Cobalamin-dependent methionine synthase (IPR011822)

Short name: MetH

Overlapping homologous superfamilies

Family relationships



Cobalamin (vitamin B12) dependent methionine synthase EC: (MetH; 5-methyltetrahydrofolate--homocysteine S-methyltransferase) catalyses the conversion of 5-methyltetrahydrofolate and L-homocysteine to tetrahydrofolate and L-methionine as the final step in de novo methionine biosynthesis. The enzyme requires methylcobalamin as a cofactor. In humans, defects in this enzyme are the cause of autosomal recessive inherited methylcobalamin deficiency (CBLG), which causes mental retardation, macrocytic anemia and homocystinuria. Mild deficiencies in activity may result in mild hyperhomocysteinemia, and mutations in the enzyme may be involved in tumorigenesis. Vitamin B12 dependent methionine synthase is found in prokaryotes and eukaryotes, but in prokaryotes the cofactor is cobalamin.

This enzyme is a large protein composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and tetrahydrofolate [PMID: 14752199], the third module binds the B12 cofactor [PMID: 7992050], and the C-terminal module (activation domain) binds S-adenosylmethionine. The activation domain is essential for the reductive activation of the enzyme. During the catalytic cycle, the highly reactive cob(I)alamin intermediate can be oxidised to produce an inactive cob(II)alamin enzyme; the enzyme is then reactivated via reductive methylation by the activation domain [PMID: 11731805]. The activation domain adopts an unusual alpha/beta fold.Recent studies suggest that this enzyme exists as an ensemble of conformations with equilibria dependent on the oxidation and methylation state of the cobalamin and on the concentrations of substrates or products [PMID: 12832615].

GO terms

Biological Process

GO:0009086 methionine biosynthetic process

Molecular Function

GO:0031419 cobalamin binding
GO:0008705 methionine synthase activity
GO:0008270 zinc ion binding

Cellular Component

No terms assigned in this category.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.