Chapter 45 Vitamin B12

Summary Pernicious anemia is caused by a lack of one or both of two components, one in the diet, originally called “extrinsic factor” (vitamin B 12 ), and one in the body, “intrinsic factor” (a protein that causes absorption of the vitamin). The disease was fatal before the realization that vitamin B 12 injections alleviated the symptoms. Both the gastrointestinal and neurological systems are affected in pernicious anemia. The vitamin was first isolated from liver, the main storage organ, and its chemical formula was established by X-ray diffraction studies. It is a cobalt-containing compound with a corrin ring system (rather like a porphyrin) and a nucleotide side chain. Humans cannot manufacture vitamin B 12 , but must obtain it from dietary sources. The actual species used in the body is a derivative of the vitamin in which one of the axial substituents on the cobalt atom is replaced by an adenosyl or methyl group with formation of a cobalt-carbon bond. These two coenzymes (adenosylcobalamic and methylcobalamin) are organometallic compounds that assist in the action of various enzymes; the most important in humans are methylmalonyl-CoA mutase (which utilizes adenosylcobalamin) and methionine synthase (which utilizes methylcobalamin). Adenosylcobalamin provides a free radical by cleavage of the Co-C bond, and this assists in the conversion of substrate to product. A deficiency in the action of this enzyme can lead to the incorporation of abnormal fatty acids into lipids and may lead to nerve sheath demyelination, a possible cause of the neurological problems associated with pernicious anemia. On the other hand, methylcobalamin provides a methyl cation by heterolytic cleavage of the Co-C bond; this coenzyme is used by the enzyme methionine synthase which demethylates methyltetrahydrofolate to give tetrahydrofolate ready for action in thymidylate production. Any interference with this enzymatic reaction leads to a lack of thymidylate, without which DNA cannot be synthesized.