Vitamin methyl folate trap

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. 

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. 

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. 

When acting as a methyl donor, 5-adenosylmethionine forms homocysteine, which may be remethylated by methyltetrahydrofolate catalyzed by methionine synthase, a vitamin Bj2-dependent enzyme (Figure 45-14). The reduction of methylene-tetrahydrofolate to methyltetrahydrofolate is irreversible, and since the major source of tetrahydrofolate for tissues is methyl-tetrahydrofolate, the role of methionine synthase is vital and provides a link between the functions of folate and vitamin B,2. Impairment of methionine synthase in Bj2 deficiency results in the accumulation of methyl-tetrahydrofolate—the folate trap. There is therefore functional deficiency of folate secondary to the deficiency of vitamin B,2. 

In vitamin B12 deficiency, a functional folate deficiency is observed because folate is "trapped" in the form of 5-methyl-THF. Both folate and vitamin B12 deficiencies result in megaloblastic anemia. Actual folate deficiency is often observed in alcoholics and pregnant women. 

The principal substrate for glutamylation is free tetrahydrofolate one-carbon substituted folates are poor substrates. Because the main circulating folate, and the main form that is taken up into tissues, is methyl-tetrahydrofolate, demethylation by the action of methionine synthetase (Section 10.3.3) is essential for effective metabolic trapping of folate. In vitamin B12 deficiency, when methionine synthetase activity is impaired, there wUl be impairment of the retention of folate in tissues. 

The activity of 10-formyl-tetrediydrofolate dehydrogenase, which catalyzes the oxidation of 10-formyl tetrahydrofolate to CO2 and tetrahydrofolate, is reduced at times of low methionine availability as a means of conserving valuable one-caibon fragments. Therefore, there is no sink for one-carbon substituted tetrahydrofolate, and increasing amounts of folate are trapped as methyl-tetrahydrofolate that cannot be used because of the lack of vitamin B12 (Krebs etal., 1976). 

Folic acid and vitamin B]2 metabohsm are linked by the reaction that transfers a methyl group from 5-MTHF to cobalamin. In cases of cobalamin deficiency, folate is trapped as 5-MTHF and is metabolically dead. It cannot... 

B. Excess folate, by overwhelming the folate pool trapped as N -methyltetrahydrofolate, can allow for formation of AI, A4°-methyl-enetetrahydrofolate which is required for the thymidylate synthase reaction for DNA synthesis and red blood cell formation. Folate is not recognized as a methyl donor by methionine synthase. Folate does not inhibit destruction of erythrocytes. Cobalamin is an important critical vitamin not synthesized by humans. 

Deficiency of either vitamin Bj or folate decreases the synthesis of methionine and SAM, thereby interfering with protein biosynthesis, a number of methylation reactions, and the synthesis of polyamines. In addition, the cell responds to the deficiency by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate this tends to preserve essential methylation reactions at the expense of nucleic acid synthesis. With vitamin Bj deficiency, methylenetetrahydro-folate reductase activity increases, directing available intracellular folates into the methyltetrahydrofolate pool (not shown in Figure 53-6). The methyltetrahydrofolate then is trapped by the lack of sufficient vitamin Bj to accept and transfer methyl groups, and subsequent steps in folate metabolism... 

If one analyzes the flow of carbon in the folate cycle, the equilibrium lies in the direction of the N -methyl FH4 form. This appears to be the most stable form of carbon attached to the vitamin. However, in only one reaction can the methyl group be removed from N -methyl FH4, and that is the methionine synthase reaction, which requires vitamin B12. Thus, if vitamin B12 is deficient, or if the methionine synthase enzyme is defective, N -methyl FH4 will accumulate. Eventually most folate forms in the body will become trapped in the N -methyl form. A functional folate deficiency results because the carbons cannot be removed from the folate. The appearance of a functional folate deficiency caused by a lack of vitamin B12 is known as the methyl-trap hypothesis, and its clinical implications are discussed in following sections. 

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