structural:expansion
Mechanism

Methionine synthase catalyzes the final step in the regeneration of methionine (Met) from homocysteine (Hcy). Both the cobalamin-dependent and cobalamin-independent forms of the enzyme carry out the same overall chemical reaction, the transfer of a methyl group from 5-methyltetrahydrofolate (N -MeTHF) to homocysteine, yielding tetrahydrofolate (THF) and methionine. Methionine synthase is the only mammalian enzyme that metabolizes N -MeTHF to regenerate the active cofactor THF. In the cobalamin -dependent (MetH) form of the enzyme, the reaction proceeds by two steps in a preferred ordered sequential mechanism. The physiological resting state of the enzyme is thought to contain the enzyme-bound(Cob) cofactor in the methylcobalamin form, with the cobalt atom in the formal +3 valence state (Cob(III)-Me). The cobalamin is then demethylated by zinc -activated thiolate homocysteine, generating methionine and reducing the cofactor to a Cob(I) state. When in the Cob(I) form, the enzyme-bound cofactor is now able to abstract a methyl group from activated 5-methyltetrahydrofolate (N -MeTHF), yielding tetrahydrofolate (THF) and regenerating the methylcoalamin form of the enzyme.