Methionine synthase reductase (MTRR) is primarily involved in the reductive methylation of homocysteine to methionine, utilizing methylcob(I)alamin as an intermediate methyl carrier. Methionine is an essential amino acid in mammals, necessary for protein synthesis and one carbon metabolism. In its activated form, S-adenosylmethionine acts as a methyl donor in biological transmethylation reactions and as a propylamine donor in polyamine synthesis. A major product of methionine demethylation is homocysteine. Remethylation of homocysteine occurs via a cobalamin dependent enzyme, methionine synthase (MTR). The folate cycle is linked to homocysteine metabolism via MTR. Circulating blood folate (5-methyl tetrahydrofolate, 5-MTHF) donates methyl groups to MTR to be utilized in cellular methylation. A methyl cobalt bond of the intermediary methyl carrier, methlycob(III)alamin is cleaved heterolytically producing cobalamin in its highly reactive oxidation state as cob(I)alamin. The enzyme bound cob(I)alamin cofactor of the MTR enzyme functions as a methyl carrier between 5-MTHF and homocysteine. Cob(I)alamin is oxidised to cob(II)alamin about once every 100 methyl transfer cycles, rendering the cob(I)alamin-MTR-enzyme complex inactive. Reactivation of this enzyme complex occurs through reductive remethylation by MTRR, utilizing S-adenosylmethionine as a methyl donor. MTR reactivation can also be NADPH dependent involving two redox proteins, soluble cytochrome b5 and reductase 1. However, this pathway is responsible for a minor role in reactivation, whilst MTRR remains a major contributor in this reductive reactivation.
