Folic acid (also known as vitamin B 9 or folacin ) and folate (the naturally occurring form), as well as pteroyl-L-glutamic acid and pteroyl-L-glutamate , are forms of the water-soluble vitamin B 9 . Folic acid is itself not biologically active with its biological importance being due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.
Vitamin B 9 (folic acid and folate inclusive) is essential to numerous bodily functions ranging from nucleotide biosynthesis to the remethylation of homocysteine. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in biological reactions involving folate. It is especially important during periods of rapid cell division and growth. Both children and adults require folic acid to produce healthy red blood cells and prevent anemia. Folate and folic acid derive their names from the Latin word folium (which means "leaf"). Leafy vegetables are a principal source, although in Western diets fortified cereals and bread may be a larger dietary source.
A lack of dietary folic acid leads to folate deficiency (FD). This can result in many health problems, most notably neural tube defects in developing embryos. Low folate can also lead to homocysteine accumulation as a result of one carbon metabolism mechanism being impaired. DNA synthesis and repair are impaired and this could lead to cancer development. Supplementation in the general population may however lead to increased rates of cancer and all-cause mortality.
DRI for Folic Acid
Folate in foods and other sources
Leafy vegetables such as spinach, asparagus, turnip greens, romaine lettuces, dried or fresh beans and peas, fortified grain products (pasta, cereal, bread), sunflower seeds and certain other fruits (orange juice, canned pineapple juice, cantaloupe, honeydew melon, grapefruit juice, banana, raspberry, grapefruit, strawberry) and vegetables (beets, broccoli, corn, tomato juice, vegetable juice, brussels sprouts, bok choy) are rich sources of folate. Liver and liver products also contain high amounts of folate, as does baker's yeast. Some breakfast cereals (ready-to-eat and others) are fortified with 25% to 100% of the recommended dietary allowance (RDA) for folic acid. A table of selected food sources of folate and folic acid can be found at the USDA National Nutrient Database for Standard Reference. Folic acid is added to grain products in many countries, and in these countries fortified products make up a significant source of the population's folic acid intake. 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. 1 DFE is defined as 1 μg of dietary folate, or 0.6 μg of folic acid supplement. This is reduced to 0.5 μg of folic acid if the supplement is taken on an empty stomach.
Folic acid naturally found in food is susceptible to high heat, UV, and is soluble in water. It is heat labile in acidic environments and may also be subject to oxidation.
Some meal replacement products do not meet the folate requirements as specified by the RDAs.
Conversion to biologically active derivatives
All the biological functions of folic acid are performed by tetrahydrofolate and other derivatives. Their biological availability to the body depends upon dihydrofolate reductase action in the liver. This action is unusually slow in humans being less than 2% of that in rats. Moreover, in contrast to rats, an almost 5-fold variation in the activity of this enzyme exists between humans. Due to this low activity it has been suggested that this limits the conversion of folic acid into its biologically active forms "when folic acid is consumed at levels higher than the Tolerable Upper Intake Level (1 mg/d for adults)."
History
In the 1920s scientists believed that folate deficiency and anemia were the same condition. A key observation by researcher Lucy Wills in 1931 led to the identification of folate as the nutrient needed to prevent anemia during pregnancy. Dr. Wills demonstrated that anemia could be reversed with brewer's yeast. Folate was identified as the corrective substance in brewer's yeast in the late 1930s and was first isolated in and extracted from spinach leaves by Mitchell and others in 1941 . 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 under the supervision and guidance of Dr. Yellapragada Subbarao, the Director of Research in Lederley Lab, Pearl River, NY and other men famously called 'folic acid boys'.This research subsequently lead to the synthesis of Aminopterin, the first ever anti-cancer drug, the clinical proof of its efficacy was proven by Dr. S. Farber in 1948. In the 1950s and 1960s scientists began to discover the biochemical mechanisms of action for folate. In 1960 experts first linked folate deficiency to neural tube defects. In the late 1990s US scientists realized that despite folate being available in foods and in supplements, there was still a challenge for people to meet their daily folate requirements, and that is when the US implemented the folate fortification program.
Biological roles
DNA and cell division
Folate is necessary for the production and maintenance of new cells, for DNA synthesis and RNA synthesis, and for preventing changes to DNA and thus preventing cancer. It is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to carry one carbon groups for methylation reactions and nucleic acid synthesis (most notably thymine, but also purine bases). Thus, folate deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of rapid 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). Since folate deficiency limits cell division, erythropoiesis, production of red blood cells is hindered and leads to megaloblastic anemia 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. Deficiency of folate in pregnant women has been implicated in neural tube defects (NTD); therefore, many developed countries have implemented mandatory folic acid fortification in cereals, etc. It must be noted that NTD's occur early in pregnancy (first month) therefore women must have abundant folate upon conception. Folate is required to make red blood cells and white blood cells and folate deficiency may lead to anemia which further leads to fatigue and weakness and inability to concentrate.
Biochemistry of DNA base and amino acid production
In the form of a series of tetrahydrofolate (THF) compounds, folate derivatives are substrates in a number of single-carbon-transfer reactions, and also are involved in the synthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). It is a substrate for an important reaction that involves vitamin B 12 and it is necessary for the synthesis of DNA, and so required for all dividing cells.
The pathway leading to the formation of tetrahydrofolate (FH 4 ) begins when folate (F) is reduced to dihydrofolate (DHF) (FH 2 ), which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B 3 in the form of NADPH is a necessary cofactor for both steps of the synthesis.
Methylene-THF (CH 2 FH 4 ) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH 3 -THF) can be made from methylene-THF by reduction of the methylene group with NADPH. It is important to note that Vitamin B 12 is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B 12 which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a deficiency of B 12 can lead to a methyl-trap of THF and a subsequent deficiency. Thus, a deficiency in B 12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency. Another form of THF, formyl-THF or folinic acid) results from oxidation
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