Cobalamin and its derivatives vitamin

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 Bj2 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. 

Vitamin Bjj deficiency normally results from indequate absorption rather than inadequate dietary intake. Pernicious anaemia is caused by vitamin Bjj deficiency symptoms include anaemia, glossitis, fatigue and degeneration of the peripheral nervous system and hypersensitivity of the skin. The adult RDA and RNI for Bj2 are 2 and 1.5 /rgday respectively. Unlike other vitamins, B12 is obtained exclusively from animal food sources, such as meat, fish, poultry, eggs, shellfish, milk, cheese and eggs. Vitamin B12 in these foods is protein-bound and released by the action of HCl and pepsin in the stomach. 

Bovine milk contains, on average, 0.4 g Bj2 per lOOg. The predominant form is hydroxycobalamin and more than 95% of this nutrient is protein bound. The concentration of B12 in milk is influenced by the Co intake of the cow. The predominant source of B12 for the cow, and hence the ultimate origin of Bjj in milk, is biosynthesis in the rumen. Therefore, its concentra- 

The B 12-binding proteins of human milk have been studied in detail. The principal binding protein (R-type B1 j-binding protein) has a molecular mass of c. 63 kDa and contains about 35% carbohydrate. Most or all of the B12 in human milk is bound to this protein. A second protein, transcobalamin II, is present at low concentrations. 

Raw ovine and pasteurized caprine milks contain 0.6 and 0.1 /ig Bj2 per 100 g, respectively. Human colostrum contains 0.1/ig per 100 g but the mature milk contains only traces of Bjj. Concentrations of B12 in dairy products (Appendix 6A) include about 0.3 fig per 100 g for cream and 1 fig per 100 g for many cheese varieties. Yogurt contains roughly 0.2 fig per 100 g of this nutrient. 

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The B-group is a heterogeneous collection of water-soluble vitamins, most of which function as co-enzymes or are precursors of co-enzymes. The B-group vitamins are thiamin, riboflavin, niacin, biotin, pantothenic acid, pyridoxine (and related substances, vitamin B6), folate and cobalamin (and its derivatives, vitamin B12). 

Researchers studying the metalloenzyme hydrogenase would like to design small compounds that mimic this enzyme s ability to reversibly reduce protons to H2 and H2 to 2H+, using an active center that contains iron and nickel. Cobalamins (vitamin and its derivatives) contain an easily activated Co-C bond that has a number of biological functions, one of which is as a methyl transferase, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). This enzyme converts homocysteine (an amino acid that has one more CH2 group in its alkyl side chain than cysteine see Figure 2.2) to methionine as methylcobalamin is converted to cobalamin. 

Vitamin B12 and its derivatives were considered as possible carrier molecules, since they meet most of the aforementioned requirements. Since the photochemical reactions of the cobalamins involve the bond breaking between the cobalt centre and the axial ligand [10-21], the model assemblies of metallocobalamins with a second metal complex (such as [Pt(CN)4]2 or [Au(CN)2] ) [14, 22,23] as the sixth ligand have been synthesized. Upon irradiation these cobalamin derivatives undergo photosolvation with the concomitant metal complex release. 

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. 

ATP to yield the d isomer of methylmalonyl CoA (Figure 22.11). This carboxylation reaction is catalyzed by propionyl CoA carboxylase, a biotin enzyme that is homologous to and has a catalytic mechanism like that of pyruvate carboxylase (Section 16.3.2). The d isomer of methylmalonyl CoA is racemized to the 1 isomer, the substrate for a mutase that converts it into succinyl CoA by an intramolecular rearrangement. The -CO-S-CoA group migrates from C-2 to C-3 in exchange for a hydrogen atom. This very unusual isomerization is catalyzed by methylmalonyl CoA mutase, which contains a derivative of vitamin Bj2, cobalamin, as its coenzyme. 

The main biological and biochemical interest in cobalt concerns vitamin B,2 and a number of its derivatives, such as 5 -deoxyadenosyl cobalamin, which function as coenzyme in a number of rearrangements involving hydrogen shifts and aquocobalamin which is involved in the synthesis of methionine, methane and acetate. Vitamin in its resting state is ESR-inactive since it contains Co , but, when reduced to Co, spectra such as that shown in Figure 4.7 are obtained. This reduced form is referred to as vitamin B,2r it does not have cyanide as a sixth ligand. Its... 

Hydroxocobalamin (vitamin another antidote, is a potential alternative to sodium nitrite treatment. It works by binding with cyanide to form nontoxic cyano-cobalamin (vitamin Bj ). Although effective and relatively safe in experimental models, the concentration available in the United States requires large infusion volumes and has a short shelf life due to light instability, and reports of anaphylactoid reactions have limited its use (8,13,21). Further studies using higher concentrations available in European formulations may eventually lead to its use as an outpatient alterative to sodium nitrite treatment in the United States (7,32). Other alternatives currently used or undergoing clinical trials in Europe include cobalt salts, limited by their toxicity, aldehydes, and aminophenol derivatives. These alternative treatments are not currently available in the United States (7). 

Vitamers are chemically similar substances that have a qualitatively similar vitamin activity. Thus, vitamin D refers to ergocalciferol (Da) and cholecalciferol (D3) and sometimes to their 25-hydroxy- and 1,25-dihydroxy derivatives (Chapter 37). Similarly, pyridoxine (pyri-doxol), pyridoxal, and pyridoxamine are vitamin Be vitamers, riboflavin is the active form of vitamin Ba and cobalamin is vitamin Bia- The members of a particular vitamin family are functionally interchangeable and protect against deficiency symptoms for that vitamin. A vitamin and its corresponding deficiency disease are related as follows ... 

Reduction of cyanocobalamin (Figure 54(a) R = CN) with sodium borohydride affords a diamagnetic grey-green product (Vitamin 6x2 which reacts with acyl or alkyl halides and with olefins to give cobalamin o-organo derivatives. There has been some discussion whether Vitamin 6x2. is a cobaltCO anion or whether it is cobalamin hydride. Some of the... 

Reduction of cyanocobalamin with sodium borohydride or zinc and acetic acid affords a diamagnetic, grey-green product (Vitamin B12,) which reacts with acyls, alkyl halides and with olefins to ve cobalamin-[Pg.248]

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

Propionyl-CoA is first carboxylated to form the d stereoisomer of methylmalonyl-CoA (Pig. 17—11) by propionyl-CoA carboxylase, which contains the cofactor biotin. In this enzymatic reaction, as in the pyruvate carboxylase reaction (see Pig. 16-16), C02 (or its hydrated ion, HCO ) is activated by attachment to biotin before its transfer to the substrate, in this case the propionate moiety. Formation of the carboxybiotin intermediate requires energy, which is provided by the cleavage of ATP to ADP and Pi- The D-methylmalonyl-CoA thus formed is enzymatically epimerized to its l stereoisomer by methylmalonyl-CoA epimerase (Pig. 17-11). The L-methylmal onyl -CoA then undergoes an intramolecular rearrangement to form succinyl-CoA, which can enter the citric acid cycle. This rearrangement is catalyzed by methylmalonyl-CoA mutase, which requires as its coenzyme 5 -deoxyadenosyl-cobalamin, or coenzyme Bi2, which is derived from vitamin B12 (cobalamin). Box 17—2 describes the role of coenzyme B12 in this remarkable exchange reaction. 

Vitamin B12 is synthesized only by microorganisms it is not present in plants. Animals obtain the vitamin preformed from their natural bacterial flora or by eating foods derived from other animals. Cobalamin is present in appreciable amounts in liver, whole milk, eggs, oysters, fresh shrimp, pork, and chicken. 

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