The Origins of Enzyme Catalysis and Reactivity: Further Assessments

Abstract

Alternatives to conventional mechanisms of enzyme catalyzed reactions, although within the ambit of transition state theory, are explored herein. This is driven by reports of a growing number of enzymes forming covalently linked enzyme-substrate intermediates, which clearly deviate from the conventional Michaelis-complex mechanism. It is argued that the formation of the covalent intermediates can be accommodated within the framework of transition state theory and the original Pauling hypothesis. This also obviates the need to invoke intramolecular reactivity to explain enzymic accelerations. Thus, the covalent binding of a substrate distorted towards the transition state, with the binding being fully manifested in the ensuing transition state, would conform to the traditional endergonic pre-equilibrium mechanism. Intriguingly, an alternative exergonic formation of the covalent intermediate would also lead to catalysis: in this case, any of the three steps–covalent binding, turnover or product release–can be rate limiting. Although the exergonic mode has been dismissed previously as leading to a “thermodynamic pit” (Michaelis complex case), this view now needs to be reassessed as it seems inaccurate. Therefore, it remains for the enzyme to stabilize the various transition states via the multifarious mechanisms available to it. The Pauling hypothesis remains vindicated.