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

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.

Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase

“…The binding affinity of MMUT for AdoCbl was indistinguishable between preparations using both methods. All binding kinetics and activity assays were conducted using MMUT prepared by method (2).…”

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

“…Hypotheses on how metabolism translates to clinics are presented and discussed. The article by Froese et al in the same issue of this journal provides more information on the biochemical and genetic background of the disorders.…”

A Rare Case of Hyperhomocysteinemia-associated Thrombotic Stroke in the Pediatric Age Group

“…Homocysteine gets eliminated from the body through vitamin B12 metabolism and folate metabolism finally converting into adenosine which gets cleared from the body. Thus, a deficiency of folate or vitamin B12 can lead to an increased level of homocysteine [3].…”