Main Article Content
New approaches towards understanding the reactivity of enzymes–central to chemical biology and a key to comprehending life itself–are discussed herein. The approach overall is based on the idea that structural and reactivity features uniquely characteristic of enzymes–in being absent in normal catalysts–are likely to hold the key to the catalytic powers of enzymes. The quintessentially physical-organic problem is addressed from several angles, both kinetic and phenomenological. (Generally, the Pauling theory of transition state stabilization is adopted as the rigorous basis for understanding enzyme action).
The kinetic approach focuses on the inadequacies of the Michaelis-Menten equation, and proposes an alternative model based on additional substrate binding at high concentrations, which satisfactorily explains experimental observations. The phenomenological approaches focus on the inadequacies of the intramolecularity criterion, thus leading to alternative strategies adopted by nature in the design of these mild yet powerful catalysts, characterized by exquisite selectivity.
Preferential transition state binding at the active site, via both hydrophobic and van der Waals forces, appears to be the major thermodynamic driver of enzymic reactivity. In operational terms, however, multifunctional catalysis–practically unique to the highly ordered enzyme interior–is likely the key to enzymic reactivity. A new concept, ‘strain delocalization’, possibly plays an important role in orchestrating these various effects, and indeed justifies the need for a large proteinic molecule for achieving the enormous rate enhancements generally observed with enzymes.
Thus, this renewed approach to understanding enzymic reactivity departs significantly from currently held views: radically, in abandoning the Michaelis-Menten and intramolecularity models; but also commandeering existing ideas and concepts, although with a shift in emphasis towards transition state effects (including the entirely novel idea of ‘strain delocalization’).The coverage is not exhaustive, but aims to introduce new ideas along with fresh insights into previous works.
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