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Charge Dispersion and Its Effects on the Reactivity of Thiamin-Derived Breslow Intermediates
journal contribution
posted on 2018-06-01, 00:00 authored by Michael Bielecki, Graeme W. Howe, Ronald KlugerThe enzymic decarboxylation
of 2-ketoacids proceeds via their C2-thiazolium
adducts of thiamin diphosphate (ThDP). Loss of CO2 from
these adducts leads to reactive species that are known as Breslow
intermediates. The protein-bound adducts of the 2-ketoacids and ThDP
are several orders of magnitude more reactive than the synthetic analogues
in solution. Studies of enzymes are consistent with formulation of
protein-bound Breslow intermediates with localized carbanionic character
at the reactive C2α position, reflecting the charge-stabilized
transition state that leads to this form. Our study reveals that nonenzymic
decarboxylation of the related thiamin adducts proceeds to the alternative
charge-dispersed enol form of the Breslow intermediate. These differences
suggest that the greatly enhanced rate of decarboxylation of the precursors
to Breslow intermediates in enzymes arises from maintenance of the
carbanionic character at the position from which the carboxyl group
departs, avoiding charge dispersion by stabilizing electrostatic interactions
with the protein as formulated by Warshel. Applying Guthrie’s
“no-barrier” addition to Marcus theory also leads to
the conclusion that maintaining the tetrahedral carbanion at C2α
of the resulting adduct minimizes associated kinetic barriers by avoiding
rehybridization as part of steps to and from the intermediate. Finally,
maintenance of the reactive energetic carbanion agrees with the concepts
of Albery and Knowles as the outcome of evolved enzymic processes.