Enzyme Inhibition

Abstract

One aspect of the importance of enzymes in biology can be appreciated by considering the attention that continues to be focused on the inhibition of enzymatic activity. Historically, inhibitors played important roles in the elucidation of metabolic pathways. An example was the use of malonate as a metabolic inhibitor, leading to the accumulation of succinate in metabolizing cell extracts. Malonate proved to be an inhibitor of succinate dehydrogenase, and its effect on metabolism revealed the importance of succinate as a metabolic intermediate and of succinate dehydrogenase in metabolism. In this way, malonate as an inhibitor played an important role in the elucidation of the tricarboxylic acid cycle. Countless competitive inhibitors have been applied in various ways to the characterization of active sites. Clues to the binding properties and specificities of active sites can be deduced by systematically varying the structures of competitive inhibitors and comparing the inhibition constants. In another application, competitive inhibitors are often used to shield active sites against the effects of group selective chemical modification. Because biological processes are catalyzed by enzymes, inhibitors can be used to manage biochemical dynamics to the advantage of humans. Examples include pharmaceutical agents and agricultural insecticides and herbicides, which are often inhibitors of specific enzymes. Many targets for ethical drugs are enzymes. For these reasons, the development of enzyme inhibitors is an important objective in pharmaceutical and agricultural research and development. We explained the simplest kinetic properties of reversible inhibitors in chapter 2, and in chapter 1, we discussed the use of competitive reversible inhibitors and affinity-labeling agents for characterizing active sites. The importance of inhibitors in the pharmaceutical and agricultural industries has led to the discovery and invention of compounds that inhibit enzymes by special mechanisms and with very high binding affinities. These inhibitors often displayed special kinetic properties, which led to the development of kinetic paradigms, including slow-binding inhibition and tight-binding inhibition. In chapter 1, we introduced the theoretical significance of transition-state analogs as potent inhibitors of enzymes, and this theory has led to practical applications in the design of inhibitors. In this chapter, we consider some of the special applications of inhibitors in the pharmaceutical and agricultural industries.