Folate trap

Figure 45-14. Homocysteinuria and the folate trap. Vitamin 6,2 deficiency leads to inhibition of methionine synthase activity causing homocysteinuria and the trapping of folate as methyltetrahydrofolate.

Vitamin 6 2 Deficiency Causes Functional Folate Deficiency—the Folate Trap... 

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. 

Enzymatic reactions that use folates. Section 1 shows the vitamin B12 -dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin B12 deficiency. Section2 shows the dTMP cycle. 

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 trap The accumulation of A/ -methyltetrahydrofolate and the resulting deficiency in tetrahydrofolate that is caused by vitamin B,j deficiency (Figure 33-2)... 

Figure 33-2. Enzymatic reactions that use folates. Section 1 shows the vitamin B,2-dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin deficiency. Section 2 shows the dTMP cycle. Section 3 shows the pathway by which folate enters the tetrahydrofolate cofactor pool. Double arrows indicate pathways with more than one intermediate step. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

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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