Methionine Synthetase

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 aspartate919 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 et al., 1999).

Cobalt accepts a methyl group from methyl-tetrahydrofolate, forming methyl Co3+ -cobalamin. Transfer of the methyl group onto homocysteine results in the formation of Co+-cobalamin, which can accept a methyl group from methyl-tetrahydrofolate to reform methyl Co3+-cobalamin. However, except under strictly anaerobic conditions, demethylated Co+-cobalamin is susceptible to oxidation to Co2+-cobalamin, which is catalytically inactive. Reactivation of the enzyme requires reductive methylation, with S-adenosyl methionine as the methyl donor, and a flavoprotein linked to NADPH. For this reductive reactivation to occur, the dimethylbenzimidazole group of the coenzyme must be displaced from the cobalt atom by a histidine residue in the enzyme (Ludwig and Matthews, 1997).

Methionine synthetase also catalyzes the reduction of nitrous oxide to nitrogen and in so doing generates a hydroxyl radical that results in irreversible inactivation of the enzyme (Frasca et al., 1986). Inactivation of methionine synthetase by nitrous oxide has been used as an acute model of vitamin B12

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