Adenosylcobalamin, Vitamin

Ligand dissociation can involve either heterolytic or homolytic processes. Most biological processes involve the former, although examples of the latter are known. For example, adenosylcobalamin (vitamin B-12 coenzyme), in association with an appropriate apoenzyme, catalyzes a variety of rearrangements via a 1,2-hydride shift (see Chapter 13). The hrst step in these reactions is thought to be homolytic dissociation of a Com—alkyl bond as shown ... 

Warren MJ, Raux E, Schubert HL, Escalante-Semerena JC. The biosynthesis of adenosylcobalamin (vitamin B12). Nat. Prod. Rep. 2002 19 390-412. 

It is recognized that there are several important forms of vitamin The active coenzyme forms are adenosylcobalamin [13870-90-1] (coenzyme... 

Methylcobalamin and adenosylcobalamin are the two coen2yme forms of vitamin B 2 in animals and humans. Each is involved in the catalysis of a specific... 

Metabolism and Mobilization. On entry of vitamin B 2 into the cell, considerable metaboHsm of the vitamin takes place. Co(III)cobalamin is reduced to Co(I)cobalamin, which is either methylated to form methylcobalamin or converted to adenosylcobalamin (coenzyme B>22)- The methylation requires methyl tetrahydrofolate. 

The name vitamin B12 indicates a group of cobalt-containing corrinoids, also described as cobala-mins. Hydroxycobalamin (HOCbl), adenosylcobalamin (AdoCbl), and methylcobalamin (MeCbl) are the natural occurring forms. Instead, cyanocobalamin (Figure 19.20) is the commercially available form used for supplements and food fortification, thanks to its greater relative stability. Occasionally, sulfitocobalmin can occur in processed foods. Vitamin B,2 functions as a coenzyme and it is linked to human growth, cell development, and is involved in metabolism of certain amino acids. Vitamin B12 is present mainly in meat and diary foods, therefore a deficiency can occur in... 

Vitamin B12 is a biologically active corrinoid, a group of cobalt-containing compounds with macrocyclic pyrrol rings. Vitamin B12 functions as a cofactor for two enzymes, methionine synthase and L-methylmalonyl coenzyme A (CoA) mutase. Methionine synthase requires methylcobalamin for the methyl transfer from methyltetrahydrofolate to homocysteine to form methionine tetrahy-drofolate. L-methylmalonyl-CoA mutase requires adenosylcobalamin to convert L-methylmalonyl-CoA to succinyl-CoA in an isomerization reaction. An inadequate supply of vitamin B12 results in neuropathy, megaloblastic anemia, and gastrointestinal symptoms (Baik and Russell, 1999). 

Oishi S. 1994. Prevention of di(2-ethylhexyl)phthalate-induced testicular atrophy in rats by coadministration of the vitamin B12 derivative adenosylcobalamin. Arch Environ Contain Toxicol 26 497-503. 

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). 

In 1980 Poston (PI) proposed that vitamin B12 was required for the conversion of the branched-chain amino acid p-leucine to leucine. He found circulating P-leucine levels elevated in patients with vitamin B12 deficiency. The concentration of leucine on the other hand was found to be much lower. He suggested that 2,3-aminomutase, which catalyzes the interconversion of P-leucine and leucine, is a vitamin B12-dependent enzyme which is consequently reduced in patients with pernicious anemia. The enzyme has been found in the liver of several animals and in human leucocytes, and in vitro experiments have shown it to be adenosylcobalamin dependent (P2). 

S-Methylmalonyl-CoA mutase (EC 5.4.99.2) is a deoxyadenoxyladen-osylcobalamin-dependent enzyme of mitochondria required to catalyze the conversion of methylmalonyl-CoA to succinyl-CoA. A decrease in the activity of methylmalonyl-CoA mutase leads to the urinary excretion of large amounts of methylmalonic acid (C22). The biochemical lesion may be at the mutase level due to an abnormality of apoenzyme protein or an inability to elaborate the required coenzyme form of vitamin B12> i.e., adenosyl-cobalamin. In rare cases the abnormality may be due to an inability to convert the d form of methylmalonyl-CoA mutase to the l form as a result of a defective racemase (EC 5.1.99.1) (Kll). In patients, the nature of the abnormality can be determined by tissue culture studies (D13) and by clinical trial, since patients with a defect in adenosylcobalamin production will show clinical improvement when treated with very large doses of vitamin B12 (Mil). 

This is another rare inherited disorder of vitamin B12 metabolism in which both coenzyme forms, adenosylcobalamin and methylcobalamin, are affected. Methylcobalamin is required for the transfer of the methyl group of 5-methyltetrahydrofolate to homocysteine to give methionine. Lack of methylcobalamin results in deficient activity of 2V5-methyltetrahydrofolate-homo-cysteine methyltransferase, resulting in a reduced ability to methylate homocysteine. A failure of methionine synthetase would produce a similar result. 

Structure-Function Relationship of Vitamin Bi2 Coenzyme (Adenosylcobalamin) in the Diol-Dehydrase System... 

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... 

The major plasma vitamer is methylcobalamin, accounting for 60% to 80% ofplasma vitamin B12, with up to 20% as adenosylcobalamin and the remainder mainly hydroxocobalamin. In tissues, the major vitamer is adenosylcobalamin (about 70% in liver), with about 25% as hydroxocobalamin and less than 5% as methylcobalamin. 

In mammals, there are only three vitamin B12 -dependent enzymes methionine synthetase, methylmalonyl CoA mutase, and leucine aminomutase. The enzymes use different coenzymes methionine synthetase uses methylcobal-amin, and cobalt undergoes oxidation during the reaction methylmalonyl CoA mutase and leucine aminomutase use adenosylcobalamin and catalyze the formation of a 5 -deoxyadenosyl radical as the catalytic intermediate. 

About 40 years ago, coenzyme B12 (adenosylcobalamin, (3)) was discovered by Barker et al, and its organometaUic nature was revealed by X-ray analysis in the laboratory of D. C. Hodgkin. The partial syntheses of the coenzyme (3), of methylcobalamin (4), and of other organometalhc B12-derivatives from vitamin Bn were rapidly developed by Smith et al. and Bemhauer et al.] later on, methylcobalamin (4) was also found in human serum. ... 

Vitamin B12 is a mixture of cobalamins. Dietary vitamin B12 is converted to the active forms, methyl-cobalamin (mecobalamin) and adenosylcobalamin. The Average Requirement of total cobalamins in adults is 1.0 microgram/day and the Population Reference Intake is 1.4 micrograms/day. The Lowest Threshold Intake is 0.6 micrograms/day. Hydroxocobalamin (rINN vitamin Bi2a) and cyanocobalamin (rINN) have been used therapeutically. 

Vitamin B12 contains cobalt in a corrin ring that resembles a porphyrin. In the cofactor forms of the vitamin, an adenosyl moiety or methyl group is attached to the cobalt, forming adenosylcobalamin or methylcobalamin (Figure 7-17). 

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