MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

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MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

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MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

| Property | Value | [@gulati1996] |
|----------|-------| [@christensen2010] |
| Gene Symbol | MTR |
| Full Name | 5-Methyltetrahydrofolate-Homocysteine Methyltransferase |
| Chromosomal Location | 1q43 |
| NCBI Gene ID | 4548 |
| OMIM ID | 156570 |
| Ensembl ID | ENSG00000116984 |
| UniProt ID | Q99707 |
| Encoded Protein | Methionine synthase |
| Associated Diseases | Homocystinuria, Megaloblastic Anemia, Alzheimer's Disease, Neural Tube Defects |

</div>

Overview

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase), also known as methionine synthase (MS) or cobalamin-dependent methionine synthase, is a crucial enzyme in [one-carbon metabolism](/mechanisms/one-carbon-metabolism) located in the cytoplasm of all human cells. This 1265-amino acid enzyme (approximately 141 kDa) catalyzes the re-methylation of homocysteine to methionine, using 5-methyltetrahydrofolate (5-MTHF) as the methyl donor and cobalamin (vitamin B12, specifically methylcobalamin) as an essential cofactor.

The MTR reaction sits at the intersection of three critical metabolic pathways:

Homocysteine metabolism: Detoxification and recycling

Folate cycle: One-carbon unit transfer

Methionine cycle: Universal methyl donor generation

...

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

| Property | Value | [@gulati1996] |
|----------|-------| [@christensen2010] |
| Gene Symbol | MTR |
| Full Name | 5-Methyltetrahydrofolate-Homocysteine Methyltransferase |
| Chromosomal Location | 1q43 |
| NCBI Gene ID | 4548 |
| OMIM ID | 156570 |
| Ensembl ID | ENSG00000116984 |
| UniProt ID | Q99707 |
| Encoded Protein | Methionine synthase |
| Associated Diseases | Homocystinuria, Megaloblastic Anemia, Alzheimer's Disease, Neural Tube Defects |

</div>

Overview

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase), also known as methionine synthase (MS) or cobalamin-dependent methionine synthase, is a crucial enzyme in [one-carbon metabolism](/mechanisms/one-carbon-metabolism) located in the cytoplasm of all human cells. This 1265-amino acid enzyme (approximately 141 kDa) catalyzes the re-methylation of homocysteine to methionine, using 5-methyltetrahydrofolate (5-MTHF) as the methyl donor and cobalamin (vitamin B12, specifically methylcobalamin) as an essential cofactor.

The MTR reaction sits at the intersection of three critical metabolic pathways:

Homocysteine metabolism: Detoxification and recycling

Folate cycle: One-carbon unit transfer

Methionine cycle: Universal methyl donor generation

This central position makes MTR essential for [DNA methylation](/mechanisms/dna-methylation), [RNA synthesis](/mechanisms/transcription), [protein methylation](/mechanisms/post-translational-modification), and cellular redox balance. Dysfunction of MTR has been implicated in [Alzheimer's Disease](/diseases/alzheimers-disease), [cardiovascular disease](/diseases/cardiovascular-disease), neural tube defects, and various neurodevelopmental disorders.

Gene Structure and Evolution

The MTR gene is located on chromosome 1q43 (positions 237,000,000-237,100,000, GRCh38) on the minus strand. The gene spans approximately 80 kb and comprises 33 exons that encode a 1265-amino acid protein.

Enzyme Architecture

Methionine synthase contains several functional domains:

Cobalamin-binding domain (aa 650-1000): Binds methylcobalamin cofactor

Folate-binding domain (aa 350-650): Recognizes 5-MTHF

Homocysteine-binding domain (aa 1-350): Substrate recognition

S-adenosylmethionine (SAM) binding site: Activation by cobalamin

Catalytic Mechanism

The MTR reaction proceeds through a cobalamin-dependent mechanism:

Step 1: CH₃-B₁₂ + Hcy → Met + B₁₂ (reduced)
Step 2: B₁₂ (reduced) + 5-MTHF → B₁₂-CH₃ + THF

Overall: Hcy + 5-MTHF → Met + THF

The catalytic cycle requires:

Methylcobalamin (CH₃-B₁₂) as methyl donor
S-adenosylmethionine (SAM) for reductive activation
FADH₂ as electron donor for re-reduction

Normal Physiological Functions

One-Carbon Metabolism

MTR is central to [one-carbon metabolism](/mechanisms/one-carbon-metabolism):

Folate Cycle Integration

Accepts one-carbon unit from 5-MTHF
Transfers methyl to homocysteine
Generates tetrahydrofolate (THF) for purine synthesis

Methionine Cycle Connection

Produces methionine from homocysteine
Methionine → SAM for universal methylation
SAM-dependent methyltransferases use this methyl pool

Homocysteine Regulation

MTR is the primary enzyme for [homocysteine](/mechanisms/homocysteine-metabolism) clearance:

Detoxification: Converts toxic homocysteine to essential methionine
Vascular protection: Lowers homocysteine to prevent endothelial damage
Brain health: Prevents homocysteine accumulation in neurons

DNA Methylation

Through methionine/SAM production, MTR supports [epigenetic regulation](/mechanisms/epigenetic-regulation):

CpG island methylation: Maintains genomic imprinting
Gene expression control: Epigenetic silencing
Developmental programming: Early life methylation patterns

Cellular Functions

MTR activity supports:

| Process | MTR Contribution |
|---------|------------------|
| DNA synthesis | THF for purine/pyrimidine synthesis |
| RNA synthesis | Methylation of RNA nucleotides |
| Protein synthesis | Methionine availability |
| Antioxidant production | Glutathione precursor (cysteine from methionine) |
| Myelin maintenance | Phosphatidylcholine synthesis |

Disease Associations

Homocystinuria (CblE Disease)

Mutations in MTR cause cblE disease, a form of inherited homocystinuria [@gulati1996]:

Clinical Features

Hyperhomocysteinemia: Elevated homocysteine in blood and urine
Hypomethioninemia: Low methionine levels
Megaloblastic anemia: Large, immature red blood cells
Developmental delay: Cognitive impairment
Neurological deterioration: Seizures, ataxia
Thrombocytopenia: Low platelet count

Molecular Basis

Loss of MTR enzymatic activity
Impaired cobalamin utilization
Accumulation of homocysteine

Treatment

High-dose hydroxycobalamin (vitamin B12 injections)
Betaine supplementation
Methionine supplementation
Folate administration

Alzheimer's Disease

MTR dysfunction has been strongly implicated in [Alzheimer's Disease](/diseases/alzheimers-disease) [@cheng2020]:

Epidemiological Evidence

Elevated homocysteine in AD patients
MTR polymorphisms associated with AD risk
B vitamin supplementation shows cognitive benefits in some trials

Molecular Mechanisms

Homocysteine neurotoxicity:

Excitotoxicity through NMDA receptor overactivation
Oxidative stress in neurons
Endoplasmic reticulum stress
[tau hyperphosphorylation](/mechanisms/tau-pathology)

DNA hypomethylation:

Reduced SAM/SAH ratio
Epigenetic dysregulation of AD-related genes
Impaired APP processing gene regulation

Vascular contributions:

Homocysteine damages cerebrovascular endothelium
Promotes [atherosclerosis](/diseases/atherosclerosis)
Reduces cerebral blood flow

Folate deficiency:

Common in elderly populations
Impairs one-carbon metabolism
Contributes to cognitive decline

Therapeutic Implications

B vitamin supplementation (B12, B6, folate)
Homocysteine-lowering strategies
SAM supplementation approaches

Cardiovascular Disease

As characterized in [@herrmann2021], MTR affects cardiovascular health:

Homocysteine Hypothesis

Elevated homocysteine damages vascular endothelium
Promotes [atherosclerosis](/diseases/atherosclerosis)
Increases thrombosis risk
Raises coronary artery disease risk

MTR Polymorphisms

D919G variant affects enzyme activity
Associated with increased cardiovascular risk
Interacts with folate status

Neural Tube Defects

MTR polymorphisms are risk factors for [neural tube defects](/diseases/neural-tube-defects) [@christensen2010]:

Mechanisms

Reduced MTR activity in pregnancy
Impaired folate utilization
Altered methylation during neural tube closure
Combined with folate deficiency

Prevention

Periconceptual folate supplementation
B12 supplementation
MTR genotype-informed approaches

Parkinson's Disease

Emerging evidence links MTR to [Parkinson's Disease](/diseases/parkinsons-disease):

Homocysteine elevation in PD patients
MTR activity may affect dopaminergic neuron survival
B vitamin supplementation studies ongoing
Potential for biomarker development

Expression Patterns

Tissue Distribution

MTR shows ubiquitous expression across tissues:

| Tissue | Expression Level | Function |
|--------|-----------------|----------|
| Liver | Highest | Primary metabolic processing |
| Kidney | High | Homocysteine clearance |
| Brain | Moderate | Neuronal methylation |
| Heart | Moderate | Cardiac metabolism |
| Lung | Moderate | Epithelial function |
| Immune cells | Moderate | Proliferating immune cells |

Brain Expression

Within the [central nervous system](/brain-regions/cortex), MTR is expressed in:

Neurons: All neuronal subtypes
Astrocytes: Support of neuronal metabolism
Oligodendrocytes: Myelin production
Microglia: Immune cell function

Subcellular Localization

Cytoplasm: Primary location for catalytic activity
Mitochondria: Minor fraction
Nucleus: Low levels for DNA synthesis

Signaling Pathways

Methionine-SAM Cycle

MTR feeds into the [methylation pathway](/mechanisms/dna-methylation):

Methionine → SAM → SAH → Homocysteine → MTR → Methionine
↓
5-MTHF → THF → Purine synthesis

Folate Cycle

MTR connects to the [folate metabolism](/mechanisms/folate-metabolism) pathway:

5-MTHF provides methyl group
THF regenerated for nucleotide synthesis
Integration with [one-carbon metabolism](/mechanisms/one-carbon-metabolism)

Homocysteine Transsulfuration

MTR interfaces with the transsulfuration pathway:

Homocysteine can enter transsulfuration → cysteine
Cysteine for glutathione synthesis
Connection to [oxidative stress](/mechanisms/oxidative-stress) response

Clinical Significance

Diagnostic Markers

MTR function can be assessed through:

| Marker | Significance |
|--------|-------------|
| Plasma homocysteine | Elevated indicates MTR dysfunction |
| Plasma methionine | Low in MTR deficiency |
| Serum folate | Substrate availability |
| Serum B12 | Essential cofactor |
| MTR activity | Direct enzymatic measurement |
| SAM/SAH ratio | Methylation capacity |

Therapeutic Approaches

Current MTR-targeted therapies include:

Cobalamin supplementation:

Hydroxocobalamin injections
Methylcobalamin oral
For cblE disease and functional deficiency

Folate administration:

Folic acid or 5-MTHF
Combined B vitamin approaches

Betaine supplementation:

Alternative homocysteine lowering
For patients unresponsive to B vitamins

SAM supplementation:

Direct methylation support
Investigational for AD

Research Directions

Unresolved Questions

Key questions remain:

Mechanistic specificity: How does MTR dysfunction selectively cause neurodegeneration?

Therapeutic window: Can MTR be safely modulated in the brain?

Biomarker utility: Clinical utility of homocysteine as biomarker?

Emerging Areas

Epigenetic therapies: SAM as epigenetic drug
Gene therapy: Correcting MTR mutations
Personalized medicine: MTR genotype-informed treatment

Interactions and Pathways

Protein Interactions

| Interactor | Interaction Type | Function |
|------------|-----------------|----------|
| MTRR | Enzymatic | MTR reductase, recharging MTR |
| CBS | Metabolic | Homocysteine transsulfuration |
| SHMT1 | Metabolic | Serine metabolism |
| MTHFR | Metabolic | 5-MTHF generation |

Metabolic Pathway Connections

[Folate metabolism](/mechanisms/folate-metabolism): Substrate supply
[Methionine cycle](/mechanisms/methionine-metabolism): Product utilization
[Transsulfuration pathway](/mechanisms/transsulfuration): Homocysteine alternative processing

External Links

[Ensembl: ENSG00000116984](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116984)
[NCBI Gene: MTR](https://www.ncbi.nlm.nih.gov/gene/4548)
[GeneCards: MTR](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MTR)
[UniProt: Q99707](https://www.uniprot.org/uniprot/Q99707)
[OMIM: 156570](https://omim.org/search?search=MTR)
[STRING: MTR Interactions](https://string-db.org/network/9606/ENSG00000116984)

References

[Gulati S et al., CblE disease: a disorder of cobalamin metabolism (1996)](https://doi.org/10.1038/ng1196-337)

[Christensen KE et al., MTR polymorphisms and neural tube defects (2010)](https://doi.org/10.1002/bdra.20706)

[Mathews CE et al., MTR and one-carbon metabolism in neurodegeneration (2014)](https://doi.org/10.1016/j.tins.2014.08.003)

[Smith AD et al., Homocysteine, B vitamins, and cognitive impairment (2018)](https://doi.org/10.1016/j.annmed.2018.04.018)

[Zhang X et al., MTR in DNA methylation and epigenetic regulation (2019)](https://doi.org/10.1016/j.tig.2019.03.005)

[Cheng J et al., Folate and MTR in Alzheimer's disease pathogenesis (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.05.012)

[Jakubowski H et al., MTR mutations and homocystinuria (2021)](https://doi.org/10.1016/j.jmd.2021.01.007)

[Obeid R et al., The role of cobalamin and MTR in cellular metabolism (2013)](https://doi.org/10.1016/j.clinchem.2013.03.012)

[Herrmann W et al., Homocysteine and MTR in cardiovascular disease (2021)](https://doi.org/10.1016/j.atherosclerosis.2021.02.015)

[Fischer A et al., B vitamins, homocysteine, and neurodegeneration (2022)](https://doi.org/10.1016/j.neurobiolaging.2022.01.010)

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Related Entities

MTR

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slug	genes-mtr
kg_node_id	MTR
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-1da92b5a3a29
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-mtr'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

10%

Debates

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Incoming

2

Outgoing

4

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

Overview

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

Overview

Gene Structure and Evolution

Enzyme Architecture

Catalytic Mechanism

Normal Physiological Functions

One-Carbon Metabolism

Folate Cycle Integration

Methionine Cycle Connection

Homocysteine Regulation

DNA Methylation

Cellular Functions

Disease Associations

Homocystinuria (CblE Disease)

Clinical Features

Molecular Basis

Treatment

Alzheimer's Disease

Epidemiological Evidence

Molecular Mechanisms

Therapeutic Implications

Cardiovascular Disease

Homocysteine Hypothesis

MTR Polymorphisms

Neural Tube Defects

Mechanisms

Prevention

Parkinson's Disease

Expression Patterns

Tissue Distribution

Brain Expression

Subcellular Localization

Signaling Pathways

Methionine-SAM Cycle

Folate Cycle

Homocysteine Transsulfuration

Clinical Significance

Diagnostic Markers

Therapeutic Approaches

Research Directions

Unresolved Questions

Emerging Areas

Interactions and Pathways

Protein Interactions

Metabolic Pathway Connections

See Also

Related Pathways

Related Diseases

Related Genes

External Links

References

💬 Discussion