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

J Inherit Metab Dis. 2019 Jul;42(4):673-685. doi: 10.1002/jimd.12009. Epub 2019 Jan 28.


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.

Keywords: folate; hyperhomocysteinemia; methionine cycle; methylmalonic acidemia; one-carbon metabolism; vitamin B12.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
  • Animals
  • Folic Acid / pharmacology
  • Folic Acid Deficiency / metabolism*
  • Humans
  • Methylmalonyl-CoA Mutase / metabolism
  • Vitamin B 12 / pharmacology
  • Vitamin B 12 Deficiency / metabolism*


  • Folic Acid
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Methylmalonyl-CoA Mutase
  • Vitamin B 12