STIMULATION OF METABOLISM BY INHIBITORS 451 



may be available. Although this is not common, it does occur occasionally. 

 When formation of ATP is suddenly stopped, phosphorylation reactions 

 will proceed until the ATP is exhausted, and in this case a reserve source 

 of high-energy phosphate is often present as creatine phosphate which can 

 be used to maintain the ATP for an interval. 



It is now clear that the original formulation of the total metabolism 

 as being made up of two parts, a sensitive and a resistant fraction, is not 

 valid for all cases; the resistant pathway may not even be operative in the 

 uninhibited cell and its eventual magnitude may depend on a number of 

 factors. It is also evident that it is not justifiable to conclude without evi- 

 dence that the resistant fraction of the metabolism is different qualitatively 

 from the sensitive fraction. In the early speculations on cyanide-stable 

 respiration it was often believed that this originated from noncarbohydrate 

 substrates, simply because the respiration resulting from added sugars 

 was mainly sensitive to cyanide, but this differentiation is no longer neces- 

 sary. The relationship of the stable fraction to cell function is important 

 and will be taken up in a later section. 



STIMULATION OF METABOLISM BY INHIBITORS 



It might seem paradoxical for an enzyme inhibitor to increase the rate 

 of some phase of metabolism but actually such stimulation is not at all un- 

 common. It is probably justifiable to say that the greater the number of 

 interrelated enzymes in the total system, and the greater the complexity 

 and organization of the metabolic pathways, the more likely will it be that 

 stimulation can occur. Although this stimulation is generally of cell me- 

 tabolism or of functions related to metabolism, it has also been observed 

 on single enzymes. 



There may be some doubt in the mind of the reader as to the advisability 

 of designating substances that stimulate as inhibitors. Some explanation 

 of what is implied is necessary. In the first place, we are concerned in these 

 volumes with substances that are generally considered as inhibitors of 

 enzymes or metabolic processes. Now, although these substances may be 

 inhibitory to many enzymes (or to one or a few specifically), they can in some 

 cases exert a stimulatory action on other enzymes. These latter actions must 

 be taken into account in any treatment of the effects these substances 

 produce in living material. One must speak not only of the beneficial 

 therapeutic actions of drugs but also of their toxic effects; likewise, one 

 cannot consider only the inhibitory aspect of compounds such as cyanide, 

 iodoacetate. or arsenite, and it is necessary to include every jDOSsible effect 

 they may have on cells and organisms. Secondly, a substance may produce 

 a stimulatory effect by a primary inhibitory action on an enzyme; the 

 response of the particular rate measured need not be identical with the 



