What does the MTHFR (Methylenetetrahydrofolate Reductase) protein do?

MTHFR Protein Function and Metabolic Significance

The MTHFR (Methylenetetrahydrofolate Reductase) protein is a key enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as the primary methyl donor in the remethylation of homocysteine to methionine, playing a critical role in folate metabolism, cardiovascular health, and methylation processes throughout the body. 1

Core Functions of MTHFR

MTHFR functions as a central enzyme in the folate cycle with two primary metabolic pathways:

1. Remethylation Pathway:

   • Converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF)
   • 5-MTHF serves as the active form of folate required for homocysteine remethylation
   • Requires important cofactors including:
     • Methylcobalamin (vitamin B12)
     • Riboflavin (vitamin B2)
     • Betaine 1

2. Trans-sulfuration Pathway:

   • Involves the conversion of homocysteine to cystathionine and ultimately to cysteine
   • Requires cofactors:
     • Pyridoxal phosphate (vitamin B6)
     • Riboflavin 1

Biochemical Significance

• MTHFR plays a central role in one-carbon metabolism which is essential for:

  • DNA and RNA synthesis
  • Amino acid metabolism
  • Methylation reactions throughout the body 2, 3

• The folate cycle facilitated by MTHFR is critical for:

  • Nucleic acid precursor synthesis
  • Metabolism of several amino acids
  • Production of S-adenosylmethionine (SAM), the universal methyl donor for numerous methylation reactions 2

Clinical Implications of MTHFR Dysfunction

MTHFR Polymorphisms

MTHFR gene has several common polymorphisms that affect enzyme function:

1. C677T Variant:

   • Results in an alanine-to-valine substitution at codon 222
   • Creates a thermolabile enzyme with reduced activity
   • Population frequencies vary (e.g., 40.4% CC, 46.6% CT, 13.0% TT in Canada) 1, 4

2. A1298C Variant:

   • Results in a glutamate-to-alanine substitution
   • Also reduces enzyme activity but to a lesser extent than C677T 1, 5

Homocysteine Elevation and Cardiovascular Risk

• MTHFR deficiency can lead to hyperhomocysteinemia, an independent risk factor for cardiovascular disease 2, 1

• Elevated homocysteine is associated with:

  • 2-3 fold increased risk for atherosclerotic vascular disease
  • Endothelial dysfunction
  • Increased oxidative stress
  • Pro-thrombotic state 2, 6

• Homocysteine severity levels are categorized as:

  • Moderate (15-30 μmol/L)
  • Intermediate (30-100 μmol/L)
  • Severe (>100 μmol/L) 2, 1

Neurological Implications

MTHFR deficiency affects neurotransmitter levels in the brain:

• Alters levels of glutamate and γ-aminobutyric acid (GABA) in the cerebellum and hippocampus
• Reduces glutamate levels in the amygdala and GABA in the thalamus
• May affect neurological function through homocysteine's excitatory mechanisms via N-methyl-D-aspartate receptor activation 7

Clinical Management Considerations

For individuals with MTHFR deficiency or polymorphisms:

• B-vitamin supplementation may reduce cardiovascular risk by lowering homocysteine levels:

  • Methylcobalamin or hydroxycobalamin (0.5-1 mg daily)
  • Folic acid (0.5-5 mg daily) or 5-methyltetrahydrofolate 2, 1

• Folate status is crucial:

  • Individuals with thermolabile MTHFR may have higher folate requirements
  • Plasma folate levels ≥15.4 nmol/L may help normalize homocysteine levels even in those with MTHFR polymorphisms 6

• Special considerations:

  • 5-methyltetrahydrofolate may be more effective than folic acid for those with MTHFR variants
  • Certain medications (antiepileptics, metformin, oral contraceptives, NSAIDs) can affect folate metabolism 1

Implications Beyond Cardiovascular Health

MTHFR function has been implicated in:

• Pregnancy complications and neural tube defects
• Cancer risk (including breast cancer, gliomas, and gastric cancer)
• Psychiatric conditions
• Renal disease 1, 5

MTHFR's central role in folate metabolism and methylation processes makes it a critical enzyme with wide-ranging effects on human health and disease.