It is suggested that in man the
methyl folate trap is a normal physiological response to impending methyl group deficiency resulting from a very low supply of
methionine. This decreases cellular S-adenosyl-
methionine (SAM), which puts at risk important methylation reactions, including those required to maintain myelin. In order to protect these methylation reactions, the cell has evolved two mechanisms to maintain supplies of
methionine and SAM as a first priority. (a) Decreased SAM causes the
folate co-factors to be directed through the cycle involving 5-methyl-tetrahydrofolate (5-methyl-THF) and
methionine synthetase and away from the cycles that produce
purines and
pyrimidines for
DNA synthesis. This enhances the remethylation of
homocysteine to
methionine and SAM. In addition, by restricting
DNA biosynthesis and with it cell, division, competition for
methionine for
protein synthesis is reduced. Thus, whatever
methionine is available is conserved for the vital methylation reactions in the nerves, brain, and elsewhere. (b) 5-methyl-THF, the form in which almost all
folate is transported in human plasma, must react with intracellular
homocysteine before it can be retained by the cell as a
polyglutamate. Since
homocysteine is derived entirely from
methionine,
methionine deficiency will cause intracellular
folate deficiency, and the rate of mitosis of rapidly dividing cells will be reduced. although these two processes have evolved as a response to
methionine deficiency, they also occur in B12 deficiency, which the cell mistakenly interprets as lack of
methionine. the resulting response is inappropriate and gives rise to a potentially lethal anaemia. In these circumstances the methylation reactions are also partly protected by the reduced rate of cell division. This explains why administration of
folic acid, which induces cell division and use of
methionine in
protein synthesis, impairs methylation of myelin and precipitates or exacerbates
subacute combined degeneration (SCD). During
folate deficiency
methionine biosynthesis is also diminished. As in
methionine deficiency, the body responds to decreasing availability of SAM by diverting
folate away from
DNA biosynthesis towards the remethylation of
homocysteine to
methionine and SAM. The selective use pf available
folate to conserve
methionine, together with the ability of nerve tissue to concentrate
folate form the plasma, explains the absence of SCD in
folate deficiency.