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.
| Attribute | Value |
|---|---|
| Gene Symbol | MTRR |
| Full Name | 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase |
| Chromosomal Location | 5p15.31 |
| NCBI Gene ID | 4552 |
| OMIM ID | 602568 |
| Ensembl ID | ENSG00000124275 |
| UniProt ID | Q9UQ50 |
MTRR (~726 amino acids, ~80 kDa) is a flavoprotein that catalyzes the reductive methylation of cobalamin, essential for methionine synthase (MTR) activity:
MTRR operates through a flavin-mediated electron transfer process:
MTRR functions in the methionine cycle, linking folate metabolism to homocysteine re-methylation:
MTRR is central to one-carbon metabolism:
| Disorder | Mechanism | Evidence |
|---|---|---|
| Homocystinuria | Impaired homocysteine re-methylation leads to elevated homocysteine | [3] |
| Megaloblastic anemia | Reduced methionine synthase activity affects DNA synthesis | Clinical observation |
| Neural tube defects | Folate/homocysteine metabolism disruption in embryonic development | [4] |
| Cardiovascular disease | Elevated homocysteine damages vascular endothelium | [5] |
| Alzheimer's Disease | Elevated homocysteine promotes neurotoxicity and reduced methylation | [6] |
| Parkinson's Disease | Homocysteine may exacerbate dopaminergic neuron stress | Indirect evidence |
| Vascular Cognitive Impairment | Hyperhomocysteinemia contributes to vascular dementia | [7] |
The MTRR A66G polymorphism (rs1801394) is one of the most studied variants:
Elevated homocysteine levels (hyperhomocysteinemia) are a recognized risk factor for AD through multiple mechanisms:
Neurotoxicity:
Epigenetic Dysregulation:
Vascular Damage:
Homocysteine elevation in PD may exacerbate dopaminergic neuron vulnerability:
Hyperhomocysteinemia is associated with:
B vitamin supplementation may help reduce homocysteine:
Folate
↓
5-Methyltetrahydrofolate
↓
MTRR ← FAD, FMN, NADPH
↓
Cobalamin (CoII)
↓
┌─────────────────────────┐
↓ ↓
Homocysteine Methionine
↓ ↓
└───────→ SAM ←───────────┘
↓
Methylation reactions
(DNA, proteins, lipids, neurotransmitters)
Olteanu H, et al. MTRR catalyzes cobalamin reduction for methionine synthase. 2007. ↩︎
Lu SC, et al. S-adenosylmethionine in brain function and disease. 2021. ↩︎
Wilson et al. MTRR variants and neural tube defects. American Journal of Human Genetics. 1999. ↩︎
Goya L, et al. MTRR and homocysteine metabolism in neurodegeneration. 2010. ↩︎
Obeid R, et al. Homocysteine as a risk factor for neurodegeneration. 2019. ↩︎
Smith AD, et al. Folate and B12 status in Alzheimer's disease. 2021. ↩︎
Hassan A, et al. Homocysteine and vascular cognitive impairment. 2020. ↩︎
Parker AM, et al. MTRR A66G polymorphism and disease risk. 2018. ↩︎
Sachdev PS, et al. Homocysteine and neuropsychiatric disorders. 2006. ↩︎