Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin. Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (By similarity). Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance (PubMed:24074862). Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme. Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme (By similarity). H(+) + 2 methylcob(III)alamin-[methionine synthase] + NADP(+) + 2 S-adenosyl-L-homocysteine = 2 cob(II)alamin-[methionine synthase] + NADPH + 2 S-adenosyl-L-methionine A + 2 cob(II)alamin + 2 H(+) + 2 H2O = AH2 + 2 aquacob(III)alamin Forms a multiprotein complex with MMACHC, MMADHC AND MTR. Female mice have more resorptions and more delayed embryos per litter as well as embryonic delays and defects: placentae of mothers are smaller and their embryos are smaller and display myocardial hypoplasia and a higher incidence of ventricular septal defects per litter (PubMed:18413293). Epigenetic transmission of developmental disorders between generations: a hypomorphic mutation disrupts folate metabolism and is associated with effects on offspring development that are transmitted transgenerationally. The epigenetic influences caused by Mtrr hypomorphic deficiency in mice leads to 2 distinctive phenotypes: (1) an atypical uterine environment in their wild-type daughters that causes growth defects in their wild-type grandprogeny and (2) congenital malformations in their wild-type grandprogeny due to epigenetic inheritance via the germline, the effects of which persist for at least up to 4 wild-type generations after an Mtrr-deficient maternal ancestor. These effects are associated with altered DNA methylation patterns (PubMed:24074862). It is debated whether the reduction of free aquacob(II)alamin occurs spontaneously or is enzyme catalyzed. The hidden things - Issue 166 of December 2014