1. PERSPECTIVES OF METABOLIC INHIBITION 3 



(2), the formation of high-energy phosphate (3), the syntlietic reactions 

 for the formation of the protoplasmic components (4), or the utilization of 

 the high-energy substances by these synthetic processes (5). With respect 

 to the functional activity of the cell, the inhibitor may act either on the 

 reactions involved in the utilization of energy (6) or directly on the function- 

 al systems themselves (7). It is necessary to realize that these intracellular 

 processes are closely related so that, for example, a primary inhibition on 

 the oxidation of substrate will depress to varying degrees the formation of 

 high-energy substances, synthesis, function, and the appearance of prod- 

 ucts. Also it must always be borne in mind that the actions of many in- 

 hibitors are not localized to a single pathway inasmuch as inhibitors are 

 seldom completely specific. 



Directly distorting the pathways of enzymically directed reactions by 

 the introduction of a chemical substance — blocking a jiathway or diverting 

 a sequence into a new channel, interfering with coupled processes or hinder- 

 ing the accumulation of energy — is one approach amongst others. It is 

 an interesting and a useful way because it often provides a rather specific 

 attack upon some particular reaction or phase of metabolism, and often 

 one is able to relate certain aspects of cellular activity to this susceptible 

 region in the metabolic network. In fact, it is often possible to isolate from 

 the cell the special enzyme or enzyme system acted upon and to study the 

 detailed mechanism of the interference, so that it becomes possible to 

 postulate more accurately what occurs within the cell when the inhibitor 

 exerts its effects. Many other ways of altering metabolic activity — for 

 example, by changing the temperature or the pH, by irradiation or high 

 pressure — are nonspecific and seldom does one have any ideas as to exactly 

 what is occurring in the complex protoplasmic matrix. If one had to cho ose 

 the most interesting and important characteristic of enzyme inhibitors, 

 what it is that makes them one of the most powerful tools in so many fields 

 of biological investigation, it would be their relative specificity, or at least 

 the possibility of attaining greater and greater specificity as new inhibitors 

 are discovered for attack upon reactions of interest. The question of spec i- 

 ficity cannot be overemphasized. The more we know about the exact nature 

 of the perturbation produced and the more selective this action can be made, 

 the more likely it is that clear interrelationships will emerge and the goal 

 of understanding the energetics of the cell be achieved. 



Sometimes in using inhibitors one does not begin initially with a normal 

 cellular system, but one in which something has gone astray in the complex 

 pattern, in other words a group of pathological cells. If this aberration 

 is basically metabolic, there is the possibility of restoring the cells towards 

 the normal pattern by the use of substances effective in specifically altering 

 appropriate reactions. It is probable that many of the most useful drugs 

 act exactly in this manner. On the other hand, if the cells have become 



