Tetrahydrofolate (THF), also known as tetrahydrofolic acid, is a biologically active form of folate, which is vitamin B9. This water-soluble vitamin functions as a coenzyme, assisting various enzymes in the body. It is a fundamental molecule involved in numerous metabolic reactions, supporting cellular processes and overall health. THF facilitates the transfer of single-carbon units—small chemical groups with one carbon atom—across different molecules in the body.
Essential Functions in the Body
Tetrahydrofolate plays a central role in one-carbon metabolism, a series of biochemical reactions that involve the transfer of single-carbon units. These reactions are fundamental for the synthesis and repair of DNA, the building blocks of our genetic material. THF contributes to the creation of purines and pyrimidines, which are the nucleotide bases that form DNA and RNA.
Beyond DNA, THF is also involved in the metabolism of several amino acids, the components that make up proteins. An important example is its role in converting homocysteine to methionine, a process that relies on the enzyme methionine synthase and also requires vitamin B12. This interconversion is part of a larger cycle that provides methyl groups for various biological reactions, including the methylation of DNA and RNA. THF also participates in the metabolism of other amino acids like serine and glycine.
THF’s role in DNA synthesis extends to the formation of red blood cells. The proper maturation and division of these cells in the bone marrow depend on adequate DNA production. Without sufficient THF, red blood cells cannot divide and mature correctly. This impacts the body’s ability to transport oxygen effectively.
Dietary Sources and Metabolism
The body obtains folate from various dietary sources, which are then converted into the active tetrahydrofolate form. Natural folates are found abundantly in foods like dark green leafy vegetables such as spinach, kale, and broccoli, as well as in legumes like beans, peas, and lentils. Citrus fruits, bananas, and liver also serve as good sources of natural folate.
Folic acid, on the other hand, is the synthetic version of folate commonly used in dietary supplements and to fortify foods like enriched breads, cereals, and pastas. While natural folates are polyglutamated, folic acid is a monoglutamate. Both forms must be converted to THF or its derivatives, such as 5-methyltetrahydrofolate (5-MTHF), to be biologically active within the body.
The conversion of dietary folates and synthetic folic acid to THF involves a series of enzymatic steps, primarily occurring in the liver. Folic acid, for instance, is reduced to dihydrofolate and then to tetrahydrofolate by the enzyme dihydrofolate reductase (DHFR).
Consequences of Insufficient Levels
When the body lacks sufficient active tetrahydrofolate, several health issues can arise. A primary symptom is megaloblastic anemia, a condition characterized by the production of abnormally large, immature red blood cells that do not function effectively. This occurs because insufficient THF impairs DNA synthesis, which is necessary for the proper division and maturation of red blood cell precursors in the bone marrow.
Another consequence of low THF levels is an increase in homocysteine, an amino acid, in the bloodstream. THF, specifically its derivative 5-methyltetrahydrofolate, is required to convert homocysteine back into methionine. Elevated homocysteine levels have been associated with an increased risk of cardiovascular concerns, including hardening of the arteries and blood clots, although the precise causal relationship is still under investigation.
A deficiency can also manifest as more general symptoms such as fatigue, weakness, and pallor. Digestive issues like a sore tongue, oral ulcers, and diarrhea can also occur. Causes of insufficient THF include inadequate dietary intake, particularly from fresh fruits and vegetables, and overcooking foods, which can destroy folate. Malabsorption conditions, such as celiac disease, certain medications like methotrexate and phenytoin, and chronic alcohol consumption can also interfere with folate absorption and metabolism, leading to deficiency.
Clinical Relevance and Considerations
Adequate folate, and by extension THF, intake is particularly important during periods of rapid cell growth, such as pregnancy. Sufficient folate levels before and during early pregnancy can significantly reduce the risk of neural tube defects (NTDs) in developing babies, which are birth defects affecting the brain and spinal cord, such as spina bifida and anencephaly. Healthcare guidelines often recommend that women who could become pregnant take a daily folic acid supplement, typically 400 micrograms.
Certain medications can interfere with the body’s folate metabolism, leading to a functional THF deficiency. Methotrexate, a drug used in chemotherapy and to treat autoimmune conditions like rheumatoid arthritis, is a well-known example. Methotrexate works by inhibiting the enzyme dihydrofolate reductase (DHFR), which is necessary for converting folate into its active THF forms. To counteract these effects and reduce side effects like mouth sores and gastrointestinal upset, folic acid supplementation is often prescribed alongside methotrexate.
Genetic variations can also influence an individual’s ability to process folate and produce active THF. One common genetic difference involves the methylenetetrahydrofolate reductase (MTHFR) enzyme. Variations in the MTHFR gene can reduce the enzyme’s activity, potentially affecting the conversion of folate forms used in homocysteine metabolism. While these genetic variations are common, the Centers for Disease Control and Prevention (CDC) states that individuals with MTHFR variants can still process folic acid, and adequate folic acid intake remains important for preventing conditions like neural tube defects.