The metal cobalt in vitamin B12 is coordinated with a tetrapyrrole ring system, called a corrin ring, which is simiilar to the porphyrin ring of heme compounds. The cyanide attached to the cobalt in the structure is an artifact of the isolation and is replaced by water or a hyrdoxyl group in cells. The presence of cobalt and amide nitrogens gives B12 compounds the name cobamides or cobalamins. About 15 different B12-requiring reactions are known, most of which occur in a few bacterial species that carry out specialized fermentations. Only two reactions occur to a significant extent in mammalian metabolism: the synthesis of methionine from homocysteine (see here) and isomerization of D-methylmalonyl-CoA to succinyl-CoA (see Figure 20.20 and here).

With one exception, the known B12-requiring reactions involve either (1) methyl group transfer or (2) adenosylcobalamin-dependent isomerizations. The isomerizations exchange a carbon-bound hydrogen with another carbon-bound functional group as shown here. The one exception is an intermolecular transfer reaction catalyzed by a ribonucleotide reductase of Lactobacillus.

B12 coenzymes have either a methyl group or a 5'-adenosyl moiety linked to cobalt making them the first known organometallics in metabolism (Figure 20.19). Free radical intermediates and a change in the oxidation of cobalt are features of catalysis of the methylmalonyl-CoA mutase. All observations of this reaction imply that the covalent carbon-cobalt bond on the coenzyme undergoes transient homolytic cleavage during catalysis. That is, the cobalt and the carbon each acquire one electron from the pair that formed the bond, creating a free radical at the adenosine C-5'. Interaction with the substrate then creates a substrate radical, as shown for methylmalonyl-CoA mutase in Figure 20.20.

Pernicious anemia arises from a B12 deficiency. Gastric tissue secretes a glycoprotein called intrinsic factor, which complexes with ingested B12 in the digestive tract and promotes its absorption through the small intestine into the blood stream. Pernicious anemia results from insufficient secretion of intrinsic factor. Figure 20.22 outlines a probable explanation for why failure to absorb B12 leads to the deficiency of red blood cells that define anemias.

1. When B12 levels are low, flux through the methionine synthase reaction decreases but, because adequate dietary methionine is usually available, protein metabolism is not immediately disturbed.

2. Reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate continues because this reaction is virtually irreversible.

3. Because methionine synthase is the only mammalian enzyme known to act on 5-methyltetrahydrofolate, the decreased intracellular activity of this enzyme causes 5-methyltetrahydrofolate to accumulate, at the expense of depleted pools of the other tetrahydrofolate coenzymes. Thus, even though total folate levels may seem ample, there is a functional folate deficiency, with insufficient levels of the formyl and methylene derivatives needed for synthesis of nucleic acid precursors.