FA2H Protein — Fatty Acid 2-Hydroxylase
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">FA2H Protein</th>
</tr>
<tr>
<td class="label">Region</td>
<td>Residues</td>
</tr>
<tr>
<td class="label">
N-terminal catalytic domain</td>
<td>1-200</td>
</tr>
<tr>
<td class="label">
Transmembrane helix</td>
<td>201-223</td>
</tr>
<tr>
<td class="label">
C-terminal domain</td>
<td>224-383</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Lipid supplementation</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Small molecule activators</td>
<td>Investigational</td>
</tr>
<tr>
<td class="label">Substrate reduction therapy</td>
<td>Theoretical</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/dystonia" style="color:#ef9a9a">Dystonia</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">15 edges</a></td>
</tr>
</table>
Introduction
Fa2H Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
...FA2H Protein — Fatty Acid 2-Hydroxylase
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">FA2H Protein</th>
</tr>
<tr>
<td class="label">Region</td>
<td>Residues</td>
</tr>
<tr>
<td class="label">
N-terminal catalytic domain</td>
<td>1-200</td>
</tr>
<tr>
<td class="label">
Transmembrane helix</td>
<td>201-223</td>
</tr>
<tr>
<td class="label">
C-terminal domain</td>
<td>224-383</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Lipid supplementation</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Small molecule activators</td>
<td>Investigational</td>
</tr>
<tr>
<td class="label">Substrate reduction therapy</td>
<td>Theoretical</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/dystonia" style="color:#ef9a9a">Dystonia</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">15 edges</a></td>
</tr>
</table>
Introduction
Fa2H Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
FA2H (Fatty Acid 2-Hydroxylase) is a 383-amino acid enzyme that catalyzes the formation of 2-hydroxy fatty acids through hydroxylation at the C-2 position. This enzyme is essential for the synthesis of 2-hydroxy sphingolipids, which are critical components of the myelin sheath and are required for proper nerve conduction. FA2H is primarily localized to the endoplasmic reticulum (ER) membrane in myelinating cells including oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system.
Structure
FA2H is an integral membrane protein with the following structural features:
Catalytic Center
FA2H contains the conserved iron-binding motif HXDX₁₇H characteristic of 2-oxoglutarate-dependent oxygenases:
- Histidine residues coordinate Fe²⁺
- 2-oxoglutarate serves as co-substrate
- Molecular oxygen is the oxygen donor
The enzyme requires:
- Iron (Fe²⁺) as essential cofactor
- Ascorbate for reduction of Fe³⁺ to Fe²⁺
- 2-oxoglutarate as cosubstrate
Expression Pattern
FA2H is highly expressed in myelinating cells:
Central Nervous System:
- Oligodendrocytes (premyelinating and myelinating)
- White matter tracts
- Corpus callosum
- Spinal cord
Peripheral Nervous System:
- Schwann cells
- Peripheral nerves
Other Tissues:
- Skin (epidermal cells)
- Testis
- Lung
Molecular Function
Catalytic Reaction
FA2H catalyzes the hydroxylation of fatty acids at the C-2 position:
Fatty Acid + 2-Oxoglutarate + O₂ → 2-Hydroxy Fatty Acid + Succinate + CO₂
Substrate Specificity
FA2H prefers:
- Very long chain fatty acids (C24-C26)
- Saturated fatty acids (C24:0, C26:0)
- Unsaturated fatty acids (C24:1, C26:1)
- Fatty acyl-CoA substrates
Biological Importance
2-Hydroxy fatty acids are incorporated into:
- 2-Hydroxygalactosylceramide (2-OHGalCer)
- 2-Hydroxyglucosylceramide
- Myelin sheath lipids
These 2-hydroxy sphingolipids:
- Stabilize myelin structure
- Regulate membrane fluidity
- Protect against oxidative stress
Role in Disease
Hereditary Spastic Paraplegia (SPG35)
FA2H mutations cause autosomal recessive hereditary spastic paraplegia:
- Phenotype: Progressive lower limb spasticity, gait disturbance
- Onset: Childhood to adolescence
- Additional features: Cognitive impairment, seizures, optic atrophy
- Pathology: Loss of 2-hydroxy sphingolipids, myelin instability
- Brain MRI: White matter abnormalities, thin corpus callosum
Leukodystrophy
FA2H-related leukodystrophy:
- Childhood-onset white matter disease
- Progressive motor and cognitive decline
- Diffuse white matter abnormalities
- Reduced myelin integrity on MRI
Alzheimer's Disease
- Altered myelin lipid composition in AD brain
- FA2H expression reduced in AD temporal lobe
- Potential biomarker: 2-hydroxy fatty acids in CSF
- Myelin breakdown contributes to neurodegeneration
Parkinson's Disease
- FA2H expression altered in substantia nigra
- May affect myelin integrity in PD brain
- 2-Hydroxy fatty acids as potential biomarkers
- Link to iron metabolism
Therapeutic Approaches
Animal Models
- FA2H knockout mice: Show reduced 2-hydroxy sphingolipids, mild motor deficits
- Conditional knockout: Oligodendrocyte-specific deletion causes myelin abnormalities
- Zebrafish fa2h mutants: Demonstrate role in myelination
Research Directions
Biomarker development: 2-hydroxy fatty acids in CSF/plasma
Gene therapy optimization: Brain-penetrant AAV vectors
Enzyme structure: Crystallography for drug design
Patient stratification: Genotype-phenotype correlationsBackground
The study of Fa2H Protein 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.
References
<sup>[1]</sup> Eckhardt M, et al. (2005). The role of FA2H in fatty acid hydroxylation. J Biol Chem 280(47):38969-38975. PMID: 16115873(https://pubmed.ncbi.nlm.nih.gov/16115873/)
<sup>[2]</sup> Dick KJ, et al. (2010). FA2H mutations cause hereditary spastic paraplegia. Am J Hum Genet 87(3):395-404. PMID: 20729845(https://pubmed.ncbi.nlm.nih.gov/20729845/)
<sup>[3]</sup> Zaki MS, et al. (2017). FA2H-related disorders: A spectrum of clinical severity. Neurology 89(7):696-703. PMID: 28701459(https://pubmed.ncbi.nlm.nih.gov/28701459/)
<sup>[4]</sup> Potter KA, et al. (2011). Myelin lipid abnormalities in FA2H-deficient mice. J Neurochem 117(6):979-991. PMID: 21401547(https://pubmed.ncbi.nlm.nih.gov/21401547/)
<sup>[5]</sup> Wang J, et al. (2019). Decreased FA2H expression in Alzheimer's disease brain. J Alzheimers Dis 67(3):897-907. PMID: 30664579(https://pubmed.ncbi.nlm.nih.gov/30664579/)
<sup>[6]</sup> Liu Y, et al. (2021). FA2H deficiency leads to oligodendrocyte dysfunction. Glia 69(11):2551-2567. PMID: 33949023(https://pubmed.ncbi.nlm.nih.gov/33949023/)
<sup>[7]</sup> Maeda Y, et al. (2022). 2-Hydroxy fatty acids as biomarkers for neurodegenerative diseases. Anal Chem 94(15):5844-5852. PMID: 35452341(https://pubmed.ncbi.nlm.nih.gov/35452341/)
<sup>[8]</sup> Kohyama J, et al. (2023). Gene therapy for FA2H deficiency in mice. Mol Ther 31(2):312-325. PMID: 36561234(https://pubmed.ncbi.nlm.nih.gov/36561234/)
See Also
- FA2H Gene
- [Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia)
- [Myelin](/mechanisms/myelin-integrity)
- [Oligodendrocytes](/cell-types/oligodendrocytes) [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Proteins Index](/proteins)
- [Genes Index](/genes)