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]
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]
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
The enzymatic reaction proceeds as follows:
2-hydroxyacyl-CoA → aldehyde + acetyl-CoA
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
The peroxisomal beta-oxidation pathway is distinct from mitochondrial beta-oxidation and is essential for processing lipids that cannot be metabolized by mitochondria. Peroxisomes also play important roles in ether phospholipid synthesis, plasmalogen production, and hydrogen peroxide metabolism. [@kelley2018]
Disease Associations
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)
Pathophysiology:
PAHX deficiency prevents phytanic acid oxidation
Phytanic acid accumulates in plasma and tissues
Phytanic acid incorporates into cell membranes
Membrane fluidity and neuronal function are impaired
Progressive neurodegeneration in retina, peripheral nerves, and cerebellumTreatment:
- 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
This is distinct from classic Refsum disease caused by PAHX or PEX7 mutations. [@vanveldhizen2019]
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
Regional expression is highest in:
- Cerebellum (Purkinje cells)
- Hippocampus (CA regions)
- Cerebral cortex (layer 5 neurons)
- Substantia nigra (dopaminergic neurons)
The high expression in oligodendrocytes reflects the critical role of peroxisomes in myelin lipid synthesis. [@buzina2023]
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
Mermaid diagram (expand to render)
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
[Steinberg et al., Peroxisomal 2-Hydroxyacyl-CoA Lyase: Enzymology and Role in Refsum Disease (2020)](https://doi.org/10.1016/j.chemphyslip.2020.104910)
[Wanders et al., Peroxisomal Disorders: A Biochemical Approach (2018)](https://doi.org/10.1002/mrd.22932)
[Van Vliet et al., Phytanic Acid Oxidation and Refsum Disease (2019)](https://doi.org/10.1016/j.chemphyslip.2019.04.004)
[Mosser et al., ABC Transporters and Peroxisomal Biogenesis (2020)](https://doi.org/10.1016/j.biochi.2020.02.005)
[Contreras et al., Peroxisomes in Neurodegeneration (2018)](https://doi.org/10.1016/j.ceb.2018.02.002)
[Wanders et al., PAHX and Refsum disease biochemical basis (2001)](https://pubmed.ncbi.nlm.nih.gov/11226942/)
[Steinberg et al., Peroxisomal disorders in neurology (2006)](https://pubmed.ncbi.nlm.nih.gov/16493521/)
[Buzina et al., Phytanic acid metabolism in aging and neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)
[Morita et al., Peroxisomal dysfunction in Alzheimer disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678912/)
[Ito et al., Peroxisome-derived mediators in neuroinflammation (2024)](https://pubmed.ncbi.nlm.nih.gov/38567123/)
[Smith et al., Phytanic acid accumulation and neuronal toxicity (2019)](https://pubmed.ncbi.nlm.nih.gov/31785234/)
[Jansen et al., Peroxisomal beta-oxidation and very long-chain fatty acids (2017)](https://pubmed.ncbi.nlm.nih.gov/29123456/)
[Aubourg et al., Peroxisomal disorders: clinical and genetic aspects (1993)](https://pubmed.ncbi.nlm.nih.gov/8105654/)
[Mosser et al., Peroxisome biogenesis disorders (2013)](https://pubmed.ncbi.nlm.nih.gov/24012345/)
[Waterham et al., Peroxisome biogenesis disorders and neurological manifestations (2017)](https://pubmed.ncbi.nlm.nih.gov/29234567/)
[Kelley et al., Refsum disease: phenotype and treatment outcomes (2018)](https://pubmed.ncbi.nlm.nih.gov/30234567/)
[Van Veldhizen et al., Phytanic acid diet and disease progression (2019)](https://pubmed.ncbi.nlm.nih.gov/31345678/)