Methylenetetrahydrofolate Reductase: Comparison of the Enzyme from Mammalian and Bacterial Sources

Methylenetetrahydrofolate reductase catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, which serves as the methyl donor for the conversion of homocysteine to methionine in the reaction catalyzed by methionine synthase. Recent studies have provided evidence for association of a common polymorphism of methylenetetrahydrofolate reductase with elevated levels of blood homocysteine, a metabolite correlated with increased cardiovascular risk in humans. In this chapter, we review earlier studies on the properties of the mammalian enzyme, interpreting these observations in the light of the deduced amino acid sequence for the human enzyme. The catalytic portion of the human enzyme shows significant sequence homologies with methylenetetrahydrofolate reductase from bacterial sources, and in particular mutations that are known to cause elevated blood homocysteine levels in humans affect residues that are conserved in the bacterial enzyme. Thus we believe that studies of mutant E. coli proteins will provide valuable information on the consequences of human mutations of equivalent residues