folate folate folate, also known as vitamin b9 and folacin, is one of the b vitamins. 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 is required for the body to make dna and rna and metabolise amino acids necessary for cell division. as humans 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. folic acidclinical datapronunciation/ˈfoʊlɪk, ˈfɒlɪk/ trade namesfolicet, folviteother namesfa, n-(4-benzoyl)-l-glutamic acid, pteroyl-l-glutamic acid, folacin, vitamin b9, and historically, vitamin bc and vitamin mahfs/drugs.commonographmedlineplusa682591license data us dailymed: folic_acid pregnancycategory au: a routes ofadministrationby mouth, intramuscular, intravenous, subcutaneousatc codeb03bb01 (who) v04cx02 (who) b03ae02 (who) b03ae01 (who) b03bb51 (who)legal statuslegal status au: s4 (prescription only) / s2 us: ℞-only / otc pharmacokinetic databioavailability50–100%metabolismliverexcretionurineidentifiers iupac name (2s)-2-benzoyl]amino]pentanedioic acid cas number59-30-3as salt: 6484-89-5pubchem cid6037iuphar/bps4563drugbankdb00158as salt: dbsalt001918chemspider5815as salt: 21512unii935e97boy8as salt: 9p9w8ggu78keggd00070as salt: d07985chebichebi:27470chemblchembl1622pdb ligandfol (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid0022519 echa infocard100.000.381 chemical and physical dataformulac19h19n7o6molar mass441.404 g·mol−13d model (jsmol)interactive imagedensity1.6±0.1 g/cm3 melting point250 °c (482 °f) (decomposition)solubility in water1.6mg/l (25 °c) smiles n1c2c(=o)nc(n)=nc2ncc1cnc3ccc(cc3)c(=o)n(c(o)=o)ccc(o)=o inchi inchi=1s/c19h19n7o6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21h,5-7h2,(h,24,29)(h,27,28)(h,31,32)(h3,20,22,25,26,30)/t12-/m0/s1key:ovbpiulpvideao-lbprgkrzsa-n 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. 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 an increased risk of prostate cancer. there are concerns that large amounts of supplemental folic acid can hide vitamin b12 deficiency. 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 blood levels of greater than 7 nmol/l (3 ng/ml). folate was discovered between 1931 and 1943. it is on the world health organization's list of essential medicines. in 2020, it was the 67th most commonly prescribed medication in the united states, with more than 10 million prescriptions. the term "folic" is from the latin word folium (which means leaf) because it was found in dark-green leafy vegetables. definition chemical structure of the folate family "folate" (vitamin b9) refers to the many forms of folic acid and its related compounds, including tetrahydrofolic acid (the active form), methyltetrahydrofolate (the primary form found in blood), methenyltetrahydrofolate, folinic acid, folacin, and pteroylglutamic acid. historic names included l. ⁠casei factor, vitamin bc and vitamin m. the terms "folate" and "folic acid" have somewhat different meanings in different contexts, although sometimes used interchangeably. within the field of organic chemistry, folate refers to the conjugate base of folic acid. within the field of biochemistry, folates refer to a class of biologically active compounds related to and including folic acid. within the field of nutrition, the "folates" are a family of essential nutrients related to folic acid obtained from natural sources whereas the term "folic acid" is reserved for the 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 that in turn is bonded through an amide linkage to either glutamic acid or poly-glutamate. 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. 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. compliance with this recommendation is not complete, and many women become pregnant without this being a planned pregnancy, or may not realize that they are pregnant until well into the first trimester, which is the critical period for reducing risk of ntds. countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains, or else have no such program and depend on public health and healthcare practitioner advice to women of childbearing age. a meta-analysis of global birth prevalence of spina bifida showed that when mandatory fortification was compared to countries with voluntary fortification or no 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, and prostate cancers. early after fortification programs were implemented, high intakes were theorized to accelerate the growth of preneoplastic lesions that could lead to cancer, specifically colon cancer. subsequent meta-analyses of the effects of low versus high dietary folate, elevated serum folate, and supplemental folate in the form of folic acid have reported at times conflicting results. comparing low to high dietary folate showed a modest but statistically significant reduced risk of colon cancer. for prostate cancer risk, comparing low to high dietary folate showed no effect. a review of trials that involved folic acid dietary supplements reported a statistically significant 24% increase in prostate cancer risk. it was shown that supplementation with folic acid at 1,000 to 2,500 μg/day – the amounts used in many of the cited supplement trials – would result in higher concentrations of serum folate than what is achieved from diets high in food-derived folate. the second supplementation review reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies in people who were consuming folic acid supplements. a third supplementation meta-analysis limited to reporting only on colorectal cancer incidence showed that folic acid treatment was not associated with colorectal cancer risk. anti-folate chemotherapy folate is important for cells and tissues that divide rapidly. cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. the antifolate drug methotrexate is often used to treat cancer because it inhibits the production of the active tetrahydrofolate (thf) from the inactive dihydrofolate (dhf). however, methotrexate can be toxic, producing side effects such as inflammation in the digestive tract that make eating normally more difficult. bone marrow depression (inducing leukopenia and thrombocytopenia) and acute kidney and liver failure have been reported. folinic acid, under the drug name leucovorin, a form of folate (formyl-thf), can help "rescue" or reverse the toxic effects of methotrexate. folic acid supplements have little established role in cancer chemotherapy. the supplement of folinic acid in people undergoing methotrexate treatment is to give less rapidly dividing cells enough folate to maintain normal cell functions. the amount of folate given is quickly depleted by rapidly dividing (cancer) cells, so this does not negate the effects of methotrexate. neurological disorders conversion of homocysteine to methionine requires folate and vitamin b12. elevated plasma homocysteine and low folate are associated with cognitive impairment, dementia and alzheimer's disease. supplementing the diet with folic acid and vitamin b12 lowers plasma homocysteine. however, several reviews reported that supplementation with folic acid alone or in combination with other b vitamins did not prevent development of cognitive impairment nor slow cognitive decline. a 2017 meta-analysis found that the relative risk of autism spectrum disorders was reduced by 23% when the maternal diet was supplemented with folic acid during pregnancy. subset analysis confirmed this among asian, european and american populations. some evidence links a shortage of folate with clinical depression. limited evidence from randomized controlled trials showed using folic acid in addition to selective serotonin reuptake inhibitors (ssris) may have benefits. research found a link between depression and low levels of folate. the exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive folate, methyltetrahydrofolate (5-mthf), a direct target of methyl donors such as s-adenosyl methionine (same), recycles the inactive dihydrobiopterin (bh2) into tetrahydrobiopterin (bh4), the necessary cofactor in various steps of monoamine synthesis, including that of dopamine and serotonin. bh4 serves a regulatory role in monoamine neurotransmission and is required to mediate the actions of most antidepressants. folic acid, b12 and iron a complex interaction occurs between folic acid, vitamin b12, and iron. a deficiency of folic acid or vitamin b12 may mask the deficiency of iron; so when taken as dietary supplements, the three need to be in balance. malaria some studies show iron–folic acid supplementation in children under five may result in increased mortality due to malaria; this has prompted the world health organization to alter their iron–folic acid supplementation policies for children in malaria-prone areas, such as india. metabolism the biological activity of folate in the body depends upon dihydrofolate reductase action in the liver which converts folate into tetrahydrofolate (thf). this action is rate-limiting in humans leading to elevated blood concentrations of unmetabolized folic acid when consumption from dietary supplements and fortified foods nears or exceeds the u.s. tolerable upper intake level of 1,000 μg per day. biosynthesis