Biosynthesis cobalamins

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

Co within all compounds of the so-called cobalamin (or B12) family. The biological functions of cobalamin cofactors are defined by their axial substituents either a methyl or an adenosyl group. Both cofactors participate in biosynthesis the former in methyl transfer reactions while the latter is a free radical initiator, abstracting H atoms from substrates. Decades after their initial characterization, the fascination with the biological chemistry of cobalamins remains.1109... 

As Co-containing organometallic compounds, cobalamins are unique in nature, and they have a genetic history of more than four billion years. Their biosynthesis, absorption, transport, and metabolism have been well documented in organisms of both marine and terrestrial origin.1110-1112... 

Naturally, the biosynthesis of cobalamins themselves require delivery of Co ions at a particular point in the reaction scheme. Cobaltochelatase catalyzes the ATP-dependent insertion of Co11 into the corrin ring during the biosynthesis of coenzyme B12 in Pseudomonas denitrifleans. Cobaltochelatase is a heterodimeric enzyme (140 KDA and 450 KDA subunits each inactive in isolation), and the two components have been isolated and purified to homogeneity.1119 The reaction product is divalent cobyrinic acid, demonstrating that hydrogenobyrinic acid and its diamide (255) are precursors of AdoCbl. 

This may be of significance in connetion with the biosynthesis of acetate from carbon dioxide, because the next step, the fixation of carbon monoxide, was demonstrated by B. Krautler. He irradiated methyl cobalamin under Co at 30 atm and obtained the acyl cobalamin as the product. Interestingly, a radical mechanism was iproposed, involving the reaction of methyl radicals with CO to give acyl radicals, which then recombine with the cobalt complex /55/. 

Rondon, M.R., lYzebiatowski, J.R., Escalante-Seinerena, J.C. (1997) Biochemistry and molecular genetics of cobalamin biosynthesis. Prog. Nucleic Acid Res. Mol. Biol. 56, 347-384. 

Raux E, Schubert HE, and Warren MJ (2000) Biosynthesis of cobalamin (vitamin B12) a bacterial conundrum. Cellular and Molecular Life Scierwes 57,1880-93. 

Figure 11 Schematic illustration of the cobalamin-dependent enzymatic biosynthesis of methionine via methyl-group transfer from A -methyltetrahydrofolate to homocysteine...

The coenzyme form of pantothenic acid is coenzyme A and is represented as CoASH. The thiol group acts as a carrier of acyl group. It is an important coenzyme involved in fatty acid oxidation, pyruvate oxidation and is also biosynthesis of terpenes. The epsilon amino group of lysine in carboxylase enzymes combines with the carboxyl carrier protein (BCCP or biocytin) and serve as an intermediate carrier of C02. Acetyl CoA pyruvate and propionyl carboxylayse require the participation of BCCP. The coenzyme form of folic acid is tetrahydro folic acid. It is associated with one carbon metabolism. The oxidised and reduced forms of lipoic acid function as coenzyme in pyruvate and a-ketoglutarate dehydrogenase complexes. The 5-deoxy adenosyl and methyl cobalamins function as coenzyme forms of vitamin B12. Methyl cobalamin is involved in the conversion of homocysteine to methionine. 

Because all vitamins are essential, it is difficult to state that one vitamin is more important than another. Nevertheless, folic acid, with its coenzyme role in purine biosynthesis, can be considered crucial for some of the cells most fundamental biochemistry, cell division. This vitamin is intimately tied to vitamin (cobalamin), which has made estimating its DRIs difficult. Also, conditions that can cause a folic acid deficiency also can result in a vitamin Bi2 deficiency. 

The chemistry of the cofactors has provided a fertile area of overlap between organic chemistry and biochemistry, and the organic chemistry of the cofactors is now a thoroughly studied area. In contrast, the chemistry of cofactor biosynthesis is still relatively underdeveloped. In this review the biosynthesis of the cofactors shown in Fig. 1 will be described. Heme and cobalamin will be omitted as these are covered in the review by Allan Battersby and Finian Leeper in this volume. We will focus on cofactor biosynthesis in Escherichia coli because the relevant genetics and biochemistry have been most intensively studied in this organism and it is the easiest system in which to carry out molecular biology [1]. Enzymes from other sources will be described only if the corresponding enzyme from E. coli has not been isolated or subjected to mechanistic studies. 

Perkins JB, Pero J (1993) Biosynthesis of riboflavin, biotin, folic acid and cobalamin. In Sonenshein AL, Hoch JA, Losick R (eds) Bacillus subtilis and other gram positive bacteria. ASM, Washington DC, p 319... 

Cobalamin-catalyzed reactions are generally classified into two groups methylcob-alamin-dependent reactions (Table 1, entry 1 to 3) and coenzyme Bi2-dependent rearrangements (Table 1, entry 4 to 11). The first group includes the biosynthesis of methionine from homocysteine, the reduction of CO2 to acetic acid via an acetyl-CoA pathway, and the biosynthesis of CH4 also via an acetyl-CoA pathway. ... 

The complete biosynthesis of cobalamin requires somewhere around 30 enzyme-mediated steps, which compares favorably to the total chemical synthesis of the compound where, for instance, 37 steps are involved in the photochemical route to synthetic cobyric acid, ° an intermediate that represents only the corrin component of the final cobalamin molecule. For this reason vitamin B12 is produced commercially by bacterial culture and is the most expensive of the water-soluble vitamins to produce because of the comparatively low yields obtained. 

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