Cobalamin Vitamin B12

Few vitamins have been more challenging to structure-function studies than vitamin B12. Among its many unique features, B12 is the only vitamin-

O Acetyl group S—C-CH3

CH2 NH

Pantothenic acid residue

O II

Pantothenic acid residue

O II

CH2 O

CH2 O

HO OH Acetyl-coenzyme A Figure 6 Pantothenic acid in the structure of coenzyme A.

coenzyme known to have a transition metal ion (cobalt) coordinated to its structure. The metal allows some usual chemistry (see 00058). The vitamin is present in a variety of foods but is almost totally lacking in plants. Although the vitamin can be synthesized de novo by intestinal flora, the absorption site anatomically is prior to the synthesis site in the gut, which means little benefit is derived from endogenous synthesis. Isolating the active form of the vitamin meant developing an in vitro assay for 'pernicious anemia,' one of the deficiency symptoms. In 1950, Shive introduced an assay in which homocysteine was converted to methionine in a B12 -dependent reaction. A second assay showed that the derivative 5-deoxyadenosyl cobalamin was essential for the interconversion of L-glutamate and ¡-methyl aspartate. The latter discovery led to the isolation of 5' adenosylcobalamine, the principal active form of the vitamin.

Reactivity The core of the vitamin consists of a corrin ring with a central cobalt atom. Corrin contains four pyrrole rings linked together, which vaguely resembles structurally the porphyin ring in heme (Figure 7). An inactive form of the vitamin contains a displaceable CN group bound to the cobalt; hence the early name cyanocobalamin for one of its more familiar forms (Figure 7). The cobalt atom in the ring can have a +1, +2, or +3 oxidation state. The fifth valence (below the ring plane) has a dimethylbenzimidazole attached to the cobalt and the six can be either a methyl group, an -OH

Figure 7 Cyanocobalamin, one of the forms of vitamin B12. Shown are the corrin ring and the attachment of the dimethylbenzimidazole to the cobalt above the ring. The cyano group is shown attached to the cobalt below the plane of the ring.

Figure 7 Cyanocobalamin, one of the forms of vitamin B12. Shown are the corrin ring and the attachment of the dimethylbenzimidazole to the cobalt above the ring. The cyano group is shown attached to the cobalt below the plane of the ring.

group, or a 5' deoxyadenosyl group depending on the reaction or enzyme. As noted, 5' deoxyade-nosylcobalamin is the most common form of the coenzyme. The 5' deoxyadenosylcobalamine arises by an attack on the 5' carbon of ATP by Co+, which displaces the triphosphate group of ATP, a rare action in biochemistry. Known enzymes that require B12 fit one of two functional categories: those that transfer methyl groups from the coenzyme to the substrate, and those that take part in positional rearrangements of neighboring groups on the substrate, or group transfer reactions.

As noted above, methylation reactions in mammalian systems that involve B12 are limited to the transfer of a methyl group to homocysteine to form methionine. Recall, N5-methyl-THF is the methyl group donor in the reaction and B12 mediates the transfer. Restoring the methyl group on methio-nine primes the system to further methylation since methionine itself, acting through its active form, S-adenosylmethionine (see below), is a primary donor of methyl groups to other substrates.

Of late, there has been considerable interest in vitamin B12 reactions that have free radicals as intermediates. This may be one of the principal advantages of the coenzyme, i.e., the ability to form and retain a stable free radical in its structure. The stability of the free radical is due to the unusual chemistry of the cobalt ion.

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