Chemical basis for enzyme catalysis.

Some half-century ago Pauling ( 1, 2) proposed that the lowering of the activation energy in enzyme catalysis stems from the enzyme’s affinity for the transition state exceeding it’s affinity for the substrate. This proposal has great popular appeal and has served as the basis for the design of transition state based inhibitors and for inducing catalytic activity in various molecular templates ( 3-5). Recent investigations, however, have brought into focus the contributions of thermal motions and ground state conformers associated with the Michaelis complex to the rate of enzymatic reactions ( 6, 7). A description and analysis of the enzyme -substrate complex characteristics are a focus of this review. The pseudothermodynamic cycle of Scheme 1 has been used to calculate the equilibrium constants (1/ KTS) for binding of various transition states by their respective enzymes. This simple cycle is subject to overinterpretation. The numerical value calculated forKTS [)(knonKm)/kcat] is one measure of the efficiency of catalysis and, therefore, is dependent on all factors in the enzymatic and nonenzymatic reactions. For instance, in the comparison of the difference of the free energy of interaction between E and S versus E and TS, one must take into account differences in the free energy of interaction of the solvent environment with S and TS in the presence and absence of E ( 7). Wolfenden observed that the ratios of kcat/knon, for a series of enzymatic reactions, are determined primarily by knon and that values ofkcat reside in a rather narrow range (Figure 1) (3). That the narrow range of log kcat values does not correlate