🧬 Methylation and the folate cycle: MTHFR biochemistry and why folic acid may be toxic
How one letter in a gene affects the absorption of the most popular vitamin B9
Methylation is one of the most fundamental biochemical processes in the body. It is the transfer of a methyl group (-CH3) to DNA, proteins and other molecules. It regulates gene expression, neurotransmitter synthesis, detoxification, cell repair and homocysteine metabolism. Methylation disturbances are linked to fatigue, mood problems, cardiovascular risks and developmental defects.
At the center of this process is the folate cycle, where the enzyme MTHFR (methylenetetrahydrofolate reductase) works. It is around MTHFR and synthetic folic acid that much controversy has arisen. Below is a full breakdown: history, benefits, food sources, norms and the role of active forms.
History of the discovery of folic acid
Folic acid was discovered in the 1930s–1940s in a search for a factor that treats anemia. This is a vivid example of how clinical observations led to a major discovery.
1931 — Wills' observation
Lucy Wills, a British doctor in India, noticed that pregnant women with anemia improved if they ate yeast or liver extract. Thus the "Wills factor" — future folate — was found.
1941 — isolation
Scientists isolated a substance from spinach, which they named "folic acid" (from Latin "folium" — leaf), because there is a lot of it in leafy greens.
1945 — chemical synthesis
American chemists synthesized folic acid artificially. This allowed its use in supplements and fortified foods.
1991 — prevention of neural tube defects
The MRC Vitamin Study proved: taking folic acid before conception reduces the risk of neural tube defects in the fetus. This led to mandatory fortification of flour with folates in dozens of countries.
What is methylation and why it is needed
Methylation is a chemical reaction in which a methyl group is "attached" to a molecule. The main donor of methyl groups in the cell is SAMe (S-adenosylmethionine). It is formed from methionine and ATP, and after donating a methyl group it turns into homocysteine. So that homocysteine does not accumulate, it is converted back into methionine — and here folates and B12 are needed.
SAMe
Formed from methionine and ATP; donates methyl groups for hundreds of reactions, turning into homocysteine.
Homocysteine recycling
Requires folates (B9), B12 and B6. This is exactly where MTHFR "works".
Why folates are good for humans
Folates (vitamin B9) are necessary for cell division and growth. Here are the main areas of their benefit:
Fetal development
Folates are critically important in the first trimester for the formation of the fetal neural tube. Prevention of defects is the main reason for taking B9 before conception.
Red blood cell production
Folates are needed for blood cell division. Their deficiency causes megaloblastic anemia with fatigue and weakness.
Neurotransmitter metabolism
They participate in the synthesis of serotonin and other neurotransmitters. Deficiency is linked to low mood and "brain fog".
Lowering homocysteine
Folates together with B12 and B6 lower homocysteine levels — a risk factor for cardiovascular disease.
DNA synthesis and repair
Folates are a cofactor of nucleotide synthesis needed for copying and repairing DNA in dividing cells.
Where folates are found: foods with numbers
Folates are found in large amounts in leafy greens, legumes and organ meats. Important: in food folates are present in natural form, while folic acid is the synthetic form in supplements and fortified products.
| Food | Folates (mcg/100 g) | Comment |
|---|---|---|
| Beef liver | ~200–300 | Record holder, + iron and B12 |
| Spinach | ~190 | Leafy greens |
| Asparagus | ~150 | Good source |
| Broccoli | ~60–90 | Moderate |
| Brussels sprouts | ~60 | Moderate |
| Lentils | ~180 | Rich source |
| Chickpeas | ~170 | Rich source |
| Beans | ~130 | Good source |
| Avocado | ~80 | Moderate source |
| Beetroot | ~110 | Good source |
| Egg (1 pc) | ~22 | Moderate |
Folate norms per day and month
| Category | Folate norm/day |
|---|---|
| Adults | 400 mcg |
| Pregnancy | 600 mcg |
| Lactation | 500 mcg |
| Upper limit (from supplements) | 1000 mcg/day |
MTHFR, UMFA and active 5-MTHF
Synthetic folic acid must go through several enzymatic stages, including MTHFR, to become active. With reduced enzyme activity (polymorphism) or large doses, some folic acid remains in the blood unchanged — this is called UMFA.
| C677T genotype | MTHFR activity | Comment |
|---|---|---|
| CC (normal) | ~100% | Regular folic acid is absorbed normally |
| CT (heterozygote) | ~60–70% | Regular intake is often enough, monitor homocysteine |
| TT (homozygote) | ~30–40% | It is reasonable to consider the active form 5-MTHF |
For most people
Cheap, proven effective for the prevention of neural tube defects. Requires the work of MTHFR.
With polymorphisms and high homocysteine
A ready active form, does not require MTHFR. Preferred with reduced enzyme activity.
What is MTHFR in simple terms?
MTHFR is an enzyme that converts folates (vitamin B9) into the active form 5-MTHF, needed for methylation and lowering homocysteine. In some people its activity is reduced due to a polymorphism.
Which foods have the most folates?
Beef liver (~200–300 mcg/100 g), spinach (~190), lentils (~180), chickpeas (~170), asparagus (~150), beans (~130), beetroot (~110), broccoli (~60–90).
What is UMFA and why is it discussed?
UMFA is unmetabolized folic acid in the blood. It appears with high doses of synthetic folic acid, especially with reduced MTHFR activity. Its high level is discussed by researchers as undesirable.
How many folates do I need per day?
Adults 400 mcg/day, in pregnancy 600 mcg, in lactation 500 mcg. The upper limit from supplements is 1000 mcg/day.
Is folic acid really "toxic"?
Strictly speaking, no — it is not a poison. The term is exaggerated. It is about the accumulation of the inactive form UMFA with high doses and reduced enzyme activity, which may have undesirable effects.
Who is active 5-MTHF suitable for?
People with confirmed reduced MTHFR activity (homozygous C677T), elevated homocysteine, and as prescribed by a doctor. For most people, regular folic acid is effective.
What is homocysteine and why lower it?
Homocysteine is an amino acid, an intermediate product of methionine metabolism. An elevated level is linked to the risk of cardiovascular disease and cognitive impairment. It is lowered by folates, B12 and B6.
How to preserve folates when cooking?
Folates are sensitive to heat and light. Eat greens fresh, cook vegetables on steam or briefly stew, do not boil for a long time — part goes into the water.
How is L-methylfolate different from folic acid?
Folic acid is a synthetic precursor that requires activation by the enzyme MTHFR. L-methylfolate (5-MTHF) is already the active form, which works immediately, bypassing MTHFR.
Does MTHFR affect mood and fatigue?
Indirectly, yes. Methylation disturbances can affect neurotransmitter synthesis and general well-being, but the link is individual and requires evaluation with a doctor, not self-diagnosis by a gene.