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.
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. 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 B12 and it is necessary for the synthesis of DNA, and so required for all dividing cells.
The pathway leading to the formation of tetrahydrofolate (FH4) begins when folate (F) is reduced to dihydrofolate (DHF) (FH2), which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis.
Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. It is important to note that Vitamin B12 is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B12 which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a deficiency of B12 can lead to a methyl-trap of THF and a subsequent deficiency
However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as cereals and grains, and as a result diets of most adults now provide recommended amounts of folate equivalents.
Further Reading
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