Kinetics of Enzymatic Reactions
Princeton University, B. A., 1956; Oxford University B. A. (1958), M. A. (1960); Rockefeller Institute, Ph.D. (1964); NIH Research Career Development Award (1971-1976); Fellow, American Association for the Advancement of Science (1983); Member, Editorial Board, Bioorganic Chemistry (1983-); North Carolina Distinguished Chemist Award, ACS (1990);Member, Editorial Board, Bioorganic and Medicinal Chemistry and Bioorganic and Medicinal Chemistry Letters (1989-) Chairman, Biological Division, American Chemical Society (2000-); Elected, Member of National Academy of Sciences (2002); Elected, Fellow of American Academy of Arts and Sciences (2002)
An enzyme, or any other catalyst, lowers the activation barrier that limits the rate of reaction. This can only be accomplished to the extent that the enzyme binds the altered substrate (S‡), in the transition state for its transformation, more tightly than it binds the substrate (S) in its ground state. During that moment, lasting roughly 10-13 sec, the "grip" of the enzyme on the substrate tightens by a factor that equals or exceeds the factor by which the enzyme enhances the rate of reaction. This picture of catalysis focuses attention on a structure rather than a process, and leads to a testable prediction. A stable compound that resembles S‡ should be a potent inhibitor, with an affinity surpassing that of the substrate by a very large factor as discussed below. Our lab is trying to work out some of the implications of this idea, for studying enzyme mechanisms and designing new enzyme antagonists as potential drugs.
To evaluate the potential strength of binding of an ideal transition state analogue inhibitor of any enzyme, it is necessary to know not only its kcat value for a good substrate, but also the rate of the same reaction proceeding under similar conditions in the absence of a catalyst. To appreciate the catalytic proficiencies of existing enzymes, and their potential sensitivities to reversible inhibitors, we have been devising new methods for measuring nonenzymatic reaction rates in aqueous solution at extremely high temperatures in quartz vessels, forextrapolation to room temperature.