MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase)

<div class="infobox infobox-gene">

| 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)

<div class="infobox infobox-gene">

| 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

See Also

Related Pathways

• [One-Carbon Metabolism](/mechanisms/one-carbon-metabolism)
• [Folate Metabolism](/mechanisms/folate-metabolism)
• [Methionine Cycle](/mechanisms/methionine-metabolism)
• [DNA Methylation](/mechanisms/dna-methylation)
• [Homocysteine Metabolism](/mechanisms/homocysteine-metabolism)

Related Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Homocystinuria](/diseases/homocystinuria)
• [Cardiovascular Disease](/diseases/cardiovascular-disease)

Related Genes

• [MTRR (Methionine Synthase Reductase)](/genes/mtrr)
• [MTHFR (Methylenetetrahydrofolate Reductase](/genes/mthfr)
• [CBS (Cystathionine Beta Synthase](/genes/cbs)
• [SHMT1 (Serine Hydroxymethyltransferase](/genes/shmt1)

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)