CHAPTER 2 



ANALOGS OF ENZYME REACTION 

 COMPONENTS 



An enzyme-catalyzed reaction involves the combination of the com- 

 ponents with specific sites on the apoenzyme protein surface, these areas 

 possessing the particular molecular configuration and the electrical field 

 distribution required for the attachment and the electronic displacements 

 characterizing the activated complex. If one of these components is modified 

 in any way, its behavior in the system will usually be altered, due primarily 

 to the new pattern of interaction between the modified component and 

 the enzyme. The development and study of such analogs of substrates and 

 coenzymes have been very active fields during the past few years for several 

 reasons. First, the determination of the relative aflfinities of analogs that 

 are substrates or inhibitors for enzymes is one of the most effective means 

 for analyzing the topography of active centers and establishing the types 

 of interaction involved in the catalysis. Second, it is hoped that inhibitors 

 more specific for blocking certain enzymes than the inhibitors previously 

 available will be found and this has been justified to a certain extent. 

 Third, it has been realized that analog inhibition has direct bearing on the 

 important phenomenon of feedback control of metabolic sequences and on 

 the general regulation of cellular metabolism. Last, it is anticipated that 

 the use of proper analogs may be useful in the specific correction of certain 

 abnormal metabolic patterns and growth processes, such as occur in here- 

 ditary enzyme defects or neoplastic changes. 



The previous chapter is concerned with malonate, a classic analog inhib- 

 itor, and in the present chapter it is proposed to extend this principle to 

 a variety of enzymes in order to establish some basic concepts. There are 

 a number of inhibitors which act, at least occasionally, because they are 

 structurally related to some enzyme reaction component, but which for 

 various reasons will be discussed in separate chapters. Such are carbon 

 monoxide, fluoroacetate and fluorocitrate, parapyruvate, arsenate, pyro- 

 phosphate, monoamine oxidase inhibitors, certain inhibitors of cholinester- 

 ase, and various drugs. Furthermore, it is necessary to point out that no 

 attempt will be made to review the vast literature on the depression of 



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