Methionine synthase reductase (MTRR) is involved in reducing cob(II)alamin (B12r) to methylcobalamin (MeCbl), the cofactor form used by methionine synthase (MTR). Regeneration of functional MTR requires reductive methylation via a reaction catalysed by MTRR in which S-adenosylmethionine (AdoMet, SAM) is used as a methyl donor. MTRR requires 1 FMN and 1 FAD per subunit for activity (Wolthers et al. 2007). MTRR exists in a stable complex with MTR, bound through their FMN-binding and C-terminal activation domains respectively (Wolthers & Scrutton 2007, Wolthers & Scrutton 2009).
When methionine synthase (MTR) is functioning properly, cobalamin (Cbl) is continuously shuttled between two forms, cob(I)alamin and MeCbl. There are 2 half reactions: transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to enzyme-bound cob(I)alamin to form MeCbl; and transfer of the methyl group from MeCbl to homocysteine (HYCS) to form AdoMet, methionine and regenerate cob(I)alamin. From time to time (every few hundred cycles), the enzyme-bound cobalamin is spontaneously oxidized to form cob(II)alamin. When this happens, MTRR in conjunction with MTR catalyzes the reductive methylation of cob(II)alamin to form MeCbl. If MTRR is defective, cob(II)alamin accumulates and methionine synthase is inactivated.
Defects in MTRR cause methylcobalamin deficiency type E (cblE; MIM:236270) (Wilson et al. 1999). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. AdoMet is used as a methyl donor in many biological reactions and its demethylation produces homocysteine. Remethylation is carried out by MTR in conjunction with MTRR but in cblE patients, MTR-bound cobalamin cannot be reduced by defective MTRR to form a functional enzyme thus homocysteine accumulates. Mutations in MTRR that cause cblE include Leu576del (Leclerc et al. 1998) and S454L (Zavadakova et al. 2005). In terms of frequency, the most common MTRR mutation is a c.903+469C>T mutation which creates a novel splice site deep in an intron and results in inclusion of a 140-bp insertion in MTRR mRNA (Homolova et al. 2010). Wilson et al. showed that a 66A G polymorphism, resulting in an Ile22Met (I22M) substitution, is associated with susceptibility to folate sensitive neural tube defects (FS NTD; MIM:601634) (Wilson et al. 1999b, Doolin et al. 2002). Serum deficiency of vitamin B12 increased the effect.