Vitamin B9

Vitamin B9, commonly known as folate or folic acid, is a water-soluble B vitamin with fundamental importance for human health. The term "folate" encompasses a family of compounds derived from pteroylglutamic acid, including naturally occurring food folates, synthetic folic acid used in fortification and supplements, and various reduced forms including 5-methyltetrahydrofolate (5-MTHF).

Folate's primary biochemical role is as a carrier of one-carbon units in metabolic reactions. These one-carbon units are essential for DNA synthesis and repair, cell division, and the metabolism of homocysteine to methionine. Because rapidly dividing cells have high folate requirements, deficiency particularly affects tissues with rapid turnover, including bone marrow (red blood cell production), intestinal lining, and the developing fetus.

The most significant public health impact of folate is the prevention of neural tube defects (NTDs). Randomized controlled trials conclusively demonstrated that periconceptional folic acid supplementation reduces NTD risk by 50-70%. This evidence led to mandatory fortification of grain products in many countries, resulting in dramatic reductions in NTD rates. The critical window for supplementation begins before conception and continues through the first trimester, often before a woman knows she is pregnant.

Folate deficiency causes megaloblastic anemia, characterized by enlarged, immature red blood cells that cannot function properly. This condition causes fatigue, weakness, and shortness of breath. Deficiency also elevates homocysteine levels, which has been associated with increased cardiovascular disease risk, though folic acid supplementation has not consistently reduced cardiovascular events in clinical trials.

Beyond its essential functions, folate has been studied for cancer prevention, cognitive function, and depression treatment. The relationship with cancer is complex: adequate folate may prevent cancer initiation by maintaining DNA integrity, but high folate intake may promote progression in established cancers. This dual role highlights the importance of appropriate dosing.

Approximately 40% of the population carries genetic variants (particularly MTHFR C677T) that reduce the efficiency of folate metabolism. These individuals may benefit from the 5-MTHF form of folate, which bypasses the MTHFR enzyme step. However, folic acid remains the only form proven to prevent neural tube defects, and current evidence indicates that individuals with MTHFR variants can still process folic acid effectively.

Folate functions biochemically as a carrier of one-carbon units (methyl, methylene, formyl groups) in numerous metabolic reactions. The active form, tetrahydrofolate (THF), serves as a coenzyme that accepts and donates these one-carbon units in reactions essential for DNA synthesis, amino acid metabolism, and methylation processes.

In DNA synthesis, 5,10-methylenetetrahydrofolate donates a methyl group to deoxyuridine monophosphate (dUMP), converting it to thymidine monophosphate (dTMP), a building block of DNA. This reaction is catalyzed by thymidylate synthase and is essential for DNA replication and repair. Without adequate folate, cells cannot produce sufficient thymidine, leading to impaired DNA synthesis and characteristic "megaloblastic" changes in rapidly dividing cells.

Folate also participates in the remethylation of homocysteine to methionine. 5-methyltetrahydrofolate (5-MTHF) donates its methyl group to homocysteine in a reaction catalyzed by methionine synthase, which requires vitamin B12 as a cofactor. This reaction produces methionine, which can be converted to S-adenosylmethionine (SAM), the body's primary methyl donor for methylation reactions affecting DNA, proteins, and neurotransmitters.

The neural tube defect prevention mechanism is not fully understood but likely involves multiple pathways. Folate is essential for rapidly dividing cells of the developing neural tube during the first 28 days after conception. Adequate folate may prevent errors in DNA synthesis and methylation that lead to failed neural tube closure. Genetic variations in folate metabolism genes may explain why some women require higher folate intake to prevent NTDs.

Folic acid from supplements and fortified foods is absorbed efficiently in the proximal small intestine through a pH-dependent carrier-mediated process. Once absorbed, it is reduced to dihydrofolate and then tetrahydrofolate by the enzyme dihydrofolate reductase. Natural food folates exist primarily as polyglutamate forms that must be deconjugated to monoglutamates by intestinal enzymes before absorption, making them somewhat less bioavailable than folic acid.

The MTHFR (methylenetetrahydrofolate reductase) enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulating form of folate. The C677T variant reduces enzyme activity by 30-70% depending on genotype, potentially impairing homocysteine remethylation. However, adequate folate intake can overcome this impairment in most individuals.

Folate is found in a variety of foods, with the highest concentrations in liver, dark leafy greens, legumes, and fortified grains. In many countries, wheat flour and other grain products are fortified with folic acid, making fortified grains a major dietary source.

Folate deficiency primarily affects rapidly dividing tissues. It causes megaloblastic anemia, characterized by production of enlarged, immature red blood cells that cannot transport oxygen efficiently. Deficiency during pregnancy causes neural tube defects in the developing fetus.

Folate requirements are expressed as dietary folate equivalents (DFE) to account for different bioavailability of natural food folate versus synthetic folic acid. 1 mcg DFE = 1 mcg food folate = 0.6 mcg folic acid from fortified foods or supplements taken with food = 0.5 mcg folic acid from supplements on an empty stomach.

Folate supplements come in several forms with different bioavailability and metabolic pathways. Folic acid is synthetic and most stable. 5-MTHF is the active circulating form that bypasses MTHFR enzyme. Food folates are polyglutamate forms with variable absorption.