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 2 enzymes: methylcobalamin and 5′-deoxyadenosylcobalamin. Methylcobalamin is generated during the catalytic cycle of methionine synthase, a cytoplasmic enzyme that catalyzes methylation of homocysteine to methionine (see Chapter 133). 5′-Deoxyadenosylcobalamin (AdoCbl) is required for the mitochondrial enzyme methylmalonyl-coenzyme A (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 132). 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. Without treatment, hyperhomocysteinemia is usually accompanied by hypomethioninemia. Significantly elevated homocysteine levels may be 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 can lead to metabolic acidosis.
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. 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 cob(I)alamin and then adding the appropriate upper axial ligand (Fig. 142-1).
Metabolic pathway of cobalamin. The steps affected by inborn errors of cobalamin metabolism are shown by the red bars. AdoCbl, 5’-deoxyadenosylcobalamin; cblA, cobalamin A deficiency; cblB, cobalamin B deficiency; cblC, cobalamin C deficiency; cblD, cobalamin D deficiency; cblD v1, cobalamin D deficiency variant 1; cblD v2, cobalamin D deficiency variant 2; cblE, cobalamin E deficiency; cblF, cobalamin F deficiency; cblG, cobalamin G deficiency; cblJ, cobalamin J deficiency; cblX, cobalamin X deficiency; MeCbl, methylcobalamin; mutase, methylmalonyl-CoA mutase; synthase, methionine synthase; TCII, transcobalamin; TCBLR, transcobalamin receptor.
Absorption of dietary cobalamin is a complex process that is dependent on several cobalamin-binding proteins. Cobalamin is released from food in the acidic environment of the stomach, where it becomes bound to transcobalamin I (TCN1) found in saliva and gastric juice. Transcobalamin I is broken down in the intestine by proteolytic enzymes, and cobalamin binds the gastric intrinsic factor (GIF). The GIF-cobalamin complex ...