Revisiting ground-state and transition-state effects, the split-site model, and the "fundamentalist position" of enzyme catalysis

Abstract

In 1978 Schowen laid out the "fundamentalist position" of enzyme catalysis: "...the entire and sole source of catalytic power is the stabilization of the transition state; reactant-state interactions are by nature inhibitory and only waste catalytic power." In 1992 Menger developed the "split-site model" in order to demonstrate contradictions of the fundamentalist position. One of Menger's examples is recounted in which the energy of the enzyme-substrate complex (delta GES) is lowered, yet the catalytic rate increases, incompatible with the claim that reactant- (i.e., ground-) state interactions are inhibitory. A rigorous definition of ground-state effect is proposed which resolves the apparent contradictions. A ground-state effect (delta delta GES) is defined as one in which the energy of the ground state has changed, but the energy of the catalyzed transition state is unchanged when one enzyme is compared to another. This is a result of the constraint that the free energy of binding of the enzyme to the uncatalyzed reaction transition state, delta Gb*, is constant. That ground-state interactions are inhibitory when a single enzyme-catalyzed reaction is considered has been proven by Schowen: this definition of ground-state effect achieves the result of making additional ground-state interactions inhibitory also. This definition is rather restrictive, however, and does not describe many of the possible changes in enzyme energy levels. A proposal is therefore put forth to simply explain the changes in terms of alterations in intrinsic and utilized binding energy.