In 1958 Daniel Koshland proposed the induced-fit model for utilizing protein-substrate binding interactions as a mechanism to obtain specificity in enzyme catalysis (Scheme). The results of work at Buffalo have shown that this model provides a simple rationalization for the specificity shown by a variety of enzymes for binding their transition states with a much higher affinity than substrates. The utilization of part of the substrate binding energy to drive protein conformational changes avoids a similar strong stabilization of the Michaelis complexes, and irreversible ligand binding. The induced-fit mechanisms has been documented for enzymes that function in glycolysis (triosephosphate isomerase), the biosynthesis of lipids (glycerol phosphate dehydrogenase), the hexose monophosphate shunt (6-phosphogluconate dehydrogenase), the mevalonate pathway (isopentenyl diphosphate isomerase), the biosynthesis of pyrimidine nucleotides (orotidine monophosphate decarboxylase), the catabolism of C1 compounds (formate dehydrogenase) and which regulate the cellular levels of adenine nucleotides (adenylate kinase). I propose that this mechanism is generally followed for enzymatic reactions which utilize cofactors such as NAD and TPP, which contain nonreacting "handles" that provide transition state binding energy to drive induced-fit type enzyme conformational changes. Representative examples will be presented for hydride transfer reactions to NAD catalyzed by formate dehydrogenase and glycerol phosphate dehdyrogenase. The lack of computational studies to model the induced-fit mechanism will be noted and discussed.

Enabling role of ligand-driven conformational changes in enzyme catalysis

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.