Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency

Abstract

Methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are coenzymes for methionine synthase and methylmalonyl-CoA mutase, respectively. Hydroxylcobalamin (HOCbl) and cyanocobalamin (CNCbl) are frequently used for supplementation. MeCbl and AdoCbl have recently emerged as alternative forms in supplements. In the light of metabolic transformation of Cbl into its cofactor forms, this review discusses current evidence on efficacy and utility of different Cbl forms in preventing or treating Cbl deficiency. Cbl-transporting proteins bind and mediate the uptake of all aforementioned forms of Cbl. After internalization and lysosomal release, Cbl binds to the cytosolic chaperon MMACHC that is responsible for (i) flavin-dependent decyanation of [CN-Co(3+) Cbl to [Co(2+)]Cbl; (ii) glutathione-dependent dealkylation of MeCbl and AdoCbl to [Co(2+/1+)]Cbl; and (iii) glutathione-dependent decyanation of CNCbl or reduction of HOCbl under anaerobic conditions. MMACHC shows a broad specificity for Cbl forms and supplies the Cbl(2+) intermediate for synthesis of MeCbl and AdoCbl. Cobalamin chemistry, physiology, and biochemistry suggest that MeCbl and AdoCbl follow the same route of intracellular processing as CNCbl does. We conclude that supplementing MeCbl or AdoCbl is unlikely to be advantageous compared to CNCbl. On the other hand, there are obvious advantages of high parenteral doses (1-2 mg) of HOCbl in treating inborn errors of Cbl metabolism.

Keywords: Adenosylcobalamin; Coenzyme; Cyanocobalamin; Deficiency; Hydroxylcobalamin; Methylcobalamin.

Figure 1

Vitamin B12 chemical structure and forms. R is bound to the upper (β-face).

Figure 2

Trafficking and assimilation of all forms of Cbl into mammalian cells is likely to follow the same steps: crossing the intestinal barrier, cellular internalization, lysosomal release, dealkylation, decyanation or reduction, forming the coenzymes and then attachment to the corresponding enzymes. Ado; adenosyl, CN; cyano-, HC; haptocorrin, HO; hydroxyl, IF; intrinsic factor, LMBRD1 and ABCD4; are lysosomal membrane exporters, Me; methyl, MMACHC; methylmalonic aciduria and homocystinuria type C protein, MM-CoA: methylmalonyl-CoA, TC; transcobalamin.

Figure 3

Human MMACHC in the cytosol mediates the removal of the upper ligand in all Cbl forms (MeCbl, AdoCbl, HOCbl, and CNCbl). Dealkylation removes Me or Ado and requires glutathione S-transferase; decyanation of CNCbl requires a flavin reductase system (FAD), and a reduction in the presence of GSH leads to decyanation under anaerobic conditions or removal of HO group. Under all circumstances, a Co⁺² intermediate is produced. AdoCbl; adenosylcobalamin, CNCbl; cyanocobalamin, FAD; flavin adenine dinucleotide, HOCbl; hydroxylcobalamin, GSH; glutathione, MeCbl; methylcobalamin, MMACHC; methylmalonic aciduria and homocystinuria type C protein, MM-CoA: methylmalonyl-CoA.