454 2. ANALOGS OF ENZYME REACTION COMPONENTS 



and thereby depress metabolism by a mechanism unrelated to direct action 

 on the individual enzymes. General macroion inhibition will be briefly dis- 

 cussed in this section, whether specific or nonspecific, and that these are all 

 instances of analog inhibition is not implied. Bernfeld (1963) has recently 

 reviewed some aspects of macroanionic inhibition. 



General Nature of the Interactions between Macroions 



Inasmuch as enzymes are macroions, the interactions involved, whether 

 specific or nonspecific, will be mainly electrostatic and will depend primarily 

 on the total charges and the distributions of charges on the enzymes and 

 the inhibitory polymers. It is likely that enzymes at pH's removed from 

 their isoelectric points will interact to varying extents with macroions of 

 opposite net charge irrespective of whether the enzymes attack high mo- 

 lecular weight or low molecular weight substrates, but we shall direct our 

 attention chiefly to enzymes whose substrates are polymeric. When inhi- 

 bition occurs under conditions in which the enzyme and the macroion are 

 carrying the same net charge, it has often been assumed that other than 

 electrostatic interactions are involved, but this is not necessary. Let us 

 picture an enzyme of isoelectric point pH 7 in a reaction medium of pH 6.5. 

 The net charge on the enzyme will be positive, but interspersed with the 

 cationic groups on the enzyme surface there will be many anionic carboxy- 

 late groups in most instances. If a macrocationic substance can orient itself 

 on the enzyme surface so as to react with these anionic groups, perhaps 

 because of complementary spacing of the oppositely charged groups, inhi- 

 bition may result, although it will undoubtedly be less than at pH's above 

 the isoelectric point. This is not said to minimize the importance of nonelec- 

 trostatic interactions, which certainly must occur, particularly when the 

 inhibitory macroions contain groups capable of forming hydrogen bonds or 

 regions contributing to the binding through van der Waals' forces. 



The question of the specificity of macroionic inhibition is a difficult one 

 and the data available do not allow us to draw general conclusions. It has 

 been established, however, that a particular enzyme will be inhibited quite 

 differently by various macroions of the opposite net charge, and that a 

 particular macroion exerts very different effects on a group of enzymes. 

 There is probably sufficient evidence, to be discussed later, that enzymes 

 acting on macroionic substrates are likely to be inhibited rather strongly 

 by other macroions in which the charge distribution is similar to that of 

 the substrate, and in such cases the inhibition may indeed be competitive. 

 A quantitative treatment of the interactions must be on a statistical basis 

 and, as far as I know, this has not been undertaken, and would indeed be 

 very difficult since there are several factors about which there is inadequate 

 information. 



The rate at which macroionic inhibition develops has not been studied 



