Cobalamins methylcobalamin

Vitamin B12 Cobalamin Methylcobalamin Deoxyadenosyl cobalamin Cofactor for reactions Homocysteine > Methionine I Methylmalonyl CoA -> Succinyl CoA j... 

Vitamin Bj2 is used for the enrichment of some foods (such as breakfast cereals, soy products, energy bars and yeast extract spread) and which maybe the source of corrinoids for strict vegetarians and vegans. Along with other vitamins, vitamin Bjj is added to many multivitamin preparations and to food supplements. Cyanocobal-amin, which is used in most supplements, is readily converted into the coenzyme forms of cobalamin (methylcobalamin and 5 -deoxyadenosylcobalamin) in the human body. 

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 total syntheses have yielded cobyric acid and thence cyanocobalamin. Routes to other cobalamins, eg, methylcobalamin and adenosylcobalamin, are known (76—79). One approach to such compounds involves the oxidative addition of the appropriate alkyl haUde (eg, CH I to give methylcobalamin) or tosylate (eg, 5 -A-tosyladenosine to yield adenosylcobalamine) to cobalt(I)alamine. 

The primary step in the photolysis of methylcobalamin is homolytic fission to give the Co(II) cobalamin and methyl radicals. Recombination can occur, i.e., the reaction is reversed, unless the radicals and/or Co(II) are removed by further reactions ... 

Enzymatic methylation of homocysteine (HSCHjCHjCHNHjCOOH) by methylcobalamin to give methionine (CH3SCH2CH2CHNH2COOH) was discovered in 1962 by Woods and co-workers, who also noticed the occurrence of a much slower, nonenzymatic reaction giving the same products. Methylcobinamide showed the same activity as the cobalamin in both the enzymatic and nonenzymatic reactions (72, 7/). It was subsequently discovered that HS, MeS , PhS , and w-BuS will dealkylate a variety of methyl complexes [DMG, DMG-BF2, DPG, G, salen, (DO)(DOH)pn, cobalamin] and even ethyl-Co(DMG)2 complexes to give the thioethers, and it was suggested that the reaction involved transfer of the carbonium ion to the attacking thiolate 161, 164), e.g.,... 

Catalytic hydrogenation with platinum liberates the hydrocarbon from methylcobalamin (57) and from alkyl-Co-DMG complexes (161), but not from pentacyanides with primary alkyl, vinyl, or benzyl ligands, though the cr-allyl complex yields propylene (109). Sodium sand gives mixtures of hydrocarbons with the alkyl-Co-salen complexes (64). Dithioerythritol will liberate methane from a variety of methyl complexes [cobalamin, DMG, DMG-BF2, G, DPG, CHD, salen, and (DO)(DOH)pn] (156), as will 1,4-butanedithiol from the DMG complex (157), and certain unspecified thiols will reduce DMG complexes with substituted alkyl ligands (e.g., C0-CH2COOH ->CH3C00H) (163, 164). Reaction with thiols can also lead to the formation of thioethers (see Section C,3). 

It soon became apparent that the biologically active forms of Vitamin Bj.2 contained the unique Co—C-a-bond, and the instability of these covalent compounds to visible light facilitated observations on the occurrence of functional corrinoids in a number of enzymes. Deoxyadenosyl-cobalamin was found to be the most abundant corrinoid in bacteria (24) and in mammalian liver (25). Methylcobalamin was found in Escherichia coli (26), calf liver and human blood plasma (27), and also in a number of Clostridia (28). 

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria. This enzyme mediates the transfer of a methyl group from methyltetrahydrofolate to homocysteine to yield methionine (Fig. 40-4 reaction 4). A cobalamin group bound to the enzyme is converted to methylcobalamin prior to formation of methionine. 

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. 

The vitamin cobalamin (vitamin Bjj) is reduced and activated in the body to two forms, adeno-sylcobalamin, used by methylmalonyl CoA mutase, and methylcobalamin, formed from methyl-THF in the N-methyl THF-homocysteine methyltransferase reaction. These are the only two enzymes that use vitamin (other than the enzymes that reduce and add an adenosyl group to it). 

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. 

Fig. 1. Folate-cobalamin interaction in the synthesis of purines and pyrimidines and, therefore, of DNA. (1) In gastrointestinal mucosa cells (2) in the liver (3) in peripheral tissues. C, cobalamine DAC, desoxyadenosylcobalamine HC, hydroxy cobalamine MC, methylcobalamine F, folic acid MTHF, methyltetrahydrofolic acid THF, tetrahydrofolic acid DHF, dihydrofolic acid dUMP, deoxyuridinemonophosphate dTMP, deoxythymidine-monophosphate. (Adapted from Far-...

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. 

Fig. 2.2.1 Outline of homocysteine metabolism in man. BMT Betaine methyltransferase, cblC cobalamin defect type C, cblD cobalamin defect type D, GNMT def glycine N-methyltransferase deficiency, MAT methionine adenosyl transferase, MeCbl methylcobalamin, Met Synth methionine synthase, MTHFR methylenetetrahydrofolate reductase, SAH Hyd dc/S-adenosylhomocys-...

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). 

Vitamin B12 (cobalamin) has as its active forms, methylcobalamin and deoxyadenosyl cobalamin. It serves as a cofactor for the conversion of homocysteine to methionine, and methylmalonyl CoA to succinyl CoA. A deficiency of cobalamin results in pernicious (megaloblastic) anemia, dementia, and spinal degeneration. The anemia is treated with IM or high oral doses of vitamin B12. There is no known toxicity for this vitamin. 

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). 

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