By Dr Ananya Mandal, MD
Folic acid is vital for humans and other animals as it is one of the basic building blocks and catalysts for several important biochemical reactions of the body.
Folate is converted to tetrahydrofolate and other derivatives that perform the biological actions. The actual biological activity depends on dihydrofolate reductase action in the liver. This action is unusually slow in humans.
History of folate discovery
Folate and its role in human biochemical functioning was first identified by researcher Lucy Wills in 1931. She found that the nutrient was needed to prevent anemia during pregnancy. Dr. Wills demonstrated that anemia could be reversed with brewer's yeast. It was in the later 1930’s that folate was isolated from brewer's yeast.
It was first extracted by Mitchell and others in 1941. Bob Stokstad isolated the pure crystalline form in 1943. This research in the Lederley Lab, Pearl River, NY under Dr. Yellapragada Subbarao, the then Director of the institute, was the basis for synthesis of Aminopterin, the first ever anti-cancer drug, the clinical proof of its efficacy was proven by Dr. S. Farber in 1948.
The basis for anti-cancer principles was found to be anti-folate actions. Antifolate actions thus acted during periods of rapid cell division and growth such as in cancer. Indirectly the role of folate on growth during infancy and pregnancy was found.
Chemical role of folate
Folic acid’s primary mechanisms of action are through its role as a one carbon donor. Folate helps in transfer of a single methyl group in various metabolic reactions in the body and in the functioning of the nervous system.
It is essential for DNA synthesis. More specifically it helps in the manufacture of nucleic acids like Thymine. For the reactions the following steps are important:
Folic acid is a composite molecule, being made up of three parts: a pteridine ring system (6-methylpterin), para-aminobenzoic acid, and glutamic acid. The glutamic acid does not participate in the coenzyme functions of folic acid.
The pteridine portion of the coenzyme and the p-aminobenzoic acid portion participate directly in the metabolic reactions of folate.
To carry out the transfer of 1-carbon units, NADPH must reduce folic acid two times in the cell. The “rightmost” pyrazine ring of the 6-methylpterin is reduced at each of the two N-C double bonds. The resulting 5,6,7,8-tetrahydrofolate is the acceptor of 1-carbon groups.
Amino acid Serine reacts with tetrahydrofolate to form 5,10-methylenetetrahydrofolate. This is the folate derivative involved in DNA synthesis.
A methyl group is donated to cobalamin (B12) by 5-methyltetrahydrofolate to form methylcobalamin.
With the help of the enzyme methionine synthase, methylcobalamin donates a methyl group to the amino acid metabolite homocysteine. This homocysteine is then converted to amino acid methionine
Methionine is then converted to S-adenosyl-methionine (SAMe), a methyl donor involved in numerous biochemical processes.
Folate is thus important in DNA synthesis and cell division, affecting hematopoietic cells or blood forming cells that are rapidly dividing as well as cancer cells. Protein synthesis and RNA transcription is less affected by folate deficiency.
Reviewed by April Cashin-Garbutt, BA Hons (Cantab)