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Abstract
Vitamin B12 (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.