Methylcobalamin structure

Methyl-cis-2-butenoic (angelic) acid, physical properties, 5 35t Methylclothiazide, molecular formula and structure, 5 162t Methylcobalamin, 25 804 Methylcyclohexanediamine, physical properties of, 2 500t... 

Figure 15.3 Structural formula of deoxyadenosylcobalamin (coenzyme B, ). (a) A plan view of the corrin nucleus with substituents, (b) The position of the remaining two ligands of the cobalt atom. No attempt is made to show correct stereochemical relationships. Related compounds have different groups in place of the 5 -deoxyadenosyl group cyanocobalamin, (vitamin Bi2)-CN hydroxycobalamin, (vitamin Bi2)-0H methylcobalamin, (vitamin Bi2)-CH3.

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. 

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

The structure of the E. coli enzyme (Fig. 16-24) shows methylcobalamin bound in a base-off conformation, with histidine 759 of the protein replacing dimethylbenzimidazole in the distal coordination position on the cobalt. This histidine is part of a sequence Asp-X-His-X-X-Gly that is found not only in methionine synthase but also in methylmalonyl-CoA mutase, glutamate mutase, and 2-methyleneglutarate mutase. However, diol dehydratase lacks this sequence and binds adenosylcobalamin with the dimethylbenz-imidazole-cobalt bond intact.417... 

Drennan, C. L., Matthews, R. G., and Ludwig, M. L., 1994b, Cobalamin-dependent methionine synthase the structure of a methylcobalamin-binding fragment and implications for other Bi2-dependent enzymes. Curr. Opin. Struct. Biol. 4 9199929. 

The structure of methylcobalamin (4) is available from X-ray analysis and NMR spectroscopy.Both axial bonds (Co-C = 1.99 A and Co N = 2.19 A) are shorter in methylcobalamin than in coenzyme B12. The upwards-folding is stronger than in coenzyme B12 (15.8° vs. 13.3°). The homolytic (Co )-bond dissociation energy of methylcobalamin (4) has been estimated from the kinetics of its thermal decomposition at elevated temperature to be ca. 37 3 kcal mol . Not unexpectedly, the Co bond of (4) is considerably more resistant to homolysis than that of coenzyme B12. 

The various photochemical studies of these compounds have been conducted primarily because of the interest of researchers in the synthesis, properties, and biological activity of vitamin and its derivatives. The structure of vitamin Bj2, as determined by Crowfoot-Hodgkin et al. 109), is shown in Fig. 2. It consists of cobalt in a corrin ring complexed axially by an a-S, 6-dimethylbenzimidazole nucleotide and by cyanide ion. Replacement of the axial CN by a methyl group gives methylcobalamin, and by 5 -deoxyadenosine gives coenzyme Bj2. The formal oxidation state of... 

Figure 1 In the above structure, R = CN denotes cyanocobalamin (CN-Cbl), whilst R = OH is hydroxocobalamin (OH-Cbl) R = 5 -deoxyadenosyl is coenzyme B12 (adenosylcobalamin, AdoCbl) and R = Me is methylcobalamin (MeCbl). By definition all cobalamins contain 5,6-dimethylbenzimidazole, which is the so-called 6th ligand to cobalt in the above structure. Substances containing the corrin ligand, i.e. the planar 14 electron p-system embracing cobalt in the above structure, are also called corrinoids.

Figure 22.12. Structure of Coenzyme B 2 (5 -deoxyadenosylcobalamin). Substitution of cyano and methyl groups create cyanocobalamin and methylcobalamin, respectively.

Structure of the cobalamin family of compounds. A through D are the four rings in the corrinoid ring system. The B ring is important for cobalamin binding to intrinsic factor. If R = -CN, the molecule is cyanocobalamin (vitamin B12) if R = 5 -deoxyadenosine, the molecule is adenosylcobalamin if R = -CH3, the molecule is methylcobalamin. Arrows pointing toward the cobalt ion represent coordinate-covalent bonds. 

Methionine synthase is composed of five structural domains that provide for binding of its substrate HCY, the methyl donor 5-methyItetrahydrofolate, cobal-amin, and SAM (Fig. 4). In most tissues SAM is utilized to methylate oxidized cobalamin, in conjunction with electron donation by methionine synthase reductase, thereby restoring methylcobalamin and allowing resumption of activity. This mode of reactivation is required approximately every 100-1,000 turnovers, even under strictly anaerobic laboratory conditions (Bandarian et al., 2003). Under physiological conditions, oxidation of cobalamin is undoubtedly much more common, illustrating how vitamin B12 serves as a sensor of redox status. During oxidative stress, cobalamin is more frequently oxidized and more HCY is diverted toward cysteine and GSH synthesis. 

Figure 42-1. The structure of cobalamin, vitamin X = deoxyadenosine in deoxyadenyosylcobalamin X = CHj in methylcobalamin X = CN in cyanocobalamin, the commercial form found in vitamin tablets.

Coenzyme B12, methylcobalamin (Fig. la and b) and closely related derivatives were the first organometallic compounds to be found in nature. Their complex structures, together with that of vitamin B12 (Fig. Ic), were elucidated by X-ray crystallography. ... 

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