Chemistry and Enzymology of Vitamin B<sub>12</sub>

Brown, Kenneth L.

doi:10.1021/cr030720z

Cited by 494 publications

(496 citation statements)

References 384 publications

(663 reference statements)

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“…On the other hand, the activation barrier of the chemical step in B 12 enzymes is estimated from the corresponding k cat to be Ϸ2-300 s Ϫ1 (⌬g # ϭ 17-16 kcal/mol) (see references in ref. 13), and the reaction free energy is estimated by some to be close to zero (13). Because the BDE and the activation barrier for the solution reaction are Ϸ30 kcal/mol, we will assume that this represents a reasonable estimate of the activation barrier for the bondbreaking process.…”

Section: Prelimenary Analysismentioning

confidence: 99%

“…11 and 12), the catalytic power of enzymes containing coenzyme B 12 cofactor (for review, see ref. 13) has been taken as major support for the strain hypothesis. More specifically, during the reaction of B 12 enzymes the Co-C bond of B 12 is cleaved, leading to the formation of 5Ј-deoxadenosyl radical and Cob(II)alamin, and to a subsequent (or concerted) radical-based rearrangement of the substrate (the reacting system is shown in Fig.…”

mentioning

confidence: 94%

“…19 and 20), biochemical, and chemical studies (for review, see ref. 13), it is very hard to determine the origin of the catalytic effect by the available experimental information. The main problem is the need to determine the relative importance of different energy contributions, and it is not clear how to obtain unique energy decomposition from experimental studies.…”

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confidence: 99%

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A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

Sharma

Chu²,

Olsson³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

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The catalytic power of enzymes containing coenzyme B12 cofactor has been, in some respects, the ''last bastion'' for the strain hypothesis. The present work explores the origin of this effect by using simulation methods that overcome the sampling difficulties of previous energy minimization studies. It is found that the major part of the catalytic effect is due to the electrostatic interaction between the ribose and the protein, and that the strain contribution is very small. Remarkably, enzymes can use electrostatic effects even in a radical process, when the charge distribution of the reacting fragments does not change significantly during the reaction. Electrostatic catalysis can, in such cases, be obtained by attaching a polar group to the leaving fragment and designing an active site that interacts more strongly with this group in the product state than in the reactant state. The finding that evolution had to use this trick provides further evidence to the observation that it is extremely hard to catalyze enzymatic reactions by nonelectrostatic factors. The trick used by B12 enzymes may, in fact, be a very powerful new strategy in enzyme design.simulation of enzymatic reactions ͉ strain effect ͉ transition state stabilization

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Section: Prelimenary Analysismentioning

confidence: 99%

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confidence: 94%

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confidence: 99%

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A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

Sharma

Chu²,

Olsson³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

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“…The environment around Cbl is dominated by uncharged residues, and the sixth coordinate position of Co 2؉ 5] is a water-soluble vitamin and is essential for the growth and development of all mammals, including humans. Cbl is a member of the corrinoid series of cobalt-containing compounds and is distinguished from some other members of this group by possessing a nucleotide side chain terminating in dimethylbenzimidazole (1,2). It serves as a key enzymatic cofactor for a number of methyltransferase and mutase reactions occurring in nature (3).…”

mentioning

confidence: 99%

“…It serves as a key enzymatic cofactor for a number of methyltransferase and mutase reactions occurring in nature (3). In mammals, it contributes the prosthetic group for two important enzymes, methionine synthase (a methyltransferase) and methylmalonylCoA mutase (1,2,4).…”

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confidence: 99%

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

Mathews¹,

Gordon

Chen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The structure of intrinsic factor (IF) in complex with cobalamin (Cbl) was determined at 2.6-Å resolution. The overall fold of the molecule is that of an ␣6/␣6 barrel. It is a two-domain protein, and the Cbl is bound at the interface of the domains in a base-on conformation. Surprisingly, two full-length molecules, each comprising an ␣-and a ␤-domain and one Cbl, and two truncated molecules with only an ␣-domain are present in the same asymmetric unit. The environment around Cbl is dominated by uncharged residues, and the sixth coordinate position of Co 2؉ is empty. A detailed comparison between the IF-B12 complex and another Cbl transport protein complex, trans-Cbl-B12, has been made. The pH effect on the binding of Cbl analogues in transport proteins is analyzed. A possible basis for the lack of interchangeability of human and rat IF receptors is presented.5] is a water-soluble vitamin and is essential for the growth and development of all mammals, including humans. Cbl is a member of the corrinoid series of cobalt-containing compounds and is distinguished from some other members of this group by possessing a nucleotide side chain terminating in dimethylbenzimidazole (1, 2). It serves as a key enzymatic cofactor for a number of methyltransferase and mutase reactions occurring in nature (3). In mammals, it contributes the prosthetic group for two important enzymes, methionine synthase (a methyltransferase) and methylmalonylCoA mutase (1, 2, 4).In mammals, three proteins are involved in the uptake, transport, and storage of Cbl. These are gastric intrinsic factor (IF), trans-Cbl II (TC), and haptocorrin (HC). These are immunologically distinct proteins with a protein core of Ϸ46 kDa. IF and HC are heavily glycosylated, but TC is not (5, 6). In humans, the genes for IF and HC are located in chromosome 22 (7,8), whereas the gene for TC is located in chromosome 11 (9). Human IF contains 399-aa residues plus Ϸ15% carbohydrate, giving it a molecular mass of Ϸ60 kDa, as observed by gel filtration (10-13). All three proteins promote Cbl entry through endocytosis involving distinct cell surface receptors (5,(14)(15)(16)(17)(18)(19)(20).Dietary Cbl is bound first to HC in the gastric lumen but is transferred to IF in the duodenum after degradation of HC by pancreatic proteases. IF is responsible for transit of Cbl through the small intestine and delivery of it to the endothelial cells that line the ileum. The IF-Cbl complex is then recognized by the IF-Cbl receptor, cubilin (CUB), located on the luminal side of the intestinal mucosal cells, and mediates its internalization. Lysosomal degradation of the internalized IF-Cbl complex releases Cbl, which is then able to bind to TC, probably within the enterocyte. The TC-Cbl complex is then translocated across the basolateral membrane and released into the circulation, to be taken up by TC-Cbl receptor-mediated process by all cells in the body. Lysosomal dissociation of the complex then occurs along with transfer of Cbl to the coenzyme methyl-and Ado-Cbl in the cytoplasm and i...

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Computational Studies:B₁₂Cofactors and their Interaction with Enzyme Active Sites

Brunold

2005

Encyclopedia of Inorganic Chemistry

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Cyanocobalamin, commonly known as vitamin B 12 , and its biologically active derivatives, 5′‐deoxyadenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), have long fascinated scientists with their elaborate structures and intriguing reactivities in enzymatic systems. While the large size and complex electronic structures of these cofactors have posed a major challenge for theoretical chemists, recent insights gained from kinetic, spectroscopic, and X‐ray crystallographic studies have established an excellent foundation for validating computational investigations of the geometric, electronic, and reactivity properties of the isolated cofactors and the molecular details of the catalytic cycles of B 12 ‐dependent enzymes. This review—which is by no means exhaustive—summarizes salient information that has been obtained from experimentally validated computational studies of the following: (i) the free B 12 cofactors in their Co 3+ , Co 2+ , and Co 1+ oxidation states; (ii) the mechanism by which enzymes involved in the biosynthesis of AdoCbl overcome the large thermodynamic barrier associated with the Co 2+ → Co 1+ reduction; (iii) plausible strategies by which AdoCbl‐dependent enzymes achieve a trillion‐fold rate of acceleration for the homolytic cleavage of the cofactor's CoC(Ado) bond; and (iv) the means by which MeCbl‐dependent methyltransferases regenerate the active MeCbl cofactor and accelerate the rate of methyl transfer via heterolytic CoC(Me) bond cleavage by as many as 6 orders of magnitude.

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Chemistry and Enzymology of Vitamin B₁₂

Cited by 494 publications

References 384 publications

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

Computational Studies:B₁₂Cofactors and their Interaction with Enzyme Active Sites

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Chemistry and Enzymology of Vitamin B12

Cited by 494 publications

References 384 publications

A new paradigm for electrostatic catalysis of radical reactions in vitamin B 12 enzymes

A new paradigm for electrostatic catalysis of radical reactions in vitamin B 12 enzymes

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

Computational Studies:B12Cofactors and their Interaction with Enzyme Active Sites

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Chemistry and Enzymology of Vitamin B₁₂

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

Computational Studies:B₁₂Cofactors and their Interaction with Enzyme Active Sites