上海交大第8章生化 (刘建华).ppt

Figure 8.24. Inhibition by Transition State Analogs. (A) The isomerization of l-proline to d-proline by proline racemase, a bacterial enzyme, proceeds through a planar transition state in which the α carbon is trigonal rather than tetrahedral. (B) Pyrrole 2-carboxylate, a transition state analog because of its trigonal geometry, is a potent inhibitor of proline racemase. This mechanism is supported by the finding that the inhibitor pyrrole 2-carboxylate binds to the racemase 160 times as tightly as does proline. The α-carbon atom of this inhibitor, like that of the transition state, is trigonal. An analog that also carries a negative charge on C -α would be expected to bind even more tightly. In general, synthesizing compounds that more closely resemble the transition state than the substrate itself can produce highly potent and specific inhibitors of enzymes. The inhibitory power of transition-state analogs underscores (强调)the essence of catalysis: selective binding of the transition state. 8.5.4. Catalytic Antibodies Demonstrate the Importance of Selective Binding of the Transition State to Enzymatic Activity Antibodies that recognize transition states should function as catalysts, if our understanding of the importance of the transition state to catalysis is correct. The preparation of an antibody that catalyzes the insertion of a metal ion into a porphyrin nicely illustrates the validity of this approach. Ferrochelatase, the final enzyme in the biosynthetic pathway for the production of heme, catalyzes the insertion of Fe2+ into protoporphyrin IX. The nearly planar porphyrin must be bent for iron to enter. The recently determined crystal structure of the ferrochelatase bound to a substrate analog confirms that the enzyme does indeed bend one of the pyrole rings, distorting it 36 degrees to insert the iron. Figure 8.25. Use of Transition-State Analogs to Generate Catalytic Antibodies. The insertion of a metal ion into a porphyrin by ferrochel