Near attack conformation enzyme catalysis

Hur S, TC Bruice (2003c) Just a near attack conformer for catalysis (chorismate to prephenate rearrangements in water, antibody, enzymes, and their mutants). J. Am. Chem. Soc. 125 (35) 10540-10542... 

The differences in the rate constant for the water reaction and the catalyzed reactions reside in the mole fraction of substrate present as near attack conformers (NACs).171 These results and knowledge of the importance of transition-state stabilization in other cases support a proposal that enzymes utilize both NAC and transition-state stabilization in the mix required for the most efficient catalysis. Using a combined QM/MM Monte Carlo/free-energy perturbation (MC/FEP) method, 82%, 57%, and 1% of chorismate conformers were found to be NAC structures (NACs) in water, methanol, and the gas phase, respectively.172 The fact that the reaction occurred faster in water than in methanol was attributed to greater stabilization of the TS in water by specific interactions with first-shell solvent molecules. The Claisen rearrangements of chorismate in water and at the active site of E. coli chorismate mutase have been compared.173 It follows that the efficiency of formation of NAC (7.8 kcal/mol) at the active site provides approximately 90% of the kinetic advantage of the enzymatic reaction as compared with the water reaction. 

Bruice and his colleagues (Bruice and Lightstone, 1998 Bruice and Benkovic, 2000) introduced the term near attack conformation (NAC) to define the requirement of conformation for juxtaposed reactants to enter the transition state. The greater the mole fraction of reactant NAC conformation in the pretransition state, the greater the reaction rate constant. It was demonstrated that in intramolecular enzyme catalysis, changes of the enthalpy activation AH as compare with chemical analoges, essentially predominate over entropic contribution, which was estimated to be TAS = - 4-6 kcal mole. 

The exact mechanism of the action by chorismate mutase is stUl not clear, in spite of extensive experimental and theoretical investigations. Several suggestions have been proposed concerning the origin of the catalysis. They include (a) the stabilization of transition state by the enzyme, presumably through electrostatic interactions from the active site residues (b) the promotion of substrate conformational transition to generate the reactive CHAIR conformer at the active site (see Scheme 1.2) (c) the increase of populations of near attack conformers (NACs) and (d) strain effects and conformational compression. These proposals will be discussed below. 

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