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1 Catalytic Mechanisms A. Acid–Base Catalysis B. Covalent Catalysis C. Metal Ion Catalysis D. Electrostatic Catalysis E. Catalysis through Proximity and Orientation Effects F. Catalysis by Preferential Transition State Binding 2 Lysozyme A. Enzyme Structure B. Catalytic Mechanism C. Testing the Phillips Mechanism 3 Serine Proteases A. Kinetics and Catalytic Groups B. X-Ray Structures C. Catalytic Mechanism D. Testing the Catalytic Mechanism E. Zymogens 4 Drug Design A. Techniques of Drug Discovery B. Introduction to Pharmacology C. HIV Protease and Its Inhibitors Enzymes, as we have seen, cause rate enhancements that are orders of magnitude greater than those of the best chemical catalysts. Yet they operate under mild conditions and are highly specific as to the identities of both their sub- strates and their products. These catalytic properties are so remarkable that many nineteenth century scientists con- cluded that enzymes have characteristics that are not shared by substances of nonliving origin. To this day, there are few enzymes for which we understand in more than cursory detail how they achieve their enormous rate ac- celerations. Nevertheless, it is now abundantly clear that the catalytic mechanisms employed by enzymes are iden- tical to those used by chemical catalysts. Enzymes are simply better designed. In this chapter we consider the nature of enzymatic catalysis. We begin by discussing the underlying principles of chemical catalysis as elucidated through the study of or- ganic reaction mechanisms. We then embark on a detailed examination of the catalytic mechanisms of several of the best characterized enzymes: lysozyme and the serine proteases. Their study should lead to an appreciation of the intracacies of these remarkably efficient catalysts as well as of the experimental methods used to elucidate their properties. We end with a discussion of how drugs are dis- covered and tested, a process that depends heavily on the principles of enzymology since many drug targets are enzymes. In doing so, we consider how therapeutically effective inhibitors of HIV-1 protease were discovered. 1 CATALYTIC MECHANISMS Catalysis is a process that increases the rate at which a reaction approaches equilibrium. Since, as we discussed in Section 14-1C, the rate of a reaction is a function of its free energy of activation ( G ), a catalyst acts by lowering the height of this kinetic barrier; that is, a catalyst stabilizes the transition state with respect to the uncatalyzed reac- tion. There is, in most cases, nothing unique about enzy- matic mechanisms of catalysis in comparison to nonenzy- matic mechanisms. What apparently make enzymes such powerful catalysts are two related properties: their specificity of substrate binding combined with their optimal arrange- ment of catalytic groups. An enzyme’s arrangement of bind- ing and catalytic groups is, of course, the product of eons of evolution: Nature has had ample opportunity to fine- tune the performances of most enzymes.
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