Explain the Functions of Folate?
Folate, also known as folic acid, is essential for good health. Folate requiring reactions include those involved in phases of amino acid metabolism, DNA (purine and pyrimidine) biosynthesis and the formation of the primary methylating agent, S-adenosyl methionine (SAM) as shown in Figure. Folate is involved in the de novo synthesis of purines (adenine and guanine), requiring the folate form, 10-formyl tetrahydro folic acid (THF), which is produced from 5, 10-methylene THF reactions catalyzed by the enzyme THF synthetase. The 510- methylene THF molecule has several fates, one of which is the reconversion to 5- methyl THF, catalyzed by methylene tetra hydrofolate reductase (MTHFR). Thus, folate in its reduced and polyglutamylated forms is essential for the DNA biosynthesis cycle, as shown in Figure. This conversion (5, 10-methylene THF molecule reconversion to 5-methyl THF) forms methionine from homocysteine. Folate, specially helps in reducing the risk of heart disease and stroke by lowering the level of the amino acid homocysteine in the blood (by forming methionine). At high levels, homocysteine can damage coronary arteries or make it easier for blood clotting cells to clump together and form a clot. This can increase the risk of heart attack or stroke. This methylation reaction (refer to Figure) requires the enzyme methionine synthase, cobalamin (vitamin BIZ) and 5-methyl THF. A methyl group is removed from 5 methyl THF and is sequentially transferred first to cobalamin coenzyme and then to homocysteine forming methionine and reconverting 5-methyl THF to tetrahydrofolate (THF). The dependency of methionine synthase on both folate and cobalamin explains why a single deficiency of either vitamin leads to the same megaloblastic changes in the bone marrow and other tissues, with rapidly dividing cells.
Alternatively 5, 10-methylenetetrahydrofolate can be channelled to the methylation cycle (refer to Figure). This cycle has two functions. It ensures that the cell always has an adequate supply of S-adenosylmethionine (SAM), an activated form of methionine which acts as a methyl donor to a wide range of methyltransferases. The methyltransferases methylate a wide range of substrates including lipids, hormones, DNA and proteins. One particularly important methylation is that of myelin basic protein, which acts as insulation for nerve cells. When the methylation cycle is interrupted, as it is during vitamin BIZ deficiency, one of the clinical consequences is the demyelination of nerve cells resulting in a neuropathy which leads to ataxia (lack of coordination), paralysis, and, if untreated, ultimately death. Other important methyltransferase enzymes down-regulate DNA and suppress cell division.