A novel reaction between adenosylcobalamin and 2-methyleneglutarate catalyzed by glutamate mutase.

Biochemistry

Department of Chemistry and Division of Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.

Published: March 2002

We describe a novel reaction of adenosylcobalamin that occurs when adenosylcobalamin-dependent glutamate mutase is reacted with the substrate analogue 2-methyleneglutarate. Although 2-methyleneglutarate is a substrate for the closely related adenosylcobalamin-dependent enzyme 2-methyleneglutarate mutase, it reacts with glutamate mutase to cause time-dependent inhibition of the enzyme. Binding of 2-methyleneglutarate to glutamate mutase initiates homolysis of adenosylcobalamin. However, instead of the adenosyl radical proceeding to abstract a hydrogen from the substrate, which is the next step in all adenosylcobalamin-dependent enzymes, the adenosyl radical undergoes addition to the exo-methylene group to generate a tertiary radical at C-2 of methyleneglutarate. This radical has been characterized by EPR spectroscopy with regiospecifically (13)C-labeled methyleneglutarates. Irreversible inhibition of the enzyme appears to be a complicated process, and the detailed chemical and kinetic mechanism remains to be elucidated. The kinetics of this process suggest that cob(II)alamin may reduce the enzyme-bound organic radical so that stable adducts between the adenosyl moiety of the coenzyme and 2-methyleneglutarate are formed.

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Source
http://dx.doi.org/10.1021/bi011965dDOI Listing

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