Methyltetrahydrofolate methylene

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. 

Riboflavin (vitamin B2) Folate cycle reduction of 5,10-methyltetrahydrofolate cofactor for methylene-tetrahydrofolate reductase... 

In vitamin Bj2 deficiency, methyltetrahydrofolate cannot donate its methyl group to homocysteine to regenerate methionine. Because the synthesis of methyltetrahydrofolate is irreversible, the cell s tetrahydrofolate will ultimately be converted into this form. No formyl or methylene tetrahydrofolate will be left for nucleotide synthesis. Pernicious anemia illustrates the intimate connection between amino acid and nucleotide metabolism. 

Methylation of homocysteine by 5-methyltetrahydrofolate-homocysteine methyl reductase depends on an adequate supply of 5-methyltetrahydrofoIate. The unmethylated folate is recycled in a cobalamin-dependent pathway, by remethylation to 5,10-methylene-tetrahydrofolate, and subsequent reduction to 5-methyltetrahydrofolate. The transferase enzyme, also named 5,10-methyltretrahydrofolate reductase catalyzes the whole cycle [3,91]. S-adenosylmethionine and 5-methyltetrahydrofolate are the most important methyl unit donors in biological system. S-adenosylmethionine is reported to regulate methylation and transsulfuration pathways in the homocysteine metabolism [3,91]. 

The interconversion of these forms of foiic acid takes place through various electron transfer reactions facilitated by specific enzyme systems and coenzymes, such as the reduced forms of fiavin-adenine dinucleotide (FADH2) and NADPH. The conversion between the N -, N -methylene form and -formyl forms is readily reversible, but the reduction of methylene to methyl and reduction of free THF to formyltetrahydrofolate is essentially irreversible. Conversion of N -methyltetrahydrofolate back to free THF. may require cobalamin. 

One form of methionine synthase common in bacteria uses lV -methyltetrahydrofolate as a methyl donor. Another form of the enzyme present in some bacteria and mammals uses A/ -methyltetrahydro-folate, but the methyl group is first transferred to cobalamin, derived from coenzyme B12, to form methylcobalamin as the methyl donor in methionine formation. This reaction and the rearrangement of L-methyl-malonyl-CoA to succinyl-CoA (see Box 17-2, Fig. la) are the only known coenzyme Bi2-dependent reactions in mammals. In cases of vitamin B12 deficiency, some symptoms can be alleviated by administering not only vitamin B12 but folate. As noted above, the methyl group of methylcobalamin is derived from W -methyltetrahy-drofolate. Because the reaction converting the methylene form to the 7V -methyl form of tetrahydrofo-... 

Because methionine synthase is the only mammalian enzyme known to act on 5-methyltetrahydrofolate, the decreased intracellular activity of this enzyme causes 5-methyltetrahydrofolate to accumulate, at the expense of depleted pools of the other tetrahydrofolate coenzymes. Thus, even though total folate levels may seem ample, there is a functional folate deficiency, with insufficient levels of the formyl and methylene derivatives needed for synthesis of nucleic acid precursors. 

Riboflavin in the form of FAD is an essential coenzyme for 5,10-methylene tetrahydrofolate reductase, a key enzyme of the folate pathway, which catalyzes the interconversion of 5,10-methylene-tetrahydrofolate and 5-methyltetrahydrofolate. Of the known single nucleotide polymorphisms affecting this enzyme, the best known are the C699T and A1298C variants. The former confer thermolability and potentially reduced enzyme activity in the TT homozygote. Marginal riboflavin status may, in some situations, be associated with increased plasma homocysteine levels (possibly predictive of increased... 

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