ALDH1L1 Protein — Aldehyde Dehydrogenase 1 Family Member L1
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<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">ALDH1L1 Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Aldehyde Dehydrogenase 1 Family Member L1</td></tr>
<tr><td><strong>Gene</strong></td><td><a href="/genes/aldh1l1">ALDH1L1</a></td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/O95392">O95392</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~99 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Aldehyde dehydrogenase family</td></tr>
<tr><td><strong>Expression</strong></td><td>High in liver, [astrocytes](/entities/astrocytes) in brain</td></tr>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/glioma" style="color:#ef9a9a">Glioma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">42 edges</a></td>
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Overview
ALDH1L1 (Aldehyde Dehydrogenase 1 Family Member L1) is a cytosolic enzyme that plays a critical role in folate metabolism and one-carbon unit transfer. It serves as a specific marker for astrocytes in the central nervous system and is involved in converting 10-formyltetrahydrofolate to tetrahydrofolate, thereby regulating intracellular folate pools and one-carbon metabolism.<sup>[1]</sup>
Structure
ALDH1L1 is a multifunctional enzyme comprising three distinct domains:
- Formyltransferase domain: Binds 10-formyl-THF and transfers the formyl group
- Dehydrogenase domain: Catalyzes the oxidation of 10-formyl-THF to formate
- Ligase domain: Facilitates THF-dependent ligase activity
The enzyme forms a homotetramer in solution, with each subunit containing the three catalytic domains arranged in a modular fashion. The active site contains a conserved catalytic cysteine (Cys-296) essential for dehydrogenase activity.<sup>[2]</sup>
Normal Function
ALDH1L1 is a central regulator of folate-dependent one-carbon metabolism:
The enzyme catalyzes the irreversible conversion of 10-formyltetrahydrofolate (10-formyl-THF) to tetrahydrofolate (THF) and formate, effectively shuttleing one-carbon units from folate into the formate pool. This reaction is crucial for:
- de novo purine and thymidylate synthesis
- Homocysteine remethylation to methionine
- Methyl group donation for DNA and histone methylation
Astrocyte Marker
ALDH1L1 is highly expressed in astrocytes throughout the brain and serves as a reliable histological marker for astrocytic populations. Its expression is upregulated during reactive astrocytosis, making it useful in neuropathological studies.<sup>[3]</sup>
By regulating the 10-formyl-THF/THF balance, ALDH1L1 influences:
- Cellular NAD(P)H production through formate oxidation
- Methyl group availability for SAM-dependent methylation reactions
- Mitochondrial one-carbon metabolism
Role in Disease
Alzheimer's Disease
ALDH1L1 expression is significantly downregulated in [Alzheimer's disease](/diseases/alzheimers-disease) brains, particularly in regions affected by neurodegeneration such as the [hippocampus](/brain-regions/hippocampus) and prefrontal [cortex](/brain-regions/cortex).<sup>[4]</sup> This reduction may contribute to:
- Folate metabolism impairment: Decreased THF availability affects homocysteine remethylation, leading to elevated homocysteine levels—a known risk factor for AD<sup>[5]</sup>
- [DNA methylation](/entities/dna-methylation) deficits: Reduced SAM/SAH ratio compromises DNA and histone methylation, potentially affecting synaptic plasticity gene expression
- Astrocytic dysfunction: Loss of ALDH1L1-positive astrocytes correlates with disease severity
Therapeutic approaches targeting folate metabolism, including supplementation with folate and B vitamins, have shown some promise in slowing cognitive decline in AD patients with elevated homocysteine.<sup>[6]</sup>
Amyotrophic Lateral Sclerosis (ALS)
ALDH1L1 is altered in ALS motor cortex and spinal cord, where astrocytic dysfunction plays a key role in disease progression. The enzyme's downregulation may contribute to:
- Metabolic stress in motor [neurons](/entities/neurons)
- Impaired detoxification of aldehydes
- Dysregulated one-carbon metabolism affecting DNA repair
Cancer
ALDH1L1 functions as a tumor suppressor in several cancers, including hepatocellular carcinoma, pancreatic cancer, and glioblastoma. Its expression is often lost during tumorigenesis, and re-expression can reduce tumor growth through:
- Metabolic vulnerability: Depleting 10-formyl-THF pools needed for rapid proliferation
- Increased oxidative stress: Altering NAD(P)H production
- Cell cycle arrest: Affecting nucleotide synthesis
Therapeutic Implications
Folate-Targeted Therapies
ALDH1L1 represents a potential therapeutic target in both neurodegeneration and cancer. In neurodegeneration, enhancing ALDH1L1 activity or folate metabolism may be beneficial, while in cancer, inhibiting the enzyme may selectively target rapidly dividing cells.
Biomarker Potential
ALDH1L1 autoantibodies have been detected in some cancer patients, suggesting potential as a paraneoplastic marker. In the brain, ALDH1L1 expression changes may serve as a biomarker for astrocytic pathology.
Key Publications
[Krupenko et al., J Biol Chem (2000)](https://pubmed.ncbi.nlm.nih.gov/10699111/): ALDH1L1 enzymatic properties and folate metabolism role
[M. T. McDerment et al., Chem Biol (2012)](https://doi.org/10.1016/j.chembiol.2012.09.011): Crystal structure of ALDH1L1 catalytic domains
[Cahoy et al., J Neurosci (2008)](https://pubmed.ncbi.nlm.nih.gov/18199764/): ALDH1L1 as astrocyte marker in transcriptome profiling
[Fischer et al., J Neurochem (2016)](https://pubmed.ncbi.nlm.nih.gov/26743233/): ALDH1L1 downregulation in AD brain
[Smith et al., Lancet Neurol (2008)](https://pubmed.ncbi.nlm.nih.gov/18565358/): Homocysteine, folate, and cognitive decline in ADReferences
<sup>[1]</sup> [ALDH1L1: A folate enzyme with multiple functions (2009)](https://pubmed.ncbi.nlm.nih.gov/19374208/)
<sup>[2]</sup> [Crystal structure of human ALDH1L1 (2012)](https://doi.org/10.1016/j.jmb.2012.02.014)
<sup>[3]</sup> [A transcriptome database for astrocytes, neurons, and oligodendrocytes (2008)](https://pubmed.ncbi.nlm.nih.gov/18199764/)
<sup>[4]</sup> [Folate metabolism dysfunction in neurodegenerative disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26743233/)
<sup>[5]</sup> [Homocysteine as a risk factor for cognitive impairment (2008)](https://pubmed.ncbi.nlm.nih.gov/18565358/)
<sup>[6]</sup> [B vitamins and cognitive decline: HOMAGE study (2019)](https://pubmed.ncbi.nlm.nih.gov/30642943/)
See Also
- ALDH1L1 Gene
- Folate Metabolism
- [Astrocytes in Neurodegeneration](/cell-types/astrocytes)
- One-Carbon Metabolism
- Homocysteine and Neurodegeneration
External Links
- [UniProt: aldh1l1](https://www.uniprot.org/)
- [PubMed: aldh1l1](https://pubmed.ncbi.nlm.nih.gov/?term=aldh1l1+neurodegeneration)