title: An alternative explanation for the catalytic proficiency of orotidine 5'-phosphate decarboxylase.
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 10(17), which corresponds to a DeltaDeltaG++ of approximately 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 DeltaDeltaG++ quantitatively, we present evidence that this DeltaDeltaG++ 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.
authors.affiliation: Accelrys, Inc., 9685 Scranton Road, San Diego, California 92121-3752, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Lee
authors.forename: L T
authors.initials: LT
authors.lastname: Chong
authors.forename: J D
authors.initials: JD
authors.lastname: Chodera
authors.forename: P A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D007700:Kinetics; D008958:Models, Molecular; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011522:Protons; D013816:Thermodynamics; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D011522:Protons; C005417:orotidylic acid; D014542:Uridine Monophosphate; D009964:Orotidine-5'-Phosphate Decarboxylase