246 2. ANALOGS OF ENZYME REACTION COMPONENTS 



growth and proliferation exerted by many analogs, inasmuch as my pur- 

 pose here is to restrict the discussion to enzymic and metabolic levels. 



TERMINOLOGY 



The term analog is defined very broadly as any substance that is in some 

 way structurally related to a substrate, coenzyme, or cofactor.* It may 

 either participate in the enzyme reaction to a greater or lesser extent than 

 the normal components, or inhibit the reaction by interfering with the 

 functioning of these normal components. The commonly used term anti- 

 metabolite generally implies that the substance is a biologically abnormal 

 compound synthesized in the laboratory and capable of interfering with the 

 reactions of some cellular metabolite. We shall in this chapter frequently 

 be concerned with inhibitions produced by substances such as carbohy- 

 drates, amino acids, purines, and nucleotides, which naturally occur in most 

 cells, and thus the more general term analog is preferred. The use of the 

 term isostere has generally been restricted to a substance produced by the 

 substitution of an atom or group in the normal compound by another atom 

 or group with similar electronic or steric properties. A homolofj is a member 

 of a series in which some part or property of a basic chemical type is progres- 

 sively varied, as is the case when an aliphatic chain is lengthened by adding 

 successive methylene groups. Most of the analogs to be discussed therefore 

 fall in to one or more of these latter categories, but it is felt that there is 

 little benefit to be derived from using these more specific terms. 



POSSIBLE SITES AND MECHANISMS OF INHIBITION 



The most common mechanism of inhibition is a competition between 

 the analog and the normal reactant for a specific site on the enzyme surface. 

 However, the frequently made assumption that this is the only mechanism 

 involved is often unjustified. Other mechanisms which should be borne in 

 mind will be mentioned here; they will be illustrated and discussed in greater 

 detail later in the chapter. Let us first consider the mechanisms which may 

 apply particularly to the inhibition of pure enzymes. 



(A) Binding of the analog to the enzyme sites for substrate, coenzyme, 

 or activator by interactions which are at least in part those involved in 

 the binding of the normal reactant and which allow reversibility. 



(B) An irreversible, or practically irreversible, reaction with the enzyme 



* The definition of analog must be imprecise because it is impossible to limit accu- 

 rately how much structural deviation can occur before the derivative can no longer 

 be thought of as related to the parent compound. 



