Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Abstract Vitamin B 12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl‐CoA mutase and methionine synthase. Methylmalonyl‐CoA mutase is required for the catabolism of certain (branched‐chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl‐Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl‐Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S‐adenosylmethionine, the most important cellular methyl‐donor. Disruption of methionine synthase has wide‐ranging implications for all methylation‐dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5‐methyltetrahydrofolate as a one‐carbon donor. Folate‐bound one‐carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate‐mediated one‐carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.