STIMULATION OF METABOLISM BY INHIBITORS 455 



must be exercised in the interpretation of a stimulatory response to an 

 inhibitor. 



III. Reduction in enzyme concentratioyi leads to an increased rate. In cer- 

 tain instances where a dissociable coenzyme or activator is required, in- 

 crease in the concentration of enzyme will augment the rate only up to a 

 point and then the rate will fall off. This is shown very well by lactic de- 

 hydrogenase (Straub, 1940) and probably is a general phenomenon for 

 such enzymes. If in the cell the enzyme concentration is in the range 

 of decreasing rate, the decrease in enzyme resulting from the action of an 

 inhibitor would actually stimulate. It is quite possible that such high 

 concentrations of enzyme occur in the cell, or at least in limited regions, 

 and so this type of stimulation should not be ignored although at present 

 there is no evidence that it is the mechanism in any particular case. 



IV. Reversal of a dynamic equilibrium. In growing cells there is a constant 

 incorporation of amino acids and their synthesis into proteins with the 

 energy provided by ATP: 



Amino acids + ATP — > protein 



Simultaneously the proteins are broken down, presumably by proteolytic 

 enzymes in the cell: 



Protein -> amino acids 



This type of dynamic equilibrium can be disturbed by an inhibitor of 

 either reaction. If the formation of ATP is depressed, as with 2,4-dinitro- 

 phenol, the over-all process may be one of protein breakdown; from limited 

 observations it might be concluded that 2,4-dinitrophenol stimulated pro- 

 teolysis. In any equilibrium of this nature, inhibition of one reaction will 

 tend to increase the other one relatively. 



V. Depression of a reaction controlling metabolism. The ability of a living 

 cell to adjust its metabolism according to its functional activity makes it 

 necessary for the principal metabolic pathways to be under some sort of 

 controlling or regulating mechanism. Thus many metabolic reactions do 

 not operate at the maximal rate in the normal resting cell. The removal of 

 the restricting control will manifest itself as stimulation. One of the chief 

 regulatory mechanisms involves the adenine nucleotides. The obligatory 

 coupling of oxidation with phosphorylation in some electron transport 

 chains limits the rate of electron flow, so that any uncoupling agent may 

 accelerate oxidation. Another very important metabolic control is the Pas- 

 teur-Crabtree relationship between glycolysis and oxidative processes, 

 whereby the concentrations of the nucleotides and inorganic phosphate 

 both control and are determined by the rates of the various reactions. It 



