5.10- Methylenetetrahydro folate

In 1995, Horie et al. described a polymorphic tandem repeat found in the 5 -un-translated region of the thymidylate synthase gene [70]. Thymidylate synthase (TS TYMS) catalyzes the intracellular transfer of a methyl group to deoxyuridine-5-monophosphate (dUMP) to form deoxythymidine-5-monophosphate (dTMP), which is anabolized in cells to the triphosphate (dTTP). This pathway is the only de- novo source of thymidine, an essential precursor for DNA synthesis and repair. The methyl donor for this reaction is the folate cofactor 5,10-methylenetetrahydro-folate (CH2-THF) (Figure 24.4). 

Molloy, A. M., Daly, S., Mills, J. L Kirke, P, Whitehead, A., Ramsbottom, D., Conley, M., Weir, D. G., and Scott, J. M. (1997). Thermolabile variant of 5,10-methylenetetrahydro-folate reductase associated with Low red cell folates Implications for folate intake recommendations. Lancet 349, 1591-1593-... 

Perry, K.M., Carreras, C.W., Chang, L.C., Santi, D.V., and Stroud, R.M. (1993) Structures of thymidylate synthase with a C-terminal deletion Role of the C-terminus in alignment of 2 -deoxyuridine 5 -mono-phosphate and 5,10-methylenetetrahydro-folate. Biochemistry 32, 7116-7125. 

Methylenetetrahydrofolate can be transformed to the other cosubstrates by the reactions given in Fig. 23. On hydrolysis of 5,10-methylenetetrahydro-folate formaldehyde is formed. It may be called therefore activated formaldehyde . Formic acid and methanol are formed from the other cosubstrates (Table 16). It is unknown, however, whether the formic acid released as an alarm phermone by certain ants (E 4), or formic acid and methanol in some plants are synthesized in this way. 

Paukert JL, Straus LD, and Rahinowitz JC (1976) Formyl-methyl-methylenetetrahydro-folate synthetase- (combined). An ovine protein with multiple catalytic activities./owr-nal of Biological Chemistry 251, 5104-11. 

Vilaseca MA, Momos E, Artnch R, Colome C, Farre C, Vails C, Cardo E, Pineda M. Anti-epileptic drug treatment in children hyperhomocysteinaemia, B-vitamins and the 677C->T mntation of the methylenetetrahydro-folate reductase gene. Enr J Paediatr Neurol 2000 4(6) 269-77. 

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... 

Methotrexate and aminopterin, a similar compound, are analogs of dihydro folate (DHF) and inhibitors of dihydrofolate reductase, an enzyme that converts DHF to tetrahydro-folate (THF). The thymidylate synthase reaction converts N, N °-methylenetetrahydro-folate to DHF in the process of methylating dUMP to form dTMP In the presence of one of the inhibitors, this reaction functions as a sink that reduces the THF level of the cell by converting THF to DHF. Since THF derivatives are substrates in two reactions of purine metabolism and one of pyrimidine metabolism, both pathways are affected by the inhibitor. 

It is not known how N, N -methylenetetrahydro-folate is formed in tissues. In the laboratory, formylal-dehyde mixed with tetrahydrofolate results in spontaneous formation of the N, N -methylenetetrahy-drofolate. In tissues, a formaldehyde-activating enzyme probably catalyzes the condensing of formaldehyde with tetrahydrofolate. 

However, in a prospective study, atherosclerosis risk in communities (ARIC), there was doubt about a relation between CHD and Hey and no association between CHD and C677T mutation of methylenetetrahydro-folate reductase gene or three mutations of cystathionine P-synthase gene. However, it was possible that vitamin Bg offered an independent protection (143), and recently a review concluded that there is insufficient evidence to regard Hey levels as a causative factor in atherosclerosis (144). 

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