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Folate, also known as vitamin B9 and folacin, is one of the
B vitamins B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexist ...
. Manufactured folic acid, which is converted into folate by the body, is used as a
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
and in
food fortification Food fortification or enrichment is the process of adding micronutrients (essential trace elements and vitamins) to food. It can be carried out by food manufacturers, or by governments as a public health policy which aims to reduce the number of p ...
as it is more stable during processing and storage. Folate is required for the body to make DNA and
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
and metabolise
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
necessary for
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
. As humans cannot make folate, it is required in the diet, making it an essential
nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400
microgram In the metric system, a microgram or microgramme is a unit of mass equal to one millionth () of a gram. The unit symbol is μg according to the International System of Units (SI); the recommended symbol in the United States and United Kingdom whe ...
s from foods or
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
s. Folate in the form of folic acid is used to treat
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
caused by
folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate ...
. Folic acid is also used as a supplement by women during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
to reduce the risk of
neural tube defect Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo ...
s (NTDs) in the baby. Low levels in early
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
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 A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
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 Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rapi ...
,
shortness of breath Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...
, 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 The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. In 2020, it was the 67th most commonly prescribed medication in the United States, with more than 10million prescriptions. The term "folic" is from the Latin word (which means leaf) because it was found in dark-green leafy vegetables.


Definition

"Folate" (vitamin B9) refers to the many forms of folic acid and its related compounds, including tetrahydrofolic acid (the active form),
methyltetrahydrofolate Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprodu ...
(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 Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, folate refers to the
conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
of folic acid. Within the field of
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
, folates refer to a class of biologically active compounds related to and including folic acid. Within the field of
nutrition Nutrition is the biochemical and physiological process by which an organism uses food to support its life. It provides organisms with nutrients, which can be metabolized to create energy and chemical structures. Failure to obtain sufficient n ...
, 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 Pterin is a heterocyclic compound composed of a pteridine ring system, with a "keto group" (a lactam) and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pterins, a ...
(2-amino-4-hydroxy-pteridine)
heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
ring is linked by a
methylene bridge In organic chemistry, a methylene bridge, methylene spacer, or methanediyl group is any part of a molecule with formula ; namely, a carbon atom bound to two hydrogen atoms and connected by single bonds to two other distinct atoms in the rest of ...
to a p-aminobenzoyl group that in turn is bonded through an amide linkage to either
glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
or poly-glutamate. One-carbon units in a variety of
oxidation state In chemistry, the oxidation state, or oxidation number, is the hypothetical charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...
s 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 Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
transcription and subsequent protein synthesis are less affected by folate deficiency, as the
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
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 Neural tube defects (NTDs) are a group of birth defects in which an opening in the Vertebral column, spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal si ...
(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 The United States Preventive Services Task Force (USPSTF) is "an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services". ...
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 defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
s. Prenatal supplementation with folic acid did not appear to reduce the risk of preterm births. One
systematic review A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
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 Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
. 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 The relative risk (RR) or risk ratio is the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group. Together with risk difference and odds ratio, relative risk measures the association bet ...
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 Absolute risk (or AR) is the probability or chance of an event. It is usually used for the number of events (such as a disease) that occurred in a group, divided by the number of people in that group. Absolute risk is one of the most understandable ...
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 Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
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 In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...
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 Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
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 Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to tr ...
, under the drug name
leucovorin Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to tr ...
, 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 Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. 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 disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...
s 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 Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
. Limited evidence from
randomized controlled trials A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
showed using folic acid in addition to
selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracell ...
s (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 Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprodu ...
(5-MTHF), a direct target of methyl donors such as
S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
(SAMe), recycles the inactive
dihydrobiopterin Dihydrobiopterin (BH2) is a pteridine compound produced in the synthesis of L-DOPA, dopamine, serotonin, norepinephrine and epinephrine. It is restored to the required cofactor tetrahydrobiopterin by dihydrobiopterin reductase. See also * Pteri ...
(BH2) into
tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...
(BH4), the necessary cofactor in various steps of monoamine synthesis, including that of
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
. 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 Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
. 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 Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
; 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 Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...
action in the liver which converts folate into
tetrahydrofolate Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is co ...
(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 The Dietary Reference Intake (DRI) is a system of nutrition recommendations from the National Academy of Medicine (NAM) of the National Academies (United States). It was introduced in 1997 in order to broaden the existing guidelines known as Reco ...
of 1,000 μg per day.


Biosynthesis

Animals, including humans, cannot synthesize folate and therefore must obtain folate from their diet. All plants and fungi and certain protozoa, bacteria, and
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
can synthesize folate de novo through variations on the same
biosynthetic Biosynthesis is a multi-step, enzyme-Catalysis, catalyzed process where substrate (chemistry), substrates are converted into more complex Product (chemistry), products in living organisms. In biosynthesis, simple Chemical compound, compounds are mo ...
pathway. The folate molecule is synthesized from pterin pyrophosphate,
para-aminobenzoic acid 4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA i ...
, and
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
through the action of
dihydropteroate synthase Dihydropteroate synthase is an enzyme classified under . It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PAB ...
and dihydrofolate synthase. Pterin is in turn derived in a series of enzymatically catalyzed steps from
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only diffe ...
(GTP), while para-aminobenzoic acid is a product of the
shikimate pathway The shikimate pathway (shikimic acid pathway) is a seven-step metabolic pathway used by bacteria, archaea, fungi, algae, some protozoans, and plants for the biosynthesis of folates and aromatic amino acids (tryptophan, phenylalanine, and tyrosine). ...
.


Bioactivation

All of the biological functions of folic acid are performed by
THF Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
and its
methylated In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
derivatives. Hence folic acid must first be reduced to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme,
dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...
. Folic acid is first reduced to
dihydrofolate Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid (vitamin B9, vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidine ...
and then to tetrahydrofolate. Each step consumes one molecule of
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
( biosynthetically derived from vitamin B3) and produces one molecule of
NADP Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
. Mechanistically, hydride is transferred from NADPH to the C6 position of the pteridine ring. A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of
serine hydroxymethyltransferase Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) (Vitamin B6) dependent enzyme () which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine ...
(SHMT) to yield
5,10-methylenetetrahydrofolate 5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer R5,10-methylene-THF. As an intermediate in one-carbon metabolism, 5,10-CH2- ...
(5,10-CH2-THF). This reaction also consumes
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
and
pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
(PLP; vitamin B6) and produces
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
and
pyridoxal Pyridoxal is one form of vitamin B6. Some medically relevant bacteria, such as those in the genera ''Granulicatella'' and ''Abiotrophia'', require pyridoxal for growth. This nutritional requirement can lead to the culture phenomenon of satellit ...
. A second enzyme, methylenetetrahydrofolate dehydrogenase (
MTHFD2 Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial is an enzyme that in humans is encoded by the ''MTHFD2'' gene. This gene encodes a nuclear-encoded mitochondrial bifunctional enzyme with methylenetetrahydrofolat ...
) oxidizes 5,10-methylenetetrahydrofolate to an
iminium In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology. Structure Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...
cation which in turn is
hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
to produce 5-formyl-THF and 10-formyl-THF. This series of reactions using the
β-carbon In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule. Numeric locants The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of n ...
atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell. Alternative carbon sources include
formate Formate (IUPAC name: methanoate) is the conjugate base of formic acid. Formate is an anion () or its derivatives such as ester of formic acid. The salts and esters are generally colorless.Werner Reutemann and Heinz Kieczka "Formic Acid" in ''Ull ...
which by the catalytic action of
formate–tetrahydrofolate ligase In enzymology, a formate—tetrahydrofolate ligase () is an enzyme that catalyzes the chemical reaction :ATP + formate + tetrahydrofolate \rightleftharpoons ADP + phosphate + 10-formyltetrahydrofolate The 3 substrates of this enzyme are ATP, ...
add a 1C unit to THF to yield 10-formyl-THF. Glycine,
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
, and
sarcosine Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a monopeptide with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
can also directly contribute to the THF-bound 1C pool.


Drug interference

A number of drugs interfere with the biosynthesis of THF from folic acid. Among them are the
antifolate Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine ...
dihydrofolate reductase inhibitors Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid ( vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines Pyri ...
such as the antimicrobial,
trimethoprim Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peop ...
, the antiprotozoal,
pyrimethamine Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic disea ...
and the chemotherapy drug
methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
, and the
sulfonamides In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
(competitive inhibitors of
4-aminobenzoic acid 4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA i ...
in the reactions of
dihydropteroate synthetase Dihydropteroate synthase is an enzyme classified under . It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PAB ...
).
Valproic acid Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
, one of the most commonly prescribed epilepsy treatment drugs, also used to treat certain psychological conditions such as bipolar disorder, is a known inhibitor of folic acid, and as such, has been shown to cause birth defects, including neural tube defects, plus increased risk for children having cognitive impairment and autism. There is evidence that folate consumption is protective.


Function

Tetrahydrofolate's main function in metabolism is transporting single-carbon groups (i.e., a
methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
,
methylene group In organic chemistry, a methylene group is any part of a molecule that consists of two hydrogen atoms bound to a carbon atom, which is connected to the remainder of the molecule by two single bonds. The group may be represented as , where the '< ...
, or
formyl group In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a 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 Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, the synthesis of
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
from
homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
, 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. Formyl folate is required for two of the steps in the biosynthesis of
inosine monophosphate Inosinic acid or inosine monophosphate (IMP) is a nucleotide (that is, a nucleoside monophosphate). Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in met ...
, the precursor to GMP and AMP. Methylenetetrahydrofolate donates the C1 center required for the biosynthesis of
dTMP Thymidine monophosphate (TMP), also known as thymidylic acid (conjugate base thymidylate), deoxythymidine monophosphate (dTMP), or deoxythymidylic acid (conjugate base deoxythymidylate), is a nucleotide that is used as a monomer in DNA. It is an ...
(2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). The conversion is catalyzed by
thymidylate synthase Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleo ...
.


Vitamin B12 activation

Methyl-THF converts vitamin B12 to methyl-B12 (
methylcobalamin Methylcobalamin (mecobalamin, MeCbl, or MeB) is a cobalamin, a form of vitamin B. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and c ...
). Methyl-B12 converts homocysteine, in a reaction catalyzed by
homocysteine methyltransferase Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the ''MTR'' gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms ...
, to
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
. 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.


Dietary recommendations

Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. One DFE is defined as 1 μg of dietary folate. 1 μg of folic acid supplement counts as 1.7 μg DFE. The reason for the difference is that when folic acid is added to food or taken as a dietary supplement with food it is at least 85% absorbed, whereas only about 50% of folate naturally present in food is absorbed. The U.S. Institute of Medicine defines Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs), Adequate Intakes (AIs), and Tolerable upper intake levels (ULs) – collectively referred to as
Dietary Reference Intake The Dietary Reference Intake (DRI) is a system of nutrition recommendations from the National Academy of Medicine (NAM) of the National Academies (United States). It was introduced in 1997 in order to broaden the existing guidelines known as Reco ...
s (DRIs). The
European Food Safety Authority The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
(EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men over age 18 the PRI is set at 330 μg/day. PRI for pregnancy is 600 μg/day, for lactation 500 μg/day. For children ages 1–17 years the PRIs increase with age from 120 to 270 μg/day. These values differ somewhat from the U.S. RDAs. The United Kingdom's Dietary Reference Value for folate, set by the Committee on Medical Aspects of Food and Nutrition Policy in 1991, is 200 μg/day for adults.


Safety

The risk of toxicity from folic acid is low because folate is a water-soluble vitamin and is regularly removed from the body through urine. One potential issue associated with high doses of folic acid is that it has a masking effect on the diagnosis of
pernicious anaemia Pernicious anemia is a type of Vitamin B12 deficiency, vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of Vitamin B12, vitamin B12. Malabsorption in pernicious anemia results fr ...
due to vitamin B12 deficiency, and may even precipitate or exacerbate neuropathy in vitamin B12-deficient individuals. This evidence justified development of a UL for folate. In general, ULs are set for vitamins and minerals when evidence is sufficient. The adult UL of 1,000 μg for folate (and lower for children) refers specifically to folic acid used as a supplement, as no health risks have been associated with high intake of folate from food sources. The EFSA reviewed the safety question and agreed with United States that the UL be set at 1,000 μg. The Japan National Institute of Health and Nutrition set the adult UL at 1,300 or 1,400 μg depending on age. Reviews of clinical trials that called for long-term consumption of folic acid in amounts exceeding the UL have raised concerns. Excessive amounts derived from supplements are more of a concern than that derived from natural food sources and the relative proportion to vitamin B12 may be a significant factor in adverse effects. One theory is that consumption of large amounts of folic acid leads to detectable amounts of unmetabolized folic acid circulating in blood because the enzyme
dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...
that converts folic acid to the biologically active forms is rate limiting. Evidence of a negative health effect of folic acid in blood is not consistent, and folic acid has no known cofactor function that would increase the likelihood of a causal role for free FA in disease development. However, low vitamin B12 status in combination with high folic acid intake, in addition to the previously mentioned neuropathy risk, appeared to increase the risk of cognitive impairment in the elderly. Long-term use of folic acid dietary supplements in excess of 1,000 μg/day has been linked to an increase in prostate cancer risk.


Food labeling

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For folate labeling purposes 100% of the Daily Value was 400 μg. As of the 27 May 2016 update, it was kept unchanged at 400 μg. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with
US$ The United States dollar (symbol: $; code: USD; also abbreviated US$ or U.S. Dollar, to distinguish it from other dollar-denominated currencies; referred to as the dollar, U.S. dollar, American dollar, or colloquially buck) is the official ...
10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at
Reference Daily Intake The Reference Daily Intake (RDI) used in nutrition labeling on food and dietary supplement products in the U.S. and Canada is the daily intake level of a nutrient that is considered to be sufficient to meet the requirements of 97–98% of health ...
. European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For folate, 100% RI was set at 200 μg in 2011.


Deficiency

Folate deficiency can be caused by unhealthy diets that do not include enough vegetables and other folate-rich foods; diseases in which folates are not well absorbed in the digestive system (such as
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
or
celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barl ...
); some genetic disorders that affect levels of folate; and certain medicines (such as phenytoin,
sulfasalazine Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is ...
, or trimethoprim-sulfamethoxazole). Folate deficiency is accelerated by alcohol consumption, possibly by interference with folate transport. Folate deficiency may lead to
glossitis Glossitis can mean soreness of the tongue, or more usually inflammation with depapillation of the dorsal surface of the tongue (loss of the lingual papillae), leaving a smooth and erythematous (reddened) surface, (sometimes specifically termed atro ...
, diarrhea, depression, confusion, anemia, and fetal neural tube and brain defects. Other symptoms include fatigue, gray hair, mouth sores, poor growth, and swollen tongue. Folate deficiency is diagnosed by analyzing a
complete blood count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cell ...
(CBC) and plasma vitamin B12 and folate levels. A serum folate of 3 μg/L or lower indicates deficiency. Serum folate level reflects folate status, but erythrocyte folate level better reflects tissue stores after intake. An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status. Serum folate reacts more rapidly to folate intake than erythrocyte folate. Since folate deficiency limits cell division,
erythropoiesis Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is stimulated by decrea ...
(production of red blood cells) is hindered. This leads to
megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...
, which is characterized by large, immature red blood cells. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division, and produces abnormally large red cells called megaloblasts (and hypersegmented neutrophils) with abundant cytoplasm capable of RNA and protein synthesis, but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature (reticulocytes), are released early from the marrow in an attempt to compensate for the anemia. Both adults and children need folate to make normal red and white blood cells and prevent anemia, which causes fatigue, weakness, and inability to concentrate. Increased homocysteine levels suggest tissue folate deficiency, but homocysteine is also affected by vitamin B12 and vitamin B6, renal function, and genetics. One way to differentiate between folate deficiency and vitamin B12 deficiency is by testing for
methylmalonic acid Methylmalonic acid (MMA) (conjugate base methylmalonate) is a dicarboxylic acid that is a ''C''-methylated derivative of malonate. The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl ...
(MMA) levels. Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B12 deficiency. Elevated MMA levels may also be due to the rare metabolic disorder
combined malonic and methylmalonic aciduria Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. Some researchers have hypothes ...
(CMAMMA). Folate deficiency is treated with supplemental oral folic acid of 400 to 1000 μg per day. This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption. People with megaloblastic anemia need to be tested for vitamin B12 deficiency before treatment with folic acid, because if the person has vitamin B12 deficiency, folic acid supplementation can remove the anemia, but can also worsen neurologic problems. Cobalamin (vitamin B12) deficiency may lead to folate deficiency, which, in turn, increases homocysteine levels and may result in the development of cardiovascular disease or birth defects.


Sources

The
United States Department of Agriculture The United States Department of Agriculture (USDA) is the United States federal executive departments, federal executive department responsible for developing and executing federal laws related to farming, forestry, rural economic development, ...
,
Agricultural Research Service The Agricultural Research Service (ARS) is the principal in-house research agency of the United States Department of Agriculture (USDA). ARS is one of four agencies in USDA's Research, Education and Economics mission area. ARS is charged with ext ...
maintains a food composition database from which folate content in hundreds of foods can be searched as shown in the table. The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods, and whether those programs are voluntary or mandatory. In the US, mandatory fortification of enriched breads, cereals, flours, corn meal, pastas, rice, and other grain products began in January 1998. As of 21 December 2018, 81 countries required food fortification with one or more vitamins. The most commonly fortified vitamin – as used in 62 countries – is folate; the most commonly fortified food is wheat flour, followed by maize flour and rice. From country to country, added folic acid amounts range from 0.4 to 5.1 μg/100 g, but the great majority are in a more narrow range of 1.5 to 2.5 μg/100 g. Folate naturally found in food is susceptible to destruction from high heat cooking, especially in the presence of acidic foods and sauces. It is soluble in water, and so may be lost from foods boiled in water. For foods that are normally consumed cooked, values in the table are for folate naturally occurring in cooked foods.


Food fortification

''Folic acid fortification'' is a process where synthetic folic acid is added to wheat flour or other foods with the intention of promoting public health through increasing blood folate levels in the populace. It is used as it is more stable during processing and storage. After the discovery of the link between insufficient folic acid and
neural tube defects Neural tube defects (NTDs) are a group of birth defects in which an opening in the Vertebral column, spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal si ...
, governments and health organizations worldwide made recommendations concerning folic acid supplementation for women intending to become pregnant. Because the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant, many countries in time decided to implement mandatory food fortification programs. 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, with some countries reporting a greater than 50% reduction. Folic acid is added to grain products in more than 80 countries, either as required or voluntary fortification, and these fortified products make up a significant source of the population's folate intake. Fortification is controversial, with issues having been raised concerning individual liberty, as well as the theorized health concerns described in the Safety section. In the U.S., there is concern that the federal government mandates fortification but does not provide monitoring of potential undesirable effects of fortification. The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods. The most commonly mandatory fortified vitamin – in 62 countries – is folate; the most commonly fortified food is wheat flour.


Australia and New Zealand

Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
and
New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...
jointly agreed to wheat flour fortification through the
Food Standards Australia New Zealand Food Standards Australia New Zealand (FSANZ) (Māori: ''Te Mana Kounga Kai – Ahitereiria me Aotearoa''), formerly Australia New Zealand Food Authority (ANZFA), is the statutory authority in the Australian Government Health portfolio that is ...
in 2007. The requirement was set at 135 µg of folate per 100 g of bread. Australia implemented the program in 2009. New Zealand was also planning to fortify bread (excluding organic and unleavened varieties) starting in 2009, but then opted to wait until more research was done. The Association of Bakers and the
Green Party A green party is a formally organized political party based on the principles of green politics, such as social justice, environmentalism and nonviolence. Greens believe that these issues are inherently related to one another as a foundation ...
had opposed mandatory fortification, describing it as "mass medication". Food Safety Minister
Kate Wilkinson Kate Wilkinson (October 25, 1916 – February 9, 1993) was an American stage, film and television actress. Career She is best known to TV audiences for her roles as Viola Stapleton in the CBS soap opera ''Guiding Light'', a role she played ...
reviewed the decision to fortify in July 2009, citing as reasons to oppose claims for links between over consumption of folate with increased risk of cancer. In 2012 the delayed mandatory fortification program was revoked and replaced by a voluntary program, with the hope of achieving a 50% bread fortification target.


Canada

Canadian public health efforts focused on promoting awareness of the importance of folic acid supplementation for all women of childbearing age and decreasing socio-economic inequalities by providing practical folic acid support to vulnerable groups of women. Folic acid
food fortification Food fortification or enrichment is the process of adding micronutrients (essential trace elements and vitamins) to food. It can be carried out by food manufacturers, or by governments as a public health policy which aims to reduce the number of p ...
became mandatory in 1998, with the fortification of 150 µg of folic acid per 100 grams of
enriched flour Enriched flour is flour with specific nutrients returned to it that have been lost while being prepared. These restored nutrients include iron and B vitamins (folic acid, riboflavin, niacin, and thiamine). Calcium may also be supplemented. The ...
and uncooked
cereal A cereal is any Poaceae, grass cultivated for the edible components of its grain (botanically, a type of fruit called a caryopsis), composed of the endosperm, Cereal germ, germ, and bran. Cereal Grain, grain crops are grown in greater quantit ...
grains. The results of folic acid fortification on the rate of neural tube defects in
Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
have been positive, showing a 46% reduction in prevalence of NTDs; the magnitude of reduction was proportional to the prefortification rate of NTDs, essentially removing geographical variations in rates of NTDs seen in Canada before fortification.


United Kingdom

While the
Food Standards Agency , type = Non-ministerial government department , nativename = , nativename_a = , nativename_r = , logo = Food Standards Agency.svg , logo_width = , logo_caption = , seal = , seal_width = , seal_caption = , picture = , picture_width = , ...
recommended folic acid fortification, and wheat flour is fortified with iron, folic acid fortification of wheat flour is allowed voluntarily rather than required. A 2018 review by authors based in the United Kingdom strongly recommended that mandatory fortification be reconsidered as a means of reducing the risk of neural tube defects.


United States

In 1996, the United States
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products. This ruling took effect on 1 January 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns. There were concerns expressed that the amount of folate added was insufficient. The fortification program was expected to raise a person's folic acid intake level by 70–130 µg/day; however, an increase of almost double that amount was actually observed. This could be from the fact that many foods are fortified by 160–175% over the required amount. Much of the elder population take supplements that add 400 µg to their daily folic acid intake. This is a concern because 70–80% of the population have detectable levels of unmetabolized folic acid in their
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
, a consequence of folic acid supplementation and fortification. However, at blood concentrations achieved via food fortification, folic acid has no known cofactor function that would increase the likelihood of a causal role for free FA in disease development. The U.S. National Center for Health Statistics conducts the biannual National Health and Nutrition Examination Survey (NHANES) to assess the health and nutritional status of adults and children in the United States. Some results are reported as What We Eat In America. The 2013–2014 survey reported that for adults ages 20 years and older, men consumed an average of 249 μg/day folate from food plus 207 μg/day of folic acid from consumption of fortified foods, for a combined total of 601 μg/day of dietary folate equivalents (DFEs because each microgram of folic acid counts as 1.7 μg of food folate). For women, the values are 199, 153 and 459 μg/day, respectively. This means that fortification led to a bigger increase in folic acid intake than first projected, and that more than half the adults are consuming more than the RDA of 400 μg (as DFEs). Even so, fewer than half of pregnant women are exceeding the pregnancy RDA of 600 μg/day. Before folic acid fortification, about 4,100 pregnancies were affected by a neural tube defect each year in the United States. The
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
reported in 2015 that since the addition of folic acid in grain-based foods as mandated by the FDA, the rate of neural tube defects dropped by 35%. This translates to an annual saving in total direct costs of approximately $508 million for the NTD-affected births that were prevented. In 2020, it was the 67th most commonly prescribed medication in the United States, with more than 10million prescriptions.


History

In the 1920s, scientists believed folate deficiency and anemia were the same condition. In 1931, researcher
Lucy Wills Lucy Wills, LRCP (10 May 1888 – 26 April 1964) was an English haematologist and physician researcher. She conducted research in India in the late 1920s and early 1930s on macrocytic anaemia of pregnancy, a disease which is characterized by ...
made a key observation that led to the identification of folate as the nutrient required to prevent
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
during pregnancy. Wills demonstrated that anemia could be reversed with
brewer's yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitu ...
. In the late 1930s, folate was identified as the corrective substance in brewer's yeast. It was first isolated via extraction from
spinach Spinach (''Spinacia oleracea'') is a leafy green flowering plant native to central and western Asia. It is of the order Caryophyllales, family Amaranthaceae, subfamily Chenopodioideae. Its leaves are a common edible vegetable consumed either f ...
leaves by Herschel K. Mitchell,
Esmond E. Snell Esmond Emerson Snell (September 22, 1914 – December 9, 2003) was an American biochemist who spent his career researching vitamins and nutritional requirements of bacteria and yeast. He is well known for his study of lactic acid-producing bact ...
, and
Roger J. Williams Roger John Williams (August 14, 1893 – February 20, 1988), was an American biochemist. He is known for is work on vitamins and human nutrition. He had leading roles in the discovery of folic acid, pantothenic acid, vitamin B6, lipoic acid ...
in 1941. The term "folic" is from the Latin word (which means leaf) because it was found in dark-green leafy vegetables. Historic names included ''L.casei'', factor vitamin Bc after research done in chicks and vitamin M after research done in monkeys. Bob Stokstad isolated the pure crystalline form in 1943, and was able to determine its chemical structure while working at the Lederle Laboratories of the American Cyanamid Company. This historical research project, of obtaining folic acid in a pure crystalline form in 1945, was done by the team called the "folic acid boys", under the supervision and guidance of Director of Research Dr.
Yellapragada Subbarow Yellapragada Subba Rao (12 January 1895 – 8 August 1948) was a pioneering Indian biochemist who discovered the function of adenosine triphosphate (ATP) as an energy source in the cell, developed methotrexate for the treatment of cancer a ...
, at the Lederle Lab, Pearl River, NY. This research subsequently led to the synthesis of the antifolate
aminopterin Aminopterin (or 4-aminopteroic acid), the 4-amino derivative of folic acid, is an antineoplastic drug with immunosuppressive properties often used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inh ...
, which was used to treat
childhood leukemia Childhood leukemia is leukemia that occurs in a child and is a type of childhood cancer. Childhood leukemia is the most common childhood cancer, accounting for 29% of cancers in children aged 0–14 in 2018. There are multiple forms of leukemia t ...
by
Sidney Farber Sidney Farber (September 30, 1903 – March 30, 1973) was an American pediatric pathologist. He is regarded as the father of modern chemotherapy for his work using folic acid antagonists to combat leukemia, which led to the development of other c ...
in 1948. In the 1950s and 1960s, scientists began to discover the biochemical mechanisms of action for folate. In 1960, researchers linked folate deficiency to risk of neural tube defects. In the late 1990s, the U.S. and Canadian governments decided that despite public education programs and the availability of folic acid supplements, there was still a challenge for women of child-bearing age to meet the daily folate recommendations, which is when those two countries implemented folate fortification programs. As of December 2018, 62 countries mandated food fortification with folic acid.


Animals

Veterinarians may test cats and dogs if a risk of folate deficiency is indicated. Cats with exocrine pancreatic insufficiency, moreso than dogs, may have low serum folate. In dog breeds at risk for cleft lip and cleft palate dietary folic acid supplementation significantly decreased incidence.


See also

*
Levomefolic acid Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprodu ...


References


External links

* ;Biochemistry links
Folate biosynthesis (early stages)
{{DEFAULTSORT:Folic Acid B vitamins Dicarboxylic acids World Health Organization essential medicines Wikipedia medicine articles ready to translate