Folate (vitamin B9, and its synthetic form, folic acid) is the water-soluble vitamin that is the essential methyl donor for the one-carbon metabolism — the network of interconnected metabolic pathways that distribute the one-carbon units (methyl groups) from the dietary sources to the methylation reactions, to the DNA synthesis, and to the amino acid metabolism. The active form of folate is the tetrahydrofolate (THF), which carries the one-carbon units at three different oxidation states — the methyl group (at the most reduced state, as 5-methyl-THF), the methylene group (at the intermediate oxidation state, as 5,10-methylene-THF), and the formyl group (at the most oxidised state, as 10-formyl-THF and 5-formyl-THF). These one-carbon units are used for the synthesis of the purine nucleotides (ATP, GTP) and of the pyrimidine nucleotides (dTMP from dUMP) — which are the building blocks of the DNA and the RNA — and for the methylation reactions that are essential for the DNA methylation, the histone methylation, the neurotransmitter synthesis, and the regulation of the one-carbon metabolism itself. Without adequate folate and functional one-carbon metabolism, the DNA synthesis is impaired (because the nucleotide precursors cannot be synthesised), the methylation reactions are compromised (because the methyl groups cannot be transferred), and the megaloblastic anaemia and the neural tube defects develop — the hallmark of the folate deficiency. The typical dietary folate intake is 200-400mcg daily (from the leafy green vegetables, the legumes, the citrus fruits, and the fortified cereals), and the RDA is 400mcg daily for adults — but the folate deficiency is common (affecting approximately 5-10% of the population), particularly in people with the malabsorption, with the alcoholism, with the MTHFR C677T polymorphism (which impairs the conversion of the folic acid to the active 5-methyl-THF), and in pregnant women (who have a dramatically increased folate requirement for the rapid cell division in the developing foetus).
Folate and the DNA Synthesis
The folate-dependent one-carbon metabolism is the primary source of the methyl groups for the DNA synthesis — the 5,10-methylene-THF is used by the thymidylate synthase enzyme to convert the deoxyuridine monophosphate (dUMP) to the deoxythymidine monophosphate (dTMP), which is the precursor of the thymidine nucleotides in the DNA. This reaction is the rate-limiting step in the DNA synthesis — without adequate folate and 5,10-methylene-THF, the dTMP cannot be synthesised, the DNA replication is impaired, the cells cannot divide, and the megaloblastic anaemia develops (because the erythroid precursors in the bone marrow are among the most rapidly dividing cells in the body and are therefore most sensitive to the folate deficiency). The megaloblastic anaemia is characterised by the large, immature red blood cells (megaloblasts) that cannot complete the cell division and that are released into the blood as the macrocytes (enlarged red blood cells) — this is in contrast to the microcytic anaemia of the iron deficiency, where the red blood cells are small because they are deficient in haemoglobin.
The clinical importance of the folate for the DNA synthesis is underscored by the observation that the folate deficiency produces the megaloblastic anaemia and the pancytopenia (reduction in all blood cell types) — which are the most sensitive haematological manifestations of the folate deficiency and which are reversed by the folate supplementation. The folate supplementation (at 400-1000mcg daily of folic acid or 5-methyl-THF) rapidly reverses the megaloblastic anaemia in people with the folate deficiency, restoring the normal red blood cell count, the normal haemoglobin level, and the normal red blood cell morphology. The folate is particularly important for the pregnant women, because the rapid cell division in the developing foetus requires an adequate supply of the folate for the DNA synthesis — and the folate deficiency in the first trimester of the pregnancy is the primary cause of the neural tube defects (NTDs), including the spina bifida and the anencephaly, which are among the most common and most severe congenital malformations.
Folate and the Neural Tube Defects
The neural tube defects (NTDs) are among the most common and most severe congenital malformations — they occur in approximately 1-2 per 1000 pregnancies worldwide, and they are caused by the failure of the neural tube to close during the embryonic development (between days 17-30 after the conception). The folate-dependent one-carbon metabolism is essential for the closure of the neural tube — it provides the methyl groups for the DNA synthesis that is required for the rapid cell division in the developing nervous system, and it also provides the methyl groups for the methylation of the neural cell adhesion molecules (which are involved in the neural tube closure). The folate supplementation before the conception and during the first trimester of the pregnancy reduces the risk of the NTDs by approximately 70% — making the folate supplementation one of the most effective and most important public health interventions for the prevention of the congenital malformations. The mandatory folic acid fortification of the flour and of other grain products (which has been implemented in over 80 countries) has dramatically reduced the prevalence of the NTDs in the countries where it has been implemented — by approximately 30-50% in the United States since the introduction of the folic acid fortification programme in 1998.
Practical Application
For general folate supplementation, the evidence-based approach is to supplement with 400-800mcg of folate daily (as folic acid or, preferably, as 5-methyl-THF (L-methylfolate), which is the active form that bypasses the MTHFR-dependent conversion step). The 5-methyl-THF form is preferred for people with the MTHFR C677T polymorphism (who have impaired conversion of the folic acid to the active form) and for people with the methylfolate deficiency. The RDA of folate is 400mcg daily for adults, 600mcg daily for pregnant women, and 500mcg daily for lactating women. For comprehensive methylation and haematinic support, folate pairs well with the vitamin B12 (as methylcobalamin at 500-1000mcg daily — because the B12 and the folate are interdependent in the methylation cycle, and the B12 deficiency can cause a functional folate deficiency by trapping the folate in the 5-methyl-THF form), with the vitamin B6 (which is required for the transsulfuration pathway that disposes of the excess homocysteine), with the magnesium (which is a cofactor for the MTHFR enzyme and for many of the other enzymes of the one-carbon metabolism), and with the betaine (which is an alternative methyl donor for the remethylation of the homocysteine to methionine and which works synergistically with folate for the lowering of the homocysteine).
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