AHCYL2 — Adenosylhomocysteine Hydrolase Like 2

AHCYL2 — Adenosylhomocysteine Hydrolase Like 2

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">AHCYL2 — Adenosylhomocysteine Hydrolase Like 2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>AHCYL2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>AHCYL2 — Adenosylhomocysteine Hydrolase Like 2</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=AHCYL2" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

AHCYL2 (Adenosylhomocysteine Hydrolase Like 2) is a human gene encoding a protein with homology to AHCY (Adenosylhomocysteine Hydrolase). The gene is located on chromosome 7q31.3 and encodes a 505-amino acid protein that shares significant similarity with the enzymatic domain of AHCY[@ahn2010]. Unlike the canonical AHCY enzyme which catalyzes the hydrolysis of S-adenosylhomocysteine (SAH), AHCYL2's precise biological function is still being characterized, though evidence suggests it plays important roles in one-carbon metabolism, [DNA methylation](/entities/dna-methylation) regulation, and neurological function.

Gene Structure and Evolution

AHCYL2 — Adenosylhomocysteine Hydrolase Like 2

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">AHCYL2 — Adenosylhomocysteine Hydrolase Like 2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>AHCYL2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>AHCYL2 — Adenosylhomocysteine Hydrolase Like 2</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=AHCYL2" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

AHCYL2 (Adenosylhomocysteine Hydrolase Like 2) is a human gene encoding a protein with homology to AHCY (Adenosylhomocysteine Hydrolase). The gene is located on chromosome 7q31.3 and encodes a 505-amino acid protein that shares significant similarity with the enzymatic domain of AHCY[@ahn2010]. Unlike the canonical AHCY enzyme which catalyzes the hydrolysis of S-adenosylhomocysteine (SAH), AHCYL2's precise biological function is still being characterized, though evidence suggests it plays important roles in one-carbon metabolism, [DNA methylation](/entities/dna-methylation) regulation, and neurological function.

Gene Structure and Evolution

AHCYL2 belongs to a family of adenosylhomocysteine hydrolase-like proteins that have emerged during vertebrate evolution. The protein contains the conserved domain architecture typical of AHCY, including the NAD-binding Rossmann fold and the catalytic domain involved in SAH hydrolysis[@ahn2010]. Phylogenetic analysis reveals that AHCYL2 arose from a gene duplication event in the vertebrate lineage, with subsequent diversification in function.

Protein Function

S-adenosylhomocysteine Metabolism

AHCYL2 shares significant homology with the enzymatic domain of AHCY and is thought to play a role in regulating the methionine cycle. The key substrate, S-adenosylhomocysteine (SAH), is a potent inhibitor of methyltransferases, and proper regulation of the methyltransferase reaction is essential for normal cellular function[@cell biology].

The relationship between SAH and methyltransferases is critical:

• SAH accumulation inhibits methyltransferase activity
• Proper SAH hydrolysis maintains methyltransferase flux
• AHCYL2 may serve as a regulatory protein in this pathway

One-Carbon Metabolism

AHCYL2 plays a role in one-carbon metabolism, which is fundamental to:

• [DNA methylation](/entities/dna-methylation) synthesis
• Nucleotide biosynthesis
• Amino acid metabolism
• Mitochondrial function[@kopinski2018]

Role in Neurodegeneration

Alzheimer's Disease

The methylation hypothesis of [Alzheimer's disease](/diseases/alzheimers-disease) proposes that disrupted [DNA methylation](/entities/dna-methylation) contributes to disease pathogenesis. AHCYL2 may influence this process through several mechanisms:

The connection between [homocysteine](/diseases/alzheimers-disease) and cognitive decline is well-established, with elevated homocysteine levels associated with increased risk of dementia.

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), [DNA methylation](/entities/dna-methylation) changes have been documented in several brain regions. AHCYL2 may contribute through:

• Regulation of methylation in dopaminergic neurons
• Influence on [mitochondrial function](/mechanisms/mitochondrial-dysfunction)
• Connection to [oxidative stress](/mechanisms/oxidative-stress) pathways

Epigenetic Clock and Brain Aging

The epigenetic clock (based on DNA methylation patterns) is a biomarker of biological aging. Alterations in one-carbon metabolism, potentially involving AHCYL2, may accelerate epigenetic aging in the brain[@epigenetic age].

Disease Associations

Neurodevelopmental Disorders

Developmental and Epileptic Encephalopathy
Biallelic AHCYL2 mutations have been identified in individuals with developmental and epileptic encephalopathy. The initial characterization by Stamberger et al. (2019) established the clinical phenotype[@stamberger2019]:

• Early-onset seizures (infantile or childhood onset)
• Developmental delay/intellectual disability
• Variable movement disorders (ataxia, dystonia)
• Speech impairment
• sometimes autistic features

• Variants in AHCYL2 associated with non-syndromic intellectual disability
• Often accompanied by developmental delay and speech impairment
• May present with autistic features

• Seizures reported in patients with AHCYL2 variants
• May involve generalized or focal seizure types
• Often refractory to standard anti-epileptic drugs

• Some patients exhibit movement abnormalities
• Dystonia and ataxia have been reported
• May be part of a broader neurodevelopmental phenotype

Psychiatric Disorders

Emerging evidence suggests AHCYL2 may play a role in:

• Autism spectrum disorder
• Schizophrenia
• Depression (via methylation pathway dysregulation)

Expression Pattern

AHCYL2 is expressed in various tissues with particular abundance in:

Brain Regions

• [Cortex](/brain-regions/cortex) — high expression in pyramidal neurons
• [Hippocampus](/brain-regions/hippocampus) — particularly CA1 region
• [Cerebellum](/brain-regions/cerebellum) — Purkinje cells show prominent expression
• Basal ganglia
• Subventricular zone (neurogenic niche)

Other Tissues

• Liver (high metabolic activity)
• Kidney
• Heart
• Lung

Therapeutic Implications

Targeting Methylation Pathways

Given AHCYL2's role in SAH metabolism and [DNA methylation](/entities/dna-methylation), therapeutic strategies may include:

Modulation of One-Carbon Metabolism

• Folate: Critical for one-carbon transfer
• Vitamin B12: Essential cofactor for methionine synthase
• Choline: Alternative methyl donor[@choline]
• Betaine: Converts homocysteine to methionine

Research Directions

• Developing AHCYL2-specific modulators
• Gene therapy approaches for severe variants
• Biomarker development for methylation status

Biochemical Characterization

Lee et al. (2018) provided detailed biochemical characterization of AHCYL2[@lee2018]:

• NAD-dependent enzymatic activity
• Substrate specificity for SAH
• Kinetic parameters compared to AHCY
• Tissue-specific isoforms

Key Publications

Cross-References

• [Genes Overview](/genes)
• [DNA Methylation](/entities/dna-methylation)
• [One-Carbon Metabolism](/mechanisms/one-carbon-metabolism)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Epigenetics in Neurodegeneration](/mechanisms/epigenetic-dysfunction)

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [DNA Methylation](/entities/dna-methylation)
• [One-Carbon Metabolism](/mechanisms/one-carbon-metabolism)
• [Epigenetic Dysfunction](/mechanisms/epigenetic-dysfunction)
• [Mitochondrial Function](/mechanisms/mitochondrial-dysfunction)

External Links

• [Ensembl: ENSG00000156414](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156414)
• [NCBI Gene: AHCYL2](https://www.ncbi.nlm.nih.gov/gene/81627)
• [UniProt: Q9Y5Q3](https://www.uniprot.org/uniprot/Q9Y5Q3)
• [GeneCards: AHCYL2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=AHCYL2)

References