Journal Article

Decyanation of vitamin B₁₂ by a trafficking chaperone

Gherasim, Carmen, Banerjee, Ruma, Kim, Jihoe

2008

Overview

The mystery of how the cyanide group in vitamin B₁₂ or cyanocobalamin, discovered 60 years ago, is removed, has been solved by the demonstration that the trafficking chaperone, MMACHC, catalyzes a reductive decyanation reaction. Electrons transferred from NADPH via cytosolic flavoprotein oxidoreductases are used to cleave the cobalt-carbon bond with reductive elimination of the cyanide ligand. The product, cob(II)alamin, is a known substrate for assimilation into the active cofactor forms, methylcobalamin and 5'-deoxyadenosylcobalamin, and is bound in the \"base-off\" state that is needed by the two B₁₂-dependent target enzymes, methionine synthase and methylmalonyl-CoA mutase. Defects in MMACHC represent the most common cause of inborn errors of B₁₂ metabolism, and our results explain the observation that fibroblasts from these patients are poorly responsive to vitamin B₁₂ but show some metabolic correction with aquocobalamin, a cofactor form lacking the cyanide ligand, which is mirrored by patients showing poorer clinical responsiveness to cyano- versus aquocobalamin.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Biochemistry / Biological Sciences / Carrier Proteins - metabolism / Catalysis / Cobamides - metabolism / Coenzymes / Cyanides / Cytosol - enzymology / electrons / Enzymes / Ferredoxin-NADP Reductase - metabolism / fibroblasts / Flavoproteins / Homocystinuria / Humans / Ligands / Line spectra / metabolism / methionine synthase / methylmalonyl-CoA mutase / Molecular Chaperones - metabolism / NADP (coenzyme) / oxidoreductases / Oxidoreductases - metabolism / patients / Protein Binding / Protein Transport / Proteins / Recombinant Proteins - metabolism / Vitamin B 12 - analogs & derivatives / Vitamin B 12 - chemistry / Vitamin B 12 - metabolism / Vitamin B12