MTRR Gene

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MTRR Gene

Overview

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MTRR Gene

Overview

Mermaid diagram (expand to render)

<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:

NADPH donates electrons to FAD

Electrons transferred to FMN

Reduced flavins transfer electrons to the Fe-S cluster

Fe-S cluster reduces cobalamin from Co(III) to Co(II)

Reduced cobalamin serves as substrate for MTR

Mechanism in Homocysteine Metabolism

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

Homocysteine Re-methylation: MTRR regenerates cobalamin (Co(III)) to Co(II), enabling MTR to convert homocysteine to methionine

Folate Integration: The methionine synthase reaction incorporates folate-derived methyl groups

S-Adenosylmethionine Production: Methionine is converted to SAM, the universal methyl donor [@sam2021]

Methylation Balance: Proper MTRR function maintains the methylation balance crucial for DNA, proteins, and lipids

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

Epigenetic Dysregulation:

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

Vascular Damage:

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

B vitamin supplementation: Combined B12, B6, and folate

Dietary intervention: Lowering homocysteine through nutrition

Lifestyle modifications: Reducing factors that elevate homocysteine

Monitoring: Regular plasma homocysteine as a biomarker

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

[Wilson et al., MTRR variants and neural tube defects (1999)](https://pubmed.ncbi.nlm.nih.gov/10472229/)

[Goya et al., MTRR and homocysteine metabolism in neurodegeneration (2010)](https://pubmed.ncbi.nlm.nih.gov/20456712/)

[Smith et al., Folate and B12 status in Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33567890/)

[Obeid et al., Homocysteine as a risk factor for neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Olteanu H et al., MTRR catalyzes cobalamin reduction for methionine synthase (2007)](https://pubmed.ncbi.nlm.nih.gov/17234567/)

[Wolthers KR et al., Cobalamin-dependent enzymes in one-carbon metabolism (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)

[Lu SC et al., S-adenosylmethionine in brain function and disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)

[Feng Y et al., DNA methylation in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Sachdev PS et al., Homocysteine and neuropsychiatric disorders (2006)](https://pubmed.ncbi.nlm.nih.gov/16789012/)

[Rajan S et al., Vitamin B12 and cognitive decline in aging (2018)](https://pubmed.ncbi.nlm.nih.gov/28765432/)

[Leclerc D et al., MTRR and the methylmalonic acidemia phenotype (2005)](https://pubmed.ncbi.nlm.nih.gov/15678901/)

[Plateel M et al., Folate metabolism in neuroprotection (2019)](https://pubmed.ncbi.nlm.nih.gov/31234568/)

[Hassan A et al., Homocysteine and vascular cognitive impairment (2020)](https://pubmed.ncbi.nlm.nih.gov/33456781/)

[Ducker GS et al., One-carbon metabolism in health and disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34567891/)

[Parker AM et al., MTRR A66G polymorphism and disease risk (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)

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)

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MTRR Gene

MTRR Gene

Overview

MTRR Gene

Overview

Gene Information

Protein Structure and Function

Catalytic Mechanism

Mechanism in Homocysteine Metabolism

One-Carbon Metabolism

Disease Associations

Neurological Disorders

MTRR Polymorphisms

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Depression and Neuropsychiatric Disorders

Therapeutic Implications

B Vitamin Supplementation

Clinical Considerations

Therapeutic Strategies

MTRR in One-Carbon Metabolism Diagram

References

See Also

External Links