish oils)
• Plasma exchange: For rapid phytanic acid reduction in severe cases
• Dietary counseling: Lifelong dietary management essential

Peroxisome Biogenesis Disorders

PAHX dysfunction may contribute to peroxisome biogenesis disorders (PBDs), a group of autosomal recessive disorders affecting peroxisome assembly:

• Zellweger syndrome: Most severe phenotype, lethal in infancy
• Neonatal adrenoleukodystrophy: Childhood-onset white matter disease
• Refsum disease (adult form): Adult-onset with slower progression

Alzheimer Disease

Peroxisomal dysfunction has been implicated in Alzheimer disease pathology:

• Reduced peroxisomal markers: Decreased PAHX and other peroxisomal enzymes in AD brain [@morita2022]
• Phytanic acid accumulation: Elevated phytanic acid in AD brain tissue
• Lipid alterations: Peroxisomes are essential for ether phospholipid synthesis, critical for myelin
• Oxidative stress: Peroxisomal dysfunction enhances ROS production

Parkinson Disease

Emerging evidence suggests peroxisomal dysfunction may play a role in PD:

• Phytanic acid metabolism: Altered phytanic acid in PD substantia nigra
• Peroxisomal numbers: Reduced peroxisomes in dopaminergic neurons
• Lipid dysregulation: Altered VLCFA metabolism in PD brain [@ito2024]

Expression

Tissue Distribution

PAHX is highly expressed in tissues with active peroxisomal metabolism:

• Liver: Highest expression - major site of peroxisomal fatty acid oxidation
• Kidney: Moderate expression
• Brain: Lower but significant expression
• Skeletal muscle: Moderate expression
• Heart: Lower expression
• Adipose tissue: Low expression

Brain Expression

In the brain, PAHX is expressed in:

• Neurons: Pyramidal cells in cortex and hippocampus
• Oligodendrocytes: High expression - myelin lipid synthesis
• Astrocytes: Moderate expression
• Microglia: Low baseline expression

• Cerebellum (Purkinje cells)
• Hippocampus (CA regions)
• Cerebral cortex (layer 5 neurons)
• Substantia nigra (dopaminergic neurons)

Therapeutic Implications

PAHX as a Therapeutic Target

• Enzyme replacement: Not currently feasible - requires peroxisomal targeting
• Gene therapy: AAV-mediated PAHX delivery under investigation
• Small molecule activators: Not current approach

Modulating Peroxisomal Function

• Peroxisome proliferators: Fibrates increase peroxisomal numbers and function
• Dietary intervention: Phytanic acid restriction is standard of care
• Antioxidants: N-acetylcysteine and CoQ10 may support peroxisomal function

Mermaid Diagram: Peroxisomal Beta-Oxidation Pathway

See Also

• [Refsum Disease](/diseases/refsum-disease)
• [Adrenoleukodystrophy](/diseases/adrenoleukodystrophy)
• [ABCD1](/genes/abcd1)
• [Peroxisomal Dysfunction](/mechanisms/peroxisomal-dysfunction)
• [Oligodendrocytes in Neurodegeneration](/cell-types/oligodendrocytes-neurodegeneration)

References