Topic summary
Methionine synthase
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 MTRgene (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.