Cobalamin coenzymes

B,2 Cobalamin Coenzyme in transfer of one-carbon fragments and metabolism of folic acid Pernicious anemia = megaloblastic anemia with degeneration of the spinal cord... 

Selected entries from Methods in Enzymology [vol, page(s)] Spectroscopic analysis of vitamin B12 derivatives, 67, 5 preparation of cryptofluorescent analogs of cobalamin coenzymes, 67,... 

In this hereditary disease up to 1 - 2 g of methylmalonic acid per day (compared to a normal of <5 mg/day) is excreted in the urine, and a high level of the compound is present in blood. Two causes of the rare disease are known/ One is the lack of functional vitamin B12-containing coenzyme. This can be a result of a mutation in any one of several different genes involved in the synthesis and transport of the cobalamin coenzyme.6 Cultured fibroblasts from patients with this form of the disease contain a very low level of the vitamin B12 coenzyme (Chapter 16), and addition of excess vitamin B12 to the diet may restore coenzyme synthesis to normal. Among elderly patients a smaller increase in methylmalonic acid excretion is a good indicator of vitamin B12 deficiency. A second form of the disease, which does not respond to vitamin B12, arises from a defect in the methylmalonyl mutase protein. Methylmalonic aciduria is often a very severe disease, frequently resulting in death in infancy. Surprisingly, some children with the condition are healthy and develop normally.3 1... 

DW Jacobsen, R Green, EV Quadro, YD Montejano. Rapid analysis of cobalamin coenzymes and related corrinoid analogs by high-performance liquid chromatography. Anal Biochem 120 394-403, 1982. 

Scheme 12.18 Simultaneous binding of a cobalamin coenzyme and a substrate by /Tcyclodextrin.

Figure 1 Schematic representation of the molecular structure, numbering of atoms, and designations of pyrrole rings of cobalamins. R = Me is methyl B12 R = Ado is adenosyl-cobalamin (coenzyme B12) X = CN is cyanocobalamin (vitamin B12). Five-membered rings are labeled A-D, and the amide side-chains are labeled a-g.

Although numerous enzymatic reactions requiring vitamin B12 have been described, and 10 reactions for adenosylcobalamin alone have been identified, only three pathways in man have so far been recognized, one of which has only recently been identified (PI). Two of these require the vitamin in the adenosyl form and the other in the methyl form. These cobalamin coenzymes are formed by a complex reaction sequence which results in the formation of a covalent carbon-cobalt bond between the cobalt nucleus of the vitamin and the methyl or 5 -deoxy-5 -adenosyl ligand, with resulting coenzyme specificity. Adenosylcobalamin is required in the conversion of methylmalonate to succinate (Fig. 2), while methylcobalamin is required by a B12-dependent methionine synthetase that enables the methyl group to be transferred from 5-methyltetrahydrofolate to homocysteine to form methionine (Fig. 3). 

Roth JR, Lawrence JG, Bobik TA. Cobalamin (coenzyme B12) synthesis and biological significance. Annu. Rev. Microbiol. 1996 50 137-181. 

Figure 30-16 Participation of cobalamin coenzymes in human metabolism.

The most reduced coenzyme is 5-methyl tetrahydrofolate poly glutamate. It is the source of the methyl group added to homocysteine regenerating methionine and tetrahydrofolate ready to accept a one-carbon unit from formate or serine. This last reaction is where folic acid and vitamin come together (Figs. 8.49, 8.52, and 8.53). The implications of this reaction and how folic acid can mask pernicious anemia are discussed in the seetion on vitamin Big (cyanocobalamin). Note that the formation of 5-methyl-THF nor-mdly is not reversible. Tetrahydrofolate can be regenerated only if there is adequate methyl cobalamin coenzyme. 

The cobalamin coenzyme is bound by the apoenzyme with no significant change in the absorption spectrum." This suggests that no major change occurs in the coordination of cobalt(IIl). The first step of the reaction involves homo-lytic fission of the Co—C bond 2-184, 186-188... 

Cyanocobalamm (B12) Deoxyadenosyl cobalamin Coenzyme in amino add metabolism... 

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