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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.
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Metabolism of Cobalamin
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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).
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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).
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