Molecular Biology of Methionine Synthase: Interrelationships with Homocysteine and Vascular Disease

Abstract

Methionine synthase is one of two key enzymes that manages cellular homocysteine and is found in most mammalian tissues. It catalyzes the B12-dependent transmethylation of homocysteine using methyltetrahydrofolate as a methyl group donor. The cDNA encoding human methionine synthase has been cloned recently and its sequence has been determined. Catastrophic mutations in methionine synthase are found in the cblG class of patients, and are correlated with severe hyperhomocysteinemia with attendant cardio­vascular diseases. However, polymorphisms have yet to be found that are correlated with the moderate hyperhomocysteinemia. A mouse knock out of the methionine synthase gene confers an embryonic lethal phenotype, indicating that it is an essential gene. The activity of methionine synthase is also dependent on redox proteins that reactivate oxidized enzyme. The components of this redox pathway have been described recently to be a cytochrome P450-like methionine synthase reductase and soluble cytochrome b5. Mutations in methionine synthase reductase have been identified in the cblE class of patients and are correlated with severe hyperhomocysteinemia.