MTRR Gene

MTRR Gene

Overview

MTRR Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MTRR Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>MTRR</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5p15.31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>4552</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>602568</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000124275</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UQ50</td>
</tr>
<tr>
<td class="label">Disorder</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Homocystinuria</td>
<td>Impaired homocysteine re-methylation leads to elevated homocysteine</td>
</tr>
<tr>
<td class="label">Megaloblastic anemia</td>
<td>Reduced methionine synthase activity affects DNA synthesis</td>
</tr>
<tr>
<td class="label">Neural tube defects</td>
<td>Folate/homocysteine metabolism disruption in embryonic development</td>
</tr>
<tr>
<td class="label">Cardiovascular disease</td>
<td>Elevated homocysteine damages vascular endothelium</td>
</tr>
<tr>
<td class="label">Alzheimer's Disease</td>
<td>Elevated homocysteine promotes neurotoxicity and reduced methylation</td>
</tr>
<tr>
<td class="label">Parkinson's Disease</td>
<td>Homocysteine may exacerbate dopaminergic neuron stress</td>
</tr>
<tr>
<td class="label">Vascular Cognitive Impairment</td>
<td>Hyperhomocysteinemia contributes to vascular dementia</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">8 edges</a></td>
</tr>
</table>

MTRR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase) is a gene encoding the enzyme methionine synthase reductase, which plays a critical role in folate and homocysteine metabolism. MTRR is essential for the re-methylation of homocysteine to methionine, a crucial process for maintaining methylation balance in the brain. This enzyme is particularly important in the methionine cycle, where it regenerates cobalamin (vitamin B12) in its active form to support methionine synthase activity.

Gene Information

Protein Structure and Function

MTRR (~726 amino acids, ~80 kDa) is a flavoprotein that catalyzes the reductive methylation of cobalamin, essential for methionine synthase (MTR) activity:

• Cobalamin Regeneration: Reduces cobalamin (Co(III)) to cobalamin (Co(II)) to regenerate methionine synthase activity [@mtrr2007]
• Flavin Binding: Contains FAD and FMN cofactors for electron transfer
• Iron-Sulfur Cluster: Contains a [4Fe-4S] cluster essential for catalytic activity
• Domain Organization: Features a flavin reductase domain and a cobalamin-binding domain

Catalytic Mechanism

MTRR operates through a flavin-mediated electron transfer process:

Mechanism in Homocysteine Metabolism

MTRR functions in the methionine cycle, linking folate metabolism to homocysteine re-methylation:

One-Carbon Metabolism

MTRR is central to one-carbon metabolism:

• Folate Cycle: Provides methyl groups for homocysteine re-methylation
• Methionine Cycle: Generates SAM for methyltransferase reactions
• Transsulfuration Pathway: Converts homocysteine to cysteine for glutathione synthesis

Disease Associations

Neurological Disorders

MTRR Polymorphisms

The MTRR A66G polymorphism (rs1801394) is one of the most studied variants:

• Increased risk of neural tube defects in offspring
• Altered B12 metabolism affecting enzyme efficiency
• Potential neurological implications in aging
• Variable responses to folate supplementation
• Association with increased risk of several diseases [@mtrrpolymorphism2018]

Role in Neurodegeneration

Alzheimer's Disease

Elevated homocysteine levels (hyperhomocysteinemia) are a recognized risk factor for AD through multiple mechanisms:

Neurotoxicity:

• NMDA receptor activation leads to calcium influx and excitotoxicity
• Direct neuronal damage at elevated homocysteine levels
• Enhanced oxidative stress in neurons

• Reduced methylation of tau and APP genes affects protein expression
• DNA hypomethylation contributes to altered gene expression patterns
• Histone methylation changes affect chromatin structure

• Endothelial dysfunction contributes to cerebral hypoperfusion
• Increased risk of white matter lesions
• Contributes to vascular dementia component

Parkinson's Disease

Homocysteine elevation in PD may exacerbate dopaminergic neuron vulnerability:

• Mitochondrial Dysfunction: Homocysteine affects mitochondrial energy production
• Oxidative Stress: Elevated homocysteine increases reactive oxygen species
• Excitotoxicity: May enhance glutamate-induced neuronal damage
• Levodopa Interaction: Homocysteine may affect levodopa metabolism and efficacy

Depression and Neuropsychiatric Disorders

Hyperhomocysteinemia is associated with:

• Depression and mood disorders [@homocysteine2006]
• Cognitive impairment
• Schizophrenia (elevated homocysteine in some patients)
• Bipolar disorder

Therapeutic Implications

B Vitamin Supplementation

B vitamin supplementation may help reduce homocysteine:

• Vitamin B12: Direct cofactor for methionine synthase
• Vitamin B6: Required for transsulfuration pathway
• Folate: Provides methyl groups for re-methylation
• Riboflavin (B2): Cofactor for MTRR flavin binding

Clinical Considerations

• Plasma homocysteine as a biomarker for neurodegeneration risk
• Individual variation in response to supplementation
• Need for personalized approaches based on genetic variants

Therapeutic Strategies

MTRR in One-Carbon Metabolism Diagram

Folate
↓
5-Methyltetrahydrofolate
↓
MTRR ← FAD, FMN, NADPH
↓
Cobalamin (CoII)
↓
┌─────────────────────────┐
↓ ↓
Homocysteine Methionine
↓ ↓
└───────→ SAM ←───────────┘
↓
Methylation reactions
(DNA, proteins, lipids, neurotransmitters)

References

See Also

• [Homocysteine Metabolism](/mechanisms/homocysteine-metabolism)
• [Vitamin B12 Deficiency](/diseases/vitamin-b12-deficiency)
• [MTR Gene](/genes/mtr)
• [Folate Metabolism](/mechanisms/folate-metabolism)
• [Methylation](/mechanisms/dna-methylation)
• [One-Carbon Metabolism](/mechanisms/one-carbon-metabolism)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [S-Adenosylmethionine](/mechanisms/sam-metabolism)

External Links

• [NCBI Gene: MTRR](https://www.ncbi.nlm.nih.gov/gene/4552)
• [UniProt: MTRR](https://www.uniprot.org/uniprot/Q9UQ50)
• [GeneCards: MTRR](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MTRR)