page_title: Methionine synthase
section_title: Mechanism
hierarchical_section_title: Methionine synthase / Mechanism
caption_attribution_description: English: User:BorisTM/ImageInfo
context_page_description: Methionine synthase also known as MS, MeSe, MetH is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene. Methionine synthase forms part of the S-adenosylmethionine biosynthesis and regeneration cycle. In animals this enzyme requires Vitamin B12 as a cofactor, whereas the form found in plants is cobalamin-independent. Microorganisms express both cobalamin-dependent and cobalamin-independent forms.
context_section_description: Methionine synthase catalyzes the final step in the regeneration of methionine(Met) from homocysteine(Hcy). The overall reaction transforms 5-methyltetrahydrofolate(N⁵-MeTHF) into tetrahydrofolate (THF) while transferring a methyl group to Homocysteine to form Methionine. Methionine synthase is the only mammalian enzyme that metabolizes N⁵-MeTHF to regenerate the active cofactor THF. In cobalamin-dependent forms of the enzyme, the reaction proceeds by two steps in a ping-pong reaction. The enzyme is initially primed into a reactive state by the transfer of a methyl group from N⁵-MeTHF to Co(I) in enzyme-bound cobalamin(Cob), forming methyl-cobalamin(Me-Cob) that now contains Me-Co(III) and activating the enzyme. Then, a Hcy that has coordinated to an enzyme-bound zinc to form a reactive thiolate reacts with the Me-Cob. The activated methyl group is transferred from Me-Cob to the Hcy thiolate, which regenerates Co(I) in cob, and Met is released from the enzyme. The cob-independent mechanism follows the same general pathway but with a direct reaction between the zinc thiolate and N⁵-MeTHF.
  The mechanism of the enzyme depends on the constant regeneration of Co(I) in cob, but this is not always guaranteed. Instead, every 1-2000 catalytic turnovers, the Co(I) may be oxidized into Co(II), which would permanently shut down catalytic activity. A separate protein, Methionine Synthase Reductase, catalyzes the regeneration of Co(I) and the restoration of enzymatic activity. Because the oxidation of cob-Co(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 discussed below. The two enzymes form a scavenger network seen on the lower left.
caption: The reaction catalyzed by methionine synthase (click to enlarge)
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