Competing Protonation and Halide Elimination as a Probe of the Character of Thiamin-Derived Reactive Intermediates

Biochemistry
Michael BieleckiRonald Kluger

Abstract

Decarboxylation reactions from comparable thiamin diphosphate- and thiamin-derived adducts of p-(halomethyl)benzoylformic acids in enzymic and non-enzymic reactions, respectively, reveal critical distinctions in otherwise similar Breslow intermediates. The ratio of protonation to chloride elimination from the Breslow intermediate is 102-fold greater in the enzymic process. This is consistent with a lower intrinsic barrier to proton transfer on the enzyme, implicating formation of a localized tetrahedral (sp3) carbanion that is formed as CO2 is produced. In contrast, slower protonation in solution of the decarboxylated intermediate is consistent with formation of a delocalized planar carbanionic enol/enamine. The proposed structural and reactive character of the enzymic Breslow intermediate is consistent with Warshel's general theory of enzymic catalysis, structural characterization of related intermediates, and the lower kinetic barrier in reactions that occur without changes in hybridization.

References

Nov 1, 1978·Proceedings of the National Academy of Sciences of the United States of America·A Warshel
Dec 14, 1976·Biochemistry·W J Albery, J R Knowles
Nov 28, 1989·Biochemistry·J J BurbaumJ R Knowles
Dec 12, 2002·Journal of the American Chemical Society·Qingyan Hu, Ronald Kluger
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Jun 26, 2012·Proceedings of the National Academy of Sciences of the United States of America·Danilo MeyerKai Tittmann
Sep 13, 2012·Angewandte Chemie·Biplab Maji, Herbert Mayr
Nov 28, 2013·Proceedings of the National Academy of Sciences of the United States of America·Alan R Fersht
Feb 16, 2016·Journal of the American Chemical Society·Mathias PaulAlbrecht Berkessel
May 24, 2016·Journal of the American Chemical Society·Haigang SongZhihong Guo
Jan 4, 2017·Journal of the American Chemical Society·Peter A ByrneHerbert Mayr
Dec 19, 2018·Journal of the American Chemical Society·Vianney RegnierDavid Martin

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Citations

Dec 3, 2021·Physical Chemistry Chemical Physics : PCCP·Ming-Hsiu Hsieh, Jen-Shiang K Yu

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