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Stabilisation of methylene radicals by Cob(II)alamin in coenzyme B12 dependent mutases

Lookup NU author(s): Professor Bernard Golding

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Abstract

Coenzyme B12 initiates radical chemistry in two types of enzymatic reactions, the irreversible eliminases (e.g., diol dehydratases) and the reversible mutases (e.g., methylmalonyl-CoA mutase). Whereas eliminases that use radical generators other than coenzyme B12 are known, no alternative coenzyme B12 independent mutases have been detected for substrates in which a methyl group is reversibly converted to a methylene radical. We predict that such mutases do not exist. However, coenzyme B 12 independent pathways have been detected that circumvent the need for glutamate, β-lysine or methylmalonyl-CoA mutases by proceeding via different intermediates. In humans the methylcitrate cycle, which is ostensibly an alternative to the coenzyme B12 dependent methylmalonyl-CoA pathway for propionate oxidation, is not used because it would interfere with the Krebs cycle and thereby compromise the high-energy requirement of the nervous system. In the diol dehydratases the 5′-deoxyadenosyl radical generated by homolysis of the carbon-cobalt bond of coenzyme B12 moves about 10 Å away from the cobalt atom in cob(II)alamin. The substrate and product radicals are generated at a similar distance from cob(II)alamin, which acts solely as spectator of the catalysis. In glutamate and methylmalonyl-CoA mutases the 5′-deoxyadenosyl radical remains within 3-4 Å of the cobalt atom, with the substrate and product radicals approximately 3 Å further away. It is suggested that cob(II)alamin acts as a conductor by stabilising both the 5′-deoxyadenosyl radical and the product-related methylene radicals. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Publication metadata

Author(s): Buckel W, Kratky C, Golding BT

Publication type: Article

Publication status: Published

Journal: Chemistry - A European Journal

Year: 2006

Volume: 12

Issue: 2

Pages: 352-362

ISSN (print): 0947-6539

ISSN (electronic): 1521-3765

Publisher: Wiley - VCH Verlag GmbH & Co. KGaA

URL: http://dx.doi.org/10.1002/chem.200501074

DOI: 10.1002/chem.200501074

PubMed id: 16304645


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