Vitamin Cobalamin, Cyanocobalamin

Structure of vitamin B12 (cyanocobalamin) and its coenzyme forms (methylcobalamin and 5 -deoxyadenosyl-cobalamin). 

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. 

Vitamin B12 (cyanocobalamin) 3 is, in fact, not a natural product as the cyanide ligand to the cobalt ion is added during the isolation procedure. Coenzyme B12 (adenosylcobalamin) 4 and methylcobalamin 5 are the true final products of the biosynthetic pathway. Coenzyme 0,2 is the cofactor for a number of enzymic rearrangement reactions, such as that catalysed by methylmalonyl CoA mutase, and methylcobalamin is the cofactor for certain methyl transfer reactions, including the synthesis of methionine. A number of anaerobic bacteria produce related corrinoids in which the dimethylbenzimidazole moiety of the cobalamins (3 - 5) is replaced by other groups which may or may not act as ligands to the cobalt ion, such as adenine orp-cresol [12]. 

Cobalamine cyanocobalamin Pteroylglutamic add (PGA) folacin vitamin Be vitamin M... 

Figure 47.1 Intracellular metabolism of vitamin Bi2- Cyanocobalamin is first converted into cob(II)alamin, which has no cyanogen group on the ligand occupying the upper axial position of the cobalamin structure. Cob(II)alamin is further reduced to cob(I)alamin, which can function as a coenzyme in the body. Removal of a cyanide molecule from cyanocobalamin is directly reduced by NADPH and flavoprotein in the presence of a cyanocobalamin trafficking chaperone. Cobalamin is reportedly converted into its inactive form, cob(H)alamin, under oxidative stress (Lemer-Ellis et al. 2006). NADPH nicotinamide adenine dinucleotide phosphate.

It was then realized that the biochemically active form of the cobalamin is the coenzyme B12, containing an adenosyl moiety bound through its 5 -carbon to form a covalent bond to the central cobalt atom of vitamin Bi2- Although the conversion of vitamin B12 (cyanocobalamin) to adenosyl-Bi2 (the coenzyme) appears to involve the replacement of a CN group by an adenosyl group from ATP, the enzymatic conversion has been found to be fairly complex. 

Deficiency of vitamin Bj2 [cyanocobalamin (R = CN), or some other important cobalamins, e.g., adenosylcobalamin (R = adenosyl), hydroxocobal-amin (R = OH), methylcobalamin (R = CH3)], see Figures 7.1.1 and 7.1.3, causes a slow-developing disease, called pernicious anemia, in which the production of red blood cells is impaired. Absence of hydrochloric acid in gastric secretions (achlorhydria) is also characteristic of this condition. Without medical treatment, the disease will end in death in about 2 to 3 years. 

The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin, resulting in diminished activity of both N5-methyltetrahydrofolate homocysteine methyltransferase and methylmalonyl-CoA mutase. Supplementation with hydroxocobalamin rectifies the aberrant biochemistry. The precise nature of the underlying defect remains obscure. Diagnosis should be suspected in a child with homocystinuria, methylmalonic aciduria, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Prenatal diagnosis is possible. 

Vitamin B12 exists as hydroxocobalamin, adeno-sylcobalamin and cyanocobalamin. Cobalamins are found exclusively in food ingredients of animal origin like meat, liver and to a lesser degree in dairy products. Vitamin B12 is absorbed in the distal ileum under the influence of the glycoprotein intrinsic... 

Cyanocobalamin and the derivative hydroxo-cobalamin, given IM or deep subcutaneously, are indicated for treating vitamin B12 deficiency. Only in strict vegetarians oral preparations may be effective. Oral preparations with added intrinsic factor mostly are not reliably in patients with pernicious anemia. More than half the dose of cyanocobalamin injected is excreted in the urine within 48 hours and the therapeutic advantages of doses higher than 100 pg are questionable because of this rapid eiimination. As... 

Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms. The ultimate source of vitamin Bi2 is from microbial synthesis the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin Bi2 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin Bi2 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12. 

Vitamin B12 consists of a porphyrin-like ring structure, with an atom of Co chelated at its centre, linked to a nucleotide base, ribose and phosphoric acid (6.34). A number of different groups can be attached to the free ligand site on the cobalt. Cyanocobalamin has -CN at this position and is the commercial and therapeutic form of the vitamin, although the principal dietary forms of B12 are 5 -deoxyadenosylcobalamin (with 5 -deoxyadeno-sine at the R position), methylcobalamin (-CH3) and hydroxocobalamin (-OH). Vitamin B12 acts as a co-factor for methionine synthetase and methylmalonyl CoA mutase. The former enzyme catalyses the transfer of the methyl group of 5-methyl-H4 folate to cobalamin and thence to homocysteine, forming methionine. Methylmalonyl CoA mutase catalyses the conversion of methylmalonyl CoA to succinyl CoA in the mitochondrion. 

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.

The ligand attached to the cobalt atom determines the activity of vitamin B12 in human enzymatic reactions. The two active coenzyme forms are methyl-cobalamin and 5 -adenosylcobalamin, the primary form of vitamin B12 in tissues. Cyanocobalamin, the therapeutic form of vitamin B12 contained in vitamin supplements, is produced by the cleavage of the unstable fink... 

Oral vitamin Bj2 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin Bj2 absorption pathway is independent of intrinsic factor. Oral cobalamin is initiated at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daUy. Parenteral therapy is more rapid acting than oral therapy and should be used if neurologic symptoms are present. A popular regimen is cyanocobalamin 1,000 meg daily for 1 week, then weekly for 1 month, and then monthly. When symptoms resolve, daily oral administration can be initiated. 

Cobalamins comprise a family of compounds which share a complex structure. Vitamin is known as cyanocobalamin because when originally isolated, an in-vitro artefact had placed a cyan group in the cobalt 3 position. Vitamin is an active cellular coenzyme essential for demethy-... 

---