Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Folate is required for the body to make DNA and RNA and metabolize amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage.
Folate in the form of folic acid is used to treat anemia caused by folate deficiency. Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby. NTDs include anencephaly and spina bifida, among other defects. Low levels in early pregnancy are believed to be the cause of more than half of babies born with NTDs. More than 80 countries use either mandatory or voluntary fortification of certain foods with folic acid as a measure to decrease the rate of NTDs. Long-term supplementation with relatively large amounts of folic acid is associated with a small reduction in the risk of stroke and, for "relatively large amount" meaning ≥ 400 μg/day, an increased risk of prostate cancer.
Not consuming enough folate can lead to folate deficiency. This may result in a type of anemia in which red blood cells become abnormally large. Symptoms may include feeling tired, heart palpitations, shortness of breath, open sores on the tongue, and changes in the color of the skin or hair. Folate deficiency in children may develop within a month of poor dietary intake. In adults, normal total body folate is between 10 and 30 mg with about half of this amount stored in the liver and the remainder in blood and body tissues. In plasma, the natural folate range is 150 to 450 nM.
Folate was discovered between 1931 and 1943. It is on the World Health Organization's List of Essential Medicines. In 2023, it was the 94th most commonly prescribed medication in the United States, with more than 7million prescriptions. The term "folic" is from the Latin word (which means leaf) because it was found in dark-green leafy vegetables.
Definition
Folates (vitamin B9) refers to the many forms of folic acid and its related compounds, including tetrahydrofolic acid (an active form), methyltetrahydrofolate (the primary form found in blood), methenyltetrahydrofolate, folinic acid, and other pteroylglutates. Historic names included L. casei factor, folacin, vitamin Bc and vitamin M.
The terms folate, folates, and folic acid have somewhat different meanings in different contexts, although sometimes used interchangeably. Within the field of organic chemistry and biochemistry, folate (singular) refers to the conjugate base of folic acid; folates (plural) refers to the family of compounds related to and including folic acid (pteroylglutamates), possibly differing in the level of reduction (see below) on the pterin ring and the number of glutamyl units. An alternative biochemical definition also requires biological activity for a compound to belong to the folates. Within the field of nutrition, the terms are often used interchangeably. When and if a distinction is made, folate refers to the natural forms where as folic acid refers to the specific manufactured form that is used as a dietary supplement.
Chemically, folates consist of three distinct chemical moieties linked together. A pterin (2-amino-4-hydroxy-pteridine) heterocyclic ring is linked by a methylene bridge to a p-aminobenzoyl group (these two make up a "pteroate") that in turn is bonded through an amide linkage to either glutamic acid or poly-glutamate. The pterin ring can be in three levels of reduction: no hydrogens (as in folic acid), two hydrogens (as in dihydrofolate), or the active form of four hydrogens (as in tetrahydrofolate and other active forms). In living organisms, one-carbon units in a variety of oxidation states may be attached to the N5 nitrogen atom of the pteridine ring and/or the N10 nitrogen atom of the p-aminobenzoyl group of tetrahydrofolate. Most folates are unstable to oxidation, with the exception of folic acid and folinic acid.
Function Tetrahydrofolate's main function in metabolism is transporting single-carbon groups (i.e., a methyl group, methylene group, or formyl group). These carbon groups can be transferred to other molecules as part of the modification or biosynthesis of a variety of biological molecules. Folates are essential for the synthesis of DNA, the modification of DNA and RNA, the synthesis of methionine from homocysteine, and various other chemical reactions involved in cellular metabolism. These reactions are collectively known as folate-mediated one-carbon metabolism.
DNA synthesis
Folate derivatives participate in the biosynthesis of both purines and pyrimidines, which leads to the building blocks of DNA and RNA.
Formyl folate is required for two of the steps in the biosynthesis of inosine monophosphate, the precursor to GMP and AMP. Methylenetetrahydrofolate donates the C1 center required for the biosynthesis of dTMP (2-deoxythymidine-5-phosphate) from dUMP (2-deoxyuridine-5-phosphate). The conversion is catalyzed by thymidylate synthase.
Vitamin b12 activation
Methyl-THF converts vitamin B12 to methyl-B12 (methylcobalamin). Methyl-B12 converts homocysteine, in a reaction catalyzed by homocysteine methyltransferase, to methionine. A defect in homocysteine methyltransferase or a deficiency of B12 may lead to a so-called "methyl-trap" of THF, in which THF converts to methyl-THF, causing a deficiency in folate. Thus, a deficiency in B12 can cause accumulation of methyl-THF, mimicking folate deficiency.
Health effects Folate is especially important during periods of frequent cell division and growth, such as infancy and pregnancy. Folate deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of their greater frequency of cell division. RNA transcription and subsequent protein synthesis are less affected by folate deficiency, as the mRNA can be recycled and used again (as opposed to DNA synthesis, where a new genomic copy must be created).
Birth defects Deficiency of folate in pregnant women has been implicated in neural tube defects (NTDs), with an estimate of 300,000 cases worldwide prior to the implementation in many countries of mandatory food fortification. NTDs occur early in pregnancy (first month), therefore women must have abundant folate upon conception and for this reason there is a recommendation that any woman planning to become pregnant consume a folate-containing dietary supplement before and during pregnancy. The Center for Disease Control and Prevention (CDC) recommends a daily amount of 400 micrograms of folic acid for the prevention of NTDs. Many women take this medication less than the CDC recommends, especially in cases where the pregnancy was unplanned, or in countries that lack healthcare resources and education. Some countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains, but many others rely on public health education and one-on-one healthcare practitioner advice. A meta-analysis of global birth prevalence of spina bifida showed that when a national, mandatory program to fortify the diet with folate was compared to countries without such a fortification program, there was a 30% reduction in live births with spina bifida. Some countries reported a greater than 50% reduction. The United States Preventive Services Task Force recommends folic acid as the supplement or fortification ingredient, as forms of folate other than folic acid have not been studied.
A meta-analysis of folate supplementation during pregnancy reported a 28% lower relative risk of newborn congenital heart defects. Prenatal supplementation with folic acid did not appear to reduce the risk of preterm births. One systematic review indicated no effect of folic acid on mortality, growth, body composition, respiratory, or cognitive outcomes of children from birth to 9 years old. There was no relation between maternal folic acid supplementation and an increased risk for childhood asthma.
Fertility Folate contributes to spermatogenesis. In women, folate is important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development.
Heart disease One meta-analysis reported that multi-year folic acid supplementation, in amounts in most of the included clinical trials at higher than the upper limit of 1,000 μg/day, reduced the relative risk of cardiovascular disease by a modest 4%. Two older meta-analyses, which would not have incorporated results from newer clinical trials, reported no changes to the risk of cardiovascular disease.
Stroke The absolute risk of stroke with supplementation decreases from 4.4% to 3.8% (a 10% decrease in relative risk). Two other meta-analyses reported a similar decrease in relative risk. Two of these three were limited to people with pre-existing cardiovascular disease or coronary heart disease. The beneficial result may be associated with lowering circulating homocysteine concentration, as stratified analysis showed that risk was reduced more when there was a larger decrease in homocysteine. The effect was also larger for the studies that were conducted in countries that did not have mandatory grain folic acid fortification. The beneficial effect was larger in the subset of trials that used a lower folic acid supplement compared to higher.
Cancer
Chronically insufficient intake of folate may increase the risk of colorectal, breast, ovarian, pancreatic, brain, lung, cervical, prostate, oesophageal, oral and pharyngeal cancers.
Higher intake of folate from foods has been associated with reducing the adverse effects of alcohol on breast cancer risk.
Due to the risks associated with folate deficiency, folic acid fortification of foods was initiated. Shortly after folic acid fortification was introduced, concerns were raised that higher intake might promote the progression of preneoplastic lesions in the colon (early cellular changes that could become cancer).
Subsequent meta-analyses of the effects of low versus high dietary folate, elevated serum folate, and folic acid supplementation have reported conflicting results. One study that compared low to high dietary folate showed a modest but statistically significant reduction in colon cancer risk. Another study that also compared low to high dietary folate showed no effect on the risk for prostate cancer, . In contrast, a review of trials involving folic acid dietary supplements reported a statistically significant 24% increase in prostate cancer risk. Supplementation in these trials typically used 1,000 to 2,500 μg/day of folic acid—higher than what is achieved through diets rich in naturally occurring folate. Another supplementation review reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies among people who consumed folic acid supplements. Another supplementation meta-analysis limited to colorectal cancer showed that folic acid supplementation was not associated with colorectal cancer risk.
Taken together, the evidence indicates that higher dietary folate intake may be associated with reduced colorectal cancer risk, while results for high-dose folic acid supplementation are inconsistent — with some studies showing no effect and others reporting a possible increased risk for prostate cancer — suggesting that effects may vary by cancer type.
Anti-folate chemotherapy