Vitamin B12 (cobalamin, Cbl) is an essential nutrient in human metabolism. Genetic diseases of vitamin B12 utilisation constitute an important fraction of inherited newborn disease. Functionally, B12 is the cofactor for methionine synthase and methylmalonyl CoA mutase. To function as a cofactor, B12 must be metabolised through a complex pathway that modifies its structure and takes it through subcellular compartments of the cell. Through the study of inherited disorders of vitamin B12 utilisation, the genes for eight complementation groups have been identified, leading to the determination of the general structure of vitamin B12 processing and providing methods for carrier testing, prenatal diagnosis and approaches to treatment.

Structure of vitamin B12 (cobalamin). (a) The ‘R group’ corresponds to substitutions at the upper or β-axial ligand (5′-deoxyadenosyl-, methyl-, hydroxo-, cyano-). The dimethylbenzimidazole constituent (DMB) is shown coordinated to the cobalt in the lower α-axial position (‘base-on’ structure). DMB is linked to the corrin ring through a phosphoribosyl attached to a propionamide side chain. (b) Structure of methylcobalamin (MeCbl) with DMB displaced from the cobalt by a histidine residue in methionine synthase (MS; the ‘base-off/His-on’ structure). A similar configuration is observed for adenosylcobalamin (AdoCbl) bound to methylmalonyl-CoA mutase. Structures are from http://www.genome.jp using the ‘SIMCOMP Search’ utility (query C00576, vitamin B12; C06410, MeCbl-MS).

Intracellular processing of vitamin B12 showing sites of defects in complementation groups. Complementation groups are in blue and are positioned at sites of metabolic blocks (shown in red). Cobalamin intermediates are in red. Excreted metabolites due to genetic defects are in shaded boxes. Pathway details are described in the text. In the lysosome, cobalamin is released from transcobalamin (TC) through its degradation (arrow pointing to dots). In the cytosol, R groups are released by the cblC protein with the cob(II)alamin [Cob(II)] product remaining bound (dotted line emanating from the cblC protein denotes complex with cobalamin forms). The three versions of the cblD protein (cblD, cblD-1, cblD-2) illustrate the role of the protein in directing cobalamin to the mitochondrial or cytosolic pathway. In the mitochondrion, the cblB protein adds the 5′-deoxyadenosyl group, generating the active cofactor [adenosylcobalamin (AdoCbl)], which is transferred to the mut [methylmalonyl-CoA mutase (MCM)] protein. The cblA protein is proposed to act as a gatekeeper to ensure that the cofactor form that is accepted and retained by MCM is AdoCbl. In the cytosolic pathway, cob(II)alamin is bound to the cblG [methionine synthase (MS)] protein. The cblE [methionine synthase reductase (MSR)] protein catalyses generation of the active cofactor, methylcobalamin (MeCbl), or its regeneration if oxidised to cob(II)alamin during reaction cycles.

Although we have gained much insight into the pathway of vitamin B12 metabolism, the goal of the medical geneticist has been to gain insight into managing the vitamin B12 disorders, providing access to carrier testing and prenatal diagnosis, and, in the best of outcomes, preventing or successfully treating symptomatic disease. The remarkable feature of vitamin B12 utilisation disorders has been their potential for treatment. The discovery that high-dose vitamin B12 can overcome pathway deficits in some patients has given new life to individuals with an otherwise potentially severe or fatal disease. The early discovery that OHCbl is effective in the treatment of cblC disorder while CNCbl is not is a powerful illustration of the complexity of vitamin B12 biochemistry. The more recent finding that AdoCbl or MeCbl may have a significant stabilising effect on MMACHC protein, despite ultimately being hydrolysed to cob(II)alamin, reminds us that there is still much to be learned on behalf of the patient. Strikingly, the most recent success with gene therapy to treat mice with knockout of the Mut gene (Ref. 151) has opened up a new avenue for treatment that might ultimately benefit patients with metabolically ‘unresponsive’ disorders. The application of widespread newborn screening for homocysteine and methylmalonate underscores the opportunity to identify and treat these patients before the onset of potentially irreversible disease.

The haematological and neurological consequences of cobalamin deficiency define the essential role of this vitamin in key metabolic reactions. The identification of cubilin-amnionless as the receptors for intestinal absorption of intrinsic factor-bound cobalamin and the plasma membrane receptor for cellular uptake of transcobalamin bound cobalamin have provided a clearer understanding of the absorption and cellular uptake of this vitamin. As the genes involved in the intracellular processing of cobalamins and genetic defects of these pathways are identified, the metabolic disposition of cobalamins and the proteins involved are being recognized. The synthesis of methylcobalamin and 5′-deoxyadenosylcobalamin, their utilization in conjunction with methionine synthase and methylmalonylCoA mutase, respectively, and the metabolic consequences of defects in these pathways could provide insights into the clinical presentation of cobalamin deficiency.

Pathways and proteins involved in the assimilation of cobalamin and inborn or acquired defects () in these pathways.
Br J Haematol. 2010 January;148(2):195-204.