An alternative explanation for the catalytic proficiency of orotidine 5′-phosphate decarboxylase

T. S. Lee, L. T. Chong, J. D. Chodera, P. A. Kollman

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34 Scopus citations

Abstract

Orotidine 5′-phosphate decarboxylase (ODCase) is the most proficient enzyme known, enhancing the rate of decarboxylation of orotidine 5′-phosphate (OMP) by a factor of 1017, which corresponds to a ΔΔG‡ of ∼24 kcal/mol. Ground-state destabilization through local electrostatic stress has been recently proposed as the basis of catalytic rate enhancement for a mechanism that is the same as in solution. We have carried out gas-phase ab initio quantum mechanical calculations combined with a free energy method, a continuum solvent model, and molecular dynamics simulations to assess an alternative mechanism. Although we are not able to reproduce the experimentally observed ΔΔG‡ quantitatively, we present evidence that this ΔΔG‡ is very large, in the range found experimentally. We thus conclude that the preferred mechanism may well be different from that in solution, involving an equilibrium pre-protonation of OMP C5 by a catalytic lysine residue that greatly reduces the barrier to subsequent decarboxylation.

Original languageEnglish (US)
Pages (from-to)12837-12848
Number of pages12
JournalJournal of the American Chemical Society
Volume123
Issue number51
DOIs
StatePublished - Dec 26 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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