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Cobalamin (vitamin B12) is a complex organometallic molecule that is synthesized by many bacteria and is obtained in the human diet from meat, fish, and dairy products. It is not present in plant foods, so strict vegetarians are at risk for dietary deficiency. Derivatives of cobalamin are required for the activity of two enzymes: (1) methylcobalamin (MeCbl) is generated during the catalytic cycle of methionine synthase, a cytoplasmic enzyme that catalyzes methylation of homocysteine to methionine (see Chapter 138), and (2) 5′-deoxyadenosylcobalamin (AdoCbl) is required for the mitochondrial enzyme methylmalonyl-CoA mutase to catalyze the conversion of methylmalonyl-CoA, formed during catabolism of branched-chain amino acids and odd-chain fatty acids, to succinyl-CoA (see Chapter 137). Therefore, inborn errors of cobalamin metabolism result in isolated methylmalonic aciduria, isolated homocystinuria, or combined methylmalonic aciduria and homocystinuria, depending on which step in cobalamin metabolism is affected.1-4 In these disorders, hypomethioninemia usually occurs together with hyperhomocysteinemia. Elevated homocysteine levels are associated with an increased risk of thrombosis; decreased methionine is associated with abnormalities of the white matter of the nervous system. Elevated levels of methylmalonic acid are usually associated with metabolic acidosis.

Metabolism of Cobalamin

Cobalamin consists of a planar corrin ring with a central cobalt atom, a 5,6-dimethylbenzimidazole base, and an upper axial ligand attached to the cobalt atom that varies in different forms of cobalamin.5 Physiologically important cobalamins include hydroxycobalamin (OHCbl), methylcobalamin (MeCbl), and adenosylcobalamin (AdoCbl). The most common commercially available form of vitamin B12 contains a cyano group in the upper axial position (CNCbl). The central cobalt can exist in the oxidized Co3+ state (cob[III]alamin), the Co2+ state (cob[II]alamin), or the fully reduced Co1+ state (cob[I]alamin). Converting exogenous cobalamin, typically in the form of cob(III)alamin, to its biologically active coenzyme forms involves reducing the central cobalt to the cob(I)alamin form, then adding the appropriate upper axial ligand (eFig. 147.1).

eFigure 147.1.

Metabolic pathway of cobalamin. The steps affected by inborn errors of cobalamin metabolism are shown by the red bars. TC, transcobalamin; AdoCbl, 5’deoxyadenosylcobalamin; MeCbl, methylcobalamin; mutase, methylmalonyl-CoA mutase; synthase, methionine synthase; cblDv1, cblD variant 1; cblDv2, cblD variant 2.

Absorption of dietary cobalamin is a complex process that is dependent on a cobalamin-binding protein, intrinsic factor (IF), secreted by the parietal cells of the stomach.6 Cobalamin in food exists bound to proteins. After proteins are digested, cobalamin becomes bound in the stomach to haptocorrin, a cobalamin-binding protein secreted in the saliva. Haptocorrin is broken down in the intestine and cobalamin binds the IF. The IF-cobalamin complex is taken up by enterocytes in the distal ileum in a process mediated by a receptor, cubam, composed of the proteins cubilin and amnionless. After uptake by enterocytes, cobalamin is released into the circulation, bound to the transport protein transcobalamin (TC).

TC-bound ...

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