Methionine synthase (MS, MeSe, MTR) is primarily responsible for the regeneration of methionine from homocysteine in most individuals. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Humans have a single methionine synthase (MTR), but despite its dependence on vitamin B12 as a cofactor, the reaction is folate‑centric: it absolutely requires 5‑methyltetrahydrofolate (an active form of vitamin B9) as the methyl donor, without which the enzyme cannot function at all. Vitamin B12 (as methylcobalamin) serves only as an internal methyl shuttle, not as the source of methyl groups; it facilitates transfer but does not drive the chemistry. Thus, folate is the essential, non‑substitutable input, while B12 is a secondary helper—important for efficiency, but not the gate‑keeper of the pathway.
Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.
Reaction
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 (N5-MeTHF) to homocysteine, yielding tetrahydrofolate (THF) and methionine. Methionine synthase is the only mammalian enzyme that metabolizes N5-MeTHF to regenerate the active cofactor THF.
Mechanism
Cobalamin-dependent (MetH)
Humans, E. coli, and many other organisms have a cobalamin-dependent version. 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 (N5-MeTHF), yielding tetrahydrofolate (THF) and regenerating the methylcobalamin form of the enzyme. Under human-physiological conditions, approximately once every 2000 catalytic turnovers the Co(I) may be oxidized into inactive Co(II) in cob-dependent MetH. To account for this effect, the protein contains a self-reactivation mechanism, a reductive methylation process that uses S-adenosylmethionine as a distinct methyl donor. In humans, the enzyme is reduced in this process by methionine synthase reductase (MTRR), which consists of flavodoxin-like and ferrodoxin-NADP+ oxidoreductase (FNR)-like domains. In many bacteria, the reduction is carried out by a single domain flavodoxin protein. The reductase protein is responsible for transfer of an electron from a reduced FMN cofactor to the inactive Cob(II), which enables regeneration of the active methylcobalamin enzyme via methyl transfer from S-adenosylmethionine to the reduced Cob(I) intermediate. This process is known as the reactivation cycle, and is thought to be gated from the normal catalytic cycle by large-scale conformational rearrangements within the enzyme. Because the oxidation of Cob(I) inevitably shuts down cob-dependent methionine synthase activity, defects or deficiencies in methionine synthase reductase have been implicated in some of the disease associations for methionine synthase deficiency.
Cobalamin-independent (MetE) The mechanism of the cobalamin-independent (MetE) form, by contrast, proceeds through a direct methyl transfer from the activated N5-MeTHF to zinc thiolate homocysteine. Although the mechanism is considerably simpler, the direct transfer reaction is much less favorable than the cobalamin-mediated reactions and as a result the turnover rate for MetE is ~100x slower than that of MetH. As it does not contain the cobalamin cofactor, the cobalamin-independent enzyme is not prone to oxidative inactivation.
Structure
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