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. [1]
| Attribute | Value | [2]
|-----------|-------| [3]
| Gene Symbol | PAHX | [4]
| Full Name | Peroxisomal 2-Hydroxyacyl-CoA Lyase | [5]
| Chromosomal Location | 10p13 | [6]
| NCBI Gene ID | 55627 | [7]
| Ensembl ID | ENSG00000107882 | [8]
| UniProt ID | Q9NXK5 | [9]
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:
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. [10]
PAHX plays a critical role in the peroxisomal beta-oxidation system, which handles:
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. [11]
PAHX mutations cause autosomal recessive adult Refsum disease, a peroxisomal storage disorder characterized by impaired phytanic acid oxidation:
Clinical Features:
Pathophysiology:
Treatment:
This is distinct from classic Refsum disease caused by PAHX or PEX7 mutations. [12]
PAHX dysfunction may contribute to peroxisome biogenesis disorders (PBDs), a group of autosomal recessive disorders affecting peroxisome assembly:
Peroxisomal dysfunction has been implicated in Alzheimer disease pathology:
Emerging evidence suggests peroxisomal dysfunction may play a role in PD:
PAHX is highly expressed in tissues with active peroxisomal metabolism:
In the brain, PAHX is expressed in:
Regional expression is highest in:
The high expression in oligodendrocytes reflects the critical role of peroxisomes in myelin lipid synthesis. [3:1]
Wanders et al. PAHX and Refsum disease biochemical basis (2001). 2001. ↩︎
Steinberg et al. Peroxisomal disorders in neurology (2006). 2006. ↩︎
Buzina et al. Phytanic acid metabolism in aging and neurodegeneration (2023). 2023. ↩︎ ↩︎
Morita et al. Peroxisomal dysfunction in Alzheimer disease (2022). 2022. ↩︎ ↩︎
Ito et al. Peroxisome-derived mediators in neuroinflammation (2024). 2024. ↩︎ ↩︎
Smith et al. Phytanic acid accumulation and neuronal toxicity (2019). 2019. ↩︎
Jansen et al. Peroxisomal beta-oxidation and very long-chain fatty acids (2017). 2017. ↩︎
Aubourg et al. Peroxisomal disorders: clinical and genetic aspects (1993). 1993. ↩︎
Mosser et al. Peroxisome biogenesis disorders (2013). 2013. ↩︎
Waterham et al. Peroxisome biogenesis disorders and neurological manifestations (2017). 2017. ↩︎
Kelley et al. Refsum disease: phenotype and treatment outcomes (2018). 2018. ↩︎
Van Veldhizen et al. Phytanic acid diet and disease progression (2019). 2019. ↩︎