Methionine synthase (MTR) catalyses the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to MTR-bound cob(I)alamin to form methylcobalamin (MeCbl). In the second step, the methyl group from MeCbl is transferred to homocysteine (HCYS), forming methionine (L-Met) (Leclerc et al. 1996). Under normal conditions, the enzyme-bound cobalamin shuttles between the cob(I)alamin and MeCbl forms. Every few hundred cycles, enzyme-bound cob(I)alamin is spontaneously oxidized to cob(II)alamin, inactivating MTR. Active MTR is regenerated by MTRR which, in conjunction with MTR, catalyzes reductive methylation of cob(II)alamin to MeCbl using SAM as a methyl donor.
Defects in MTR cause methylcobalamin deficiency type G (cblG, methionine synthase deficiency; MIM:250940), an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria. Mutations causing cblG include P1173L, Ile881, H920D, R585*, E1204* and A1204P (Leclerc et al. 1996, Gulati et al. 1996, Watkins et al. 2002).