| 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 |
MTR (5-Methyltetrahydrofolate-Homocysteine Methyltransferase), also known as methionine synthase (MS) or cobalamin-dependent methionine synthase, is a crucial enzyme in 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, RNA synthesis, protein methylation, and cellular redox balance. Dysfunction of MTR has been implicated in Alzheimer's Disease, 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.
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
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
MTR is central to one-carbon metabolism:
- Accepts one-carbon unit from 5-MTHF
- Transfers methyl to homocysteine
- Generates tetrahydrofolate (THF) for purine synthesis
- Produces methionine from homocysteine
- Methionine → SAM for universal methylation
- SAM-dependent methyltransferases use this methyl pool
MTR is the primary enzyme for homocysteine clearance:
- Detoxification: Converts toxic homocysteine to essential methionine
- Vascular protection: Lowers homocysteine to prevent endothelial damage
- Brain health: Prevents homocysteine accumulation in neurons
Through methionine/SAM production, MTR supports epigenetic regulation:
- CpG island methylation: Maintains genomic imprinting
- Gene expression control: Epigenetic silencing
- Developmental programming: Early life methylation patterns
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 |
Mutations in MTR cause cblE disease, a form of inherited homocystinuria [@gulati1996]:
- 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
- Loss of MTR enzymatic activity
- Impaired cobalamin utilization
- Accumulation of homocysteine
- High-dose hydroxycobalamin (vitamin B12 injections)
- Betaine supplementation
- Methionine supplementation
- Folate administration
MTR dysfunction has been strongly implicated in Alzheimer's Disease [@cheng2020]:
- Elevated homocysteine in AD patients
- MTR polymorphisms associated with AD risk
- B vitamin supplementation shows cognitive benefits in some trials
-
Homocysteine neurotoxicity:
- Excitotoxicity through NMDA receptor overactivation
- Oxidative stress in neurons
- Endoplasmic reticulum stress
- tau hyperphosphorylation
-
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
- Reduces cerebral blood flow
-
Folate deficiency:
- Common in elderly populations
- Impairs one-carbon metabolism
- Contributes to cognitive decline
- B vitamin supplementation (B12, B6, folate)
- Homocysteine-lowering strategies
- SAM supplementation approaches
As characterized in [@herrmann2021], MTR affects cardiovascular health:
- Elevated homocysteine damages vascular endothelium
- Promotes atherosclerosis
- Increases thrombosis risk
- Raises coronary artery disease risk
- D919G variant affects enzyme activity
- Associated with increased cardiovascular risk
- Interacts with folate status
MTR polymorphisms are risk factors for neural tube defects [@christensen2010]:
- Reduced MTR activity in pregnancy
- Impaired folate utilization
- Altered methylation during neural tube closure
- Combined with folate deficiency
- Periconceptual folate supplementation
- B12 supplementation
- MTR genotype-informed approaches
Emerging evidence links MTR to Parkinson's Disease:
- Homocysteine elevation in PD patients
- MTR activity may affect dopaminergic neuron survival
- B vitamin supplementation studies ongoing
- Potential for biomarker development
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 |
Within the central nervous system, MTR is expressed in:
- Neurons: All neuronal subtypes
- Astrocytes: Support of neuronal metabolism
- Oligodendrocytes: Myelin production
- Microglia: Immune cell function
- Cytoplasm: Primary location for catalytic activity
- Mitochondria: Minor fraction
- Nucleus: Low levels for DNA synthesis
MTR feeds into the methylation pathway:
Methionine → SAM → SAH → Homocysteine → MTR → Methionine
↓
5-MTHF → THF → Purine synthesis
MTR connects to the folate metabolism pathway:
- 5-MTHF provides methyl group
- THF regenerated for nucleotide synthesis
- Integration with one-carbon metabolism
MTR interfaces with the transsulfuration pathway:
- Homocysteine can enter transsulfuration → cysteine
- Cysteine for glutathione synthesis
- Connection to oxidative stress response
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 |
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
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?
- Epigenetic therapies: SAM as epigenetic drug
- Gene therapy: Correcting MTR mutations
- Personalized medicine: MTR genotype-informed treatment
¶ Interactions and Pathways
| Interactor |
Interaction Type |
Function |
| MTRR |
Enzymatic |
MTR reductase, recharging MTR |
| CBS |
Metabolic |
Homocysteine transsulfuration |
| SHMT1 |
Metabolic |
Serine metabolism |
| MTHFR |
Metabolic |
5-MTHF generation |
- Gulati S et al., CblE disease: a disorder of cobalamin metabolism (1996)
- Christensen KE et al., MTR polymorphisms and neural tube defects (2010)
- Mathews CE et al., MTR and one-carbon metabolism in neurodegeneration (2014)
- Smith AD et al., Homocysteine, B vitamins, and cognitive impairment (2018)
- Zhang X et al., MTR in DNA methylation and epigenetic regulation (2019)
- Cheng J et al., Folate and MTR in Alzheimer's disease pathogenesis (2020)
- Jakubowski H et al., MTR mutations and homocystinuria (2021)
- Obeid R et al., The role of cobalamin and MTR in cellular metabolism (2013)
- Herrmann W et al., Homocysteine and MTR in cardiovascular disease (2021)
- Fischer A et al., B vitamins, homocysteine, and neurodegeneration (2022)