FA2H Protein

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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.

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FA2H Protein — Fatty Acid 2-Hydroxylase

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 correlations

Background

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

[1] 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/)

[2] 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/)

[3] 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/)

[4] 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/)

[5] 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/)

[6] 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/)

[7] 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/)

[8] 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/)

FA2H Protein

FA2H Protein — Fatty Acid 2-Hydroxylase

Introduction

FA2H Protein — Fatty Acid 2-Hydroxylase

Introduction

Overview

Structure

Catalytic Center

Expression Pattern

Molecular Function

Catalytic Reaction

Substrate Specificity

Biological Importance

Role in Disease

Hereditary Spastic Paraplegia (SPG35)

Leukodystrophy

Alzheimer's Disease

Parkinson's Disease

Therapeutic Approaches

Animal Models

Research Directions

Background

References

See Also