Folate is the B vitamin that is the foundation of one-carbon metabolism — the network of biochemical reactions that transfer one-carbon units (methyl groups) between molecules, and which is fundamentally involved in the synthesis, repair, and methylation of DNA, in the synthesis of the purine and pyrimidine nucleotides that are the building blocks of DNA and RNA, in the conversion of homocysteine to methionine, and in the regulation of the methylation cycle that controls gene expression, neurotransmitter synthesis, and cell membrane integrity. Folate is present in foods as folylpolyglutamates (polyglutamated forms that must be deconjugated to monoglutamates in the gut before absorption), and it is found in dark leafy green vegetables, legumes, citrus fruits, and fortified cereals. The synthetic form, folic acid, is widely used in supplements and in food fortification programmes because it is more stable and better absorbed than the natural folates. Folic acid fortification of cereal grains has dramatically reduced the incidence of neural tube defects in countries where it has been implemented, making folate one of the most successful public health nutrition interventions in history.
Folate and the Synthesis of DNA and RNA
Folate is required for the synthesis of the purine nucleotides (adenine and guanine) and of the pyrimidine nucleotide thymidine, all of which are the building blocks of DNA and RNA. In the de novo synthesis of purine nucleotides, folate derivatives (10-formyl-THF and 5,10-methylene-THF) donate one-carbon units at two steps in the pathway. In the synthesis of thymidine (the rate-limiting step in DNA synthesis), the enzyme thymidylate synthase uses 5,10-methylene-THF as the one-carbon donor and converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). This folate-dependent thymidylate synthesis is the rate-limiting step in DNA synthesis, and when folate is deficient, the rate of DNA synthesis is impaired, the cell cycle is arrested at the S phase, and the cells that have the highest turnover rates (including the erythroid precursors in the bone marrow, the enterocytes of the gut, and the cells of the immune system) are most affected. This is the mechanism of the megaloblastic anaemia, the GI symptoms, and the immune dysfunction that are the clinical hallmarks of folate deficiency.
Megaloblastic anaemia is the haematological manifestation of folate deficiency — it is characterised by the presence of large, immature red blood cell precursors (megaloblasts) in the bone marrow, which result from the impaired DNA synthesis that occurs when folate is not available for thymidylate synthase. The megaloblasts are larger than normal erythroid precursors because the impaired DNA synthesis prevents them from dividing normally, and they accumulate in the bone marrow as large, immature cells that are released into the bloodstream as macrocytes (large red blood cells). The macrocytosis of folate deficiency is one of the most characteristic haematological findings and is often the first clue to the diagnosis of folate deficiency.
Folate and Neural Tube Defects
The most important public health consequence of folate deficiency is its association with neural tube defects (NTDs) — the birth defects that result from the failure of the neural tube to close properly during embryonic development, producing anencephaly (absence of the brain) and spina bifida (incomplete closure of the spinal cord). The evidence for a causal relationship between maternal folate deficiency and NTDs is one of the strongest and most consistent findings in all of nutritional epidemiology — randomised controlled trials demonstrated that folic acid supplementation before and during early pregnancy reduced the risk of NTDs by approximately 70%, and population-level folic acid fortification programmes have reduced the incidence of NTDs by 25-50% in the countries where they have been implemented. The mechanism by which folate prevents NTDs is thought to involve the folate-dependent regulation of the cell proliferation and the gene expression that are required for the proper closure of the neural tube during the critical window of embryonic development (days 21-28 after conception, when most women do not yet know that they are pregnant).
Practical Application
For general folate supplementation, the evidence-based approach is to supplement with folic acid at 400-800mcg daily (for general prevention) or with 5-methyltetrahydrofolate (5-MTHF) at 400-800mcg daily (for people with the MTHFR C677T polymorphism, who have impaired conversion of folic acid to 5-MTHF). For women of childbearing age who may become pregnant, the recommendation is to supplement with at least 400mcg of folic acid daily, beginning at least one month before conception and continuing through the first trimester. For comprehensive one-carbon metabolism support, folate pairs well with vitamin B12 (which is required for the methionine synthase reaction, which is the only methylation reaction that uses B12), with vitamin B6 (which is required for the transsulfuration pathway), with zinc (which is required for the enzymes of DNA synthesis), and with the omega-3 fatty acids (which are required for the synthesis of the cell membranes of rapidly proliferating cells).
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