A comprehensive theory for relating free-energy profiles to kinetic equations of enzyme reactions has been developed. It enables expression of the overall rate and the concentrations of reaction intermediates in terms of the heights of peaks in free-energy profiles for various reactions. The reactions include consecutive reactions with intermittent irreversible steps, those with dead-end side reactions and completely reversible reactions. The usefulness of the theory is shown by analysis of a single-substrate reaction, a reaction with a covalent intermediate, and product inhibition in a two-substrate reaction, in which kinetic parameters such as Vmax and Km are related to the peak heights in free-energy profiles. The paper refers also to the concept of rate-determining step (RDS) and shows the utility of a related concept rate-determining zone (RDZ) which indicates the reaction steps between the main intermediate and the RDS. The concept of RDZ is useful for resolving confusion related to the concept of RDS. It should be emphasized that the present approach is applicable only to linear reactions.
Close examination of the concept of the rate-determining step (RDS) shows that there are two types of RDS depending on the definition of 'rate'. One is represented by the highest peak of the free-energy diagram of consecutive reactions and holds true where the rate is defined in terms of the concentration of the first reactant. The other is represented by the peak showing the maximum free-energy difference, where the free-energy difference is the height of a peak measured from the bottom of any preceding troughs, where the definition of the rate is in terms of the total reactant concentration including intermediates. There are no criteria a priori for selecting one of them.
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