Methylene tetrahydrofolate polymorphism

A second relevant enzyme to 5-FU metabolism is thymidylate synthetase (TYMS). If this enzyme is complexed with 5-FU metabolites along with 5,10-methylene-tetrahydrofolate, it cannot maintain a thymidine-5 -monophosphate pool required for DNA replication and repair. A tandem repeat polymorphism in the 5 -promoter region of the TYMS gene can increase enzyme expression (85,86). Tumors carrying the repeats have higher enzyme expression, resulting in lower response to chemotherapy compared to wild type (87). 

There is a second polymorphism of methylene-tetrahydrofolate reductase in about 10% of the population, in which adenosine is replaced by cytosine. 

As shown in Figure 10.9, the overall reaction of methionine synthetase is the transfer of the methyl group from methyl-tetrahydrofolate to homocysteine. However, the enzyme also requires S-adenosyl methionine and a flavoprotein reducing system in addition to the cobalamin prosthetic group. A common polymorphism of methionine synthetase, in which aspartate is replaced by glycine, is associated with elevated plasma homocysteine in some cases, although it is less important than methylene-tetrahydrofolate reductase polymorphisms (Section 10.3.2.1 Harmon etal., 1999). 

Hanson, H. Q. et al., C677T and A1298C polymorphisms of methylene tetrahydrofolate reductase gene Incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease, Clin. Chem., 47, 661-666, 2001. 

Shi, Q., Zhang, Z., Li, G., Pillow, P.C., Hernandez, L.M., Spitz, M.R., and Wei, Q., 2005. Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms. Cancer Epidemiology, Biomarkers Prevention. 14 1477-1484. 

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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