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Thiamin diphosphate-dependent decarboxylases form addition intermedi-ates between thiamin diphosphate (ThDP) and 2-ketoacids. Although it appears that the intermediate should react without the intervention of cata-lysts, evidence has clearly shown that Brønsted acid catalysis occurs through a pre-associated system. | REVIEW ARTICLE Catalyzing separation of carbon dioxide in thiamin diphosphate-promoted decarboxylation Ronald Kluger and Steven Rathgeber Davenport ChemicalLaboratories Department of Chemistry University of Toronto Canada Keywords active site benzoylformate decarboxylase carbanion catalysis decarboxylation diffusion fragmentation pre-association thiamin thiamin diphosphate Correspondence R. Kluger Davenport ChemicalLaboratories Department of Chemistry University of Toronto Toronto Ontario M5S 3H6 Canada Fax 1 416 978 8775 Tel 1 416 978 3582 E-mail rkluger@chem.utoronto.ca Received 22 July 2008 revised 2 October 2008 accepted 10 October 2008 doi 10.1111 j.1742-4658.2008.06739.x Thiamin diphosphate-dependent decarboxylases form addition intermediates between thiamin diphosphate ThDP and 2-ketoacids. Although it appears that the intermediate should react without the intervention of catalysts evidence has clearly shown that Bronsted acid catalysis occurs through a pre-associated system. This can promote separation of carbon dioxide from the residual carbanion by protonation of the carbanion. Proteins operate through pre-association and may readily promote the separation of carbon dioxide by protonating or oxidizing the nascent carbanion. Alternatively a nucleophilic side chain may trap carbon dioxide as an unstable hemi-carbonate. Mutagenesis experiments by others have shown that enhanced activity due to the protein in the presence of thiamin diphosphate does not depend on the presence of any one proton donor consistent with pooled activity within the active site. This form of catalysis has not been widely recognized but should be considered an integral aspect of enzyme-promoted decarboxylation. Decarboxylases and intermediates Thiamin diphosphate ThDP is a cofactor that promotes the decarboxylation of 2-ketoacids through formation of covalent derivatives between its C2 thia-zolium and the carbonyl of the substrate. Combination of a protein and ThDP in a holoenzyme .
