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How the Co−C Bond Is Cleaved in Coenzyme B12 Enzymes: A Theoretical Study
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Abstract
The homolytic cleavage of the organometallic Co−C bond in vitamin B12-dependent enzymes is accelerated by a factor of 
1012 in the protein compared to that of the isolated cofactor in aqueous solution. To understand this much debated effect, we have studied the Co−C bond cleavage in the enzyme glutamate mutase with combined quantum and molecular mechanics methods. We show that the calculated bond dissociation energy (BDE) of the Co−C bond in adenosyl cobalamin is reduced by 135 kJ/mol in the enzyme. This catalytic effect can be divided into four terms. First, the adenosine radical is kept within 4.2 Å of the Co ion in the enzyme, which decreases the BDE by 20 kJ/mol. Second, the surrounding enzyme stabilizes the dissociated state by 42 kJ/mol using electrostatic and van der Waals interactions. Third, the protein itself is stabilized by 11 kJ/mol in the dissociated state. Finally, the coenzyme is geometrically distorted by the protein, and this distortion is 61 kJ/mol larger in the CoIII state. This deformation of the coenzyme is caused mainly by steric interactions, and it is especially the ribose moiety and the Co−C5‘−C4‘ angle that are distorted. Without the polar ribose group, the catalytic effect is much smaller, e.g. only 42 kJ/mol for methyl cobalamin. The deformation of the coenzyme is caused mainly by the substrate, a side chain of the coenzyme itself, and a few residues around the adenosine part of the coenzyme.
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History
- Published In Issue June 29, 2005
- Received February 4, 2005
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