An energy decomposition scheme has been used to elucidate the importance of the changes of enzyme conformational substates to the reduction of the activation barrier in enzyme-catalyzed reactions. This analysis may be illustrated by the reaction of orotidine 5′-monophosphate decarboxylase, which exhibits a remarkable rate enhancement of over 17 orders of magnitude compared to the uncatalyzed process. The mechanism shows that the enzyme conformation is more distorted in the reactant state than in the transition state. The energy released from protein conformation relaxation provides the predominant contribution to the rate enhancement of orotidine 5′-monophosphate decarboxylase. The proposed mechanism is consistent with results from site-directed mutagenesis experiments, in which mutations distant from the reactive center can have significant effects on the catalytic rate enhancement (kcat), but rather a small influence on the binding affinity for the substrate (KM).