Methylation folates

The Methyl Folate Trap Hypothesis The reduction of meth-ylene-tetrahydrofolate to methyl-tetrahydrofolate is irreversible (Section 10.3.2.1), and the major source of folate for tissues is methyl-tetrahydrofolate. The only metabolic role of methyl-tetrahydrofolate is the methylation of homocysteine to methionine, and this is the only way in which methyl-tetrahydrofolate can be demethylated to yield free tetrahydrofolate in tissues. Methionine synthetase thus provides the link between the physiological functions of folate and vitamin B12. 

This has been called the methyl folate trap and appears to explain many of the similarities between the symptoms and metabolic effects of folate and vitamin B12 deficiency, although it does not provide a completely satisfactory explanation (Chanarin et al., 1985). 

The cause of megaloblastosis is depressed DNA synthesis, as a result of impaired methylation of dCDP to TDP, catalyzed by thymidylate synthetase, but more or less normal synthesis of RNA. As discussed in Section 10.3.3, thymidylate synthetase uses methylene tetrahydrofolate as the methyl donor it is obvious that folic acid deficiency will result in unpaired thymidylate synthesis. It is less easy to see how vitamin B12 deficiency results in impaired thymidylate synthesis without invoking the methyl folate trap hypothesis (Section 10.3.4.1). The main circulating form of folic acid is methyl-tetrahydrofolate before this can be used for other reactions in tissues, it must be demethylated to yield free folic acid. The only reaction that achieves this is the reaction of methionine synthetase (Section 10.8.1). Thus, vitamin B12 deficiency results in a functional deficiency of folate. 

Administration of diphenylhydantoin leads to decreased activity of methylene tetrahydrofolate reductase and an increased rate of oxidation of formyl tetrahydrofolate (increased oxidation of formate and histidine), with a fall in methylene- and methyl-tetrahydrofolate - the reverse of the effect of the methyl folate trap (Billings, 1984a, 1984b). 

About30% ofvitamin Bi2-deficient subjects have elevated serum folate. This is mainly methyl-tetrahydrofolate, the result of the methyl folate trap (Section 10.3.4.1). About one-third of folate-deficient subjects have low serum vitamin B12 the reason for this is not clear, but it responds to the administration of folate supplements. 

The Methyl Folate Trap Hypothesis The reduction of meth-ylene-tetreihydrofolate to methyl-tetreihydrofolate is irreversible (Section... 

About30% of vitaminBi2-deficient subjects have elevated serum folate. This is mednly methyl-tetrahydrofolate, the result of the methyl folate trap (Section... 

If folate is given without cobalamin to a B 12-deficient patient, the drug only partially corrects the megaloblastic anemia because it will bypass the methyl-folate trap and provide adequate FH4 coenzyme for the conversion of dUMP to dTMP and for a resurgence of purine synthesis. As a result, normal DNA synthesis, DNA repair, and cell division occur. However, the neurologic syndrome, resulting from hypomethylation in nervous tissue, may progress unless the physician realizes that B12 supplementation is required. In Jean Ann s case, in which the serum B12 concentration was borderline low and in which the dietary history supported the possibility of a B12 deficiency, a combination of folate and B12 supplements is required to avoid this potential therapeutic trap. 

Folate, bound to protein, is transported in the blood to the liver. There it is methylated and carried to the bone marrow cells, the maturing red blood cells, and perhaps to other cells. Methyl-folate seems to be the chief form of the vitamin in body tissues. Serum levels of folacin range from 7 to 16 nanograms per milliliter of serum. The total body stores of folate normally range between 5 and 12 mg, about half of which is in the liver. The measurement of folacin levels in both blood serum and red blood cells is the procedure used to evaluate folacin nutriture in human beings. 

Red blood cell folate levels which are reduced in vitamin Bj 2 deficient patients increase upon initiation of vitamin therapy (Herbert and Zalusky, 1962). The reduction in total RBC folate is due primarily to decreased folyl polyglutamates with little change in monoglutamates (Jeejeebhoy et al., 1965 Chanarin et al, 1974). Stokstad and co-workers have demonstrated decreased pteroylpolygluta-mates (Thenen and Stokstad, 1973) and an increase in the ratio of methylated to non-methylated folates in the livers of vitamin B 2 deficient rats (Vidal and Stokstad, 1974). Reduction of Me THF uptake was seen in bone marrow cells (Tisman and Herbert, 1973) and PHA-stimulated lymphocytes (Lavoie et al., 1974) from vitamin patients. Lavoie et al. also found a reduction in transfer of methyl groups from C-Me THF to non-folate compounds. 

Sauer, H. and Wilmans, W. (1977) Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B 2 deficiency, B. J. Haematol., 36 189. 

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