1

FIGLU Deoxyadenosyl B12

L-Methylmalonyl Succinyl Glutamic CoA CoA acid

10-CHOH4PteGlu

^5,10-CH2H4PteGlu-,

Serine Glycine

5,10-CHH4PteGlu

5-CHOH4PteGlu

10-CHOH4PteGlu

5-CHNHH4PteGlux

FIGURE 53-6 Interrelationships and metabolic roles of vitamin B12 and folic acid. See text for explanation and Figure 53-9 for structures of the various folate coenzymes. FIGLU, formiminoglutamic acid, which arises from the catabolism of histidine; TcII, transcobalamin II; CH3H4PteGlu1, methyltetrahydrofolate.

reaction in carbohydrate and lipid metabolism. This reaction has no direct relationship to the metabolic pathways that involve folate. In contrast, methylcobalamin (CH3B12) supports the methionine synthetase reaction, which is essential for normal metabolism of folate. Methyl groups contributed by methyltetrahydrofolate (CH3H4PteGlu1) are used to form methylcobalamin, which then acts as a methyl group donor for the conversion of homocysteine to methionine. This folate-cobalamin interaction is pivotal for normal synthesis of purines and pyrimidines, and therefore of DNA. The methionine synthetase reaction is largely responsible for the control of the recycling of folate cofactors; the maintenance of intracellular concentrations of folylpolyglutamates; and, through the synthesis of methionine and its product, S-adenosylmethionine (SAM), the maintenance of a number of methylation reactions.

Since methyltetrahydrofolate is the principal folate congener supplied to cells, the transfer of the methyl group to cobalamin is essential for the adequate supply of tetrahydrofolate (H4PteGlu1), the substrate for a number of metabolic steps. Tetrahydrofolate is a precursor for the formation of intracellular folylpolyglutamates; it also acts as the acceptor of a one-carbon unit in the conversion of Ser to Gly, with the resultant formation of 5,10-methylenetetrahydrofolate (5,10-CH2H4PteGlu). The latter derivative donates the methylene group to deoxyuridylate (dUMP) for the synthesis of thymidylate (dTMP)—an extremely important reaction in DNA synthesis. In the process, the 5,10-CH2H4PteGlu is converted to dihydrofolate (H2PteGlu). The cycle then is completed by the reduction of the H2PteGlu to H4PteGlu by dihydrofolate reductase, the step that is blocked by folate antagonists such as methotrexate (see Chapter 51). As shown in Figure 53-6, other pathways also lead to the synthesis of 5,10-methylenetetrahydrofolate. These pathways are important in the metabolism of formiminoglutamic acid (FIGLU) and purines and pyrimidines.

Deficiency of either vitamin B12 or folate decreases the synthesis of methionine and SAM, thereby interfering with protein biosynthesis, a number of methylation reactions, and the synthesis of polyamines. In addition, the cell responds to the deficiency by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate; this tends to preserve essential methylation reactions at the expense of nucleic acid synthesis. With vitamin B12 deficiency, methylenetetrahydro-folate reductase activity increases, directing available intracellular folates into the methyltetrahydro-folate pool (not shown in Figure 53-6). The methyltetrahydrofolate then is trapped by the lack of sufficient vitamin B12 to accept and transfer methyl groups, and subsequent steps in folate metabolism that require tetrahydrofolate are deprived of substrate. This process provides a common basis for the development of megaloblastic anemia with deficiency of either vitamin B12 or folic acid.

The mechanisms responsible for the neurological lesions of vitamin B12 deficiency are less well understood. Damage to the myelin sheath is the most striking lesion in this neuropathy; this observation led to the early suggestion that the deoxyadenosyl B 12-dependent methylmalonyl CoA mutase reaction, a step in propionate metabolism, is related to the abnormality. However, other evidence suggests that the deficiency of methionine synthetase and the block of the conversion of methionine to SAM are more likely to be responsible.

VITAMIN B12 CHEMISTRY

Vitamin B12 (Figure 53-7) contains three major portions: a planar group or corrin nucleus— a porphyrin-like ring structure with four reduced pyrrole rings (A to D in Figure 53-7) linked to a central cobalt atom and extensively substituted with methyl, acetamide, and propionamide residues; a 5,6-dimethylbenzimidazolyl nucleotide, which links almost at right angles to the corrin nucleus with bonds to the cobalt atom and to the propionate side chain of the C pyrrole ring; and a variable R group—the most important of which are found in cyanocobalamin and hydroxocobalamin and the active coenzymes methylcobalamin and 5-deoxyadenosylcobal-amin. The terms vitamin B12 and cyanocobalamin are used interchangeably as generic terms for all of the cobamides active in humans. Preparations of vitamin B12for therapeutic use contain either cyanocobalamin or hydroxocobalamin, since only these derivatives remain active after storage.

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