Folate
Vitamin B9—essential for one-carbon metabolism, DNA synthesis, and methylation. Critical during pregnancy and increasingly important to understand with MTHFR variants.
🌿 Folate vs. Folic Acid: A Critical Distinction
Folate (Natural)
- • Found naturally in food (leafy greens, liver, legumes)
- • Easily converted to active forms
- • No accumulation concerns
- • Works with natural metabolic pathways
Folic Acid (Synthetic)
- • Synthetic form used in supplements and fortification
- • Requires DHFR enzyme (slow in humans) for conversion
- • Can accumulate as unmetabolized folic acid (UMFA)
- • May mask B12 deficiency; potential concerns with excess
Methylfolate (5-MTHF) is the active, methylated form that bypasses MTHFR entirely— immediately bioavailable and preferred for supplementation, especially with MTHFR variants.
🔄 The Folate Cycle
The folate cycle is a system of interconversions that allow folate to carry and donate "one-carbon" units for various reactions. Think of it as a delivery service for molecular building blocks.
THF (Tetrahydrofolate)
The "empty carrier"—ready to pick up one-carbon units from amino acid metabolism.
5,10-Methylene-THF
Used for DNA synthesis (making thymidine). Also the substrate for MTHFR.
5-Methyl-THF (Methylfolate)
The methyl donor form. Gives its methyl to homocysteine (requires B12).
🧬 Core Functions
DNA Synthesis
Required for making thymidine (DNA base). Rapidly dividing cells need abundant folate.
Methylation Support
Methylfolate donates its methyl group to regenerate methionine and SAM-e.
Amino Acid Metabolism
Involved in histidine, serine, and glycine interconversions.
Neurotransmitter Support
Indirectly supports BH4 regeneration for serotonin and dopamine synthesis.
🥗 Food Sources
Excellent Sources
- • Liver (chicken, beef) - highest natural source
- • Dark leafy greens (spinach, kale, collards)
- • Legumes (lentils, black beans, chickpeas)
Good Sources
- • Asparagus, Brussels sprouts, broccoli
- • Avocado
- • Eggs
- • Beets
Note: Folate is heat-sensitive. Raw or lightly cooked vegetables retain more folate.
🧬 The MTHFR Connection
MTHFR (methylenetetrahydrofolate reductase) is the enzyme that converts 5,10-methylene-THF into methylfolate. Common genetic variants reduce this enzyme's efficiency:
C677T Variant
Heterozygous (one copy): ~30% reduced activity
Homozygous (two copies): ~60-70% reduced activity
A1298C Variant
Milder effect on methylfolate production.
May affect BH4 recycling more significantly.
Practical implication: With MTHFR variants, taking folic acid may not help much because the conversion to methylfolate is impaired. Supplementing directly with methylfolate (5-MTHF) bypasses this bottleneck.
🪤 The Methyl Trap
"Methyl trap" describes what happens when B12 is deficient: methylfolate accumulates because it can't donate its methyl group without B12. This creates a functional folate deficiency despite adequate folate intake.
This is why B12 and folate should be assessed and addressed together—they are metabolically inseparable.
🚨 Signs of Folate Deficiency
Blood & Energy
- • Megaloblastic anemia (large red blood cells)
- • Fatigue and weakness
- • Shortness of breath
Neurological & Mood
- • Depression and irritability
- • Cognitive difficulties
- • Elevated homocysteine (cardiovascular risk)
Physical Signs
- • Glossitis (smooth, sore tongue)
- • Mouth ulcers
- • Poor wound healing
Pregnancy
- • Neural tube defects (spina bifida, anencephaly)
- • Increased miscarriage risk
- • Low birth weight
Metabolic Connections
MTHFR
Converts methylenetetrahydrofolate to methylfolate—the rate-limiting step
Vitamin B12
B12 and methylfolate work together to power methylation
Methylation
Methylfolate is the primary folate form that donates methyl groups
Homocysteine
Folate (with B12) recycles homocysteine back to methionine
Vitamin B6
B6 is needed for folate cycle enzymes SHMT and CBS
Choline
Alternative methyl donor—can compensate for low folate