Biochemistry

Lowering the Barrier with Electrostatics

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Science  21 Apr 2000:
Vol. 288, Issue 5465, pp. 401
DOI: 10.1126/science.288.5465.401d

The decarboxylation of orotidine 5′-monophosphate (OMP) to uridine 5′-monophosphate is accelerated by a factor of 1017 by the enzyme OMP decarboxylase. Several mechanisms have been proposed to account for this enormous rate enhancement in the absence of cofactors or metals; recent structural studies have revealed the arrangement of amino acid side chains within the enzyme active site. In perhaps the final chapter to this tale, Rishavy and Cleland now have measured nitrogen-15 isotope effects and show that the bond order at N-1 does not change during the reaction. From this result, they conclude that negative charge that develops at C-6 during decarboxylation cannot be stabilized by formation of an ylide. Thus, it appears that catalysis results from: (1) stabilization of the transition state carbanion by electrostatic interaction between C-6 and Lys-93, and (2) destabilization of the ground state via electrostatic repulsion between the departing carboxylate and Asp-91.—VV

Biochemistry, in press.

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