SPONTANEOUS KEACTIVATION OF INHIBITED ENZYMES 



627 



the inhibitor will be taken up in a later section and here we shall confine 

 ourselves to the latter situation. Chemical modification of the inhibitor by 

 the enzyme usually occurs when the inhibitor in some manner resembles 

 the substrate and attaches to the enzyme in a way characteristic of the 

 substrate. 



The most thoroughly documented example of such a spontaneous re- 

 versal occurs in the inhibition of cholinesterase by certain organophosphorus 

 compounds (Aldridge, 1953 a. b; Aldridge and Davison, 1953). The time 

 courses of inhibition of rabbit erythrocyte cholinesterase by dimethyl- 

 and diethyl-p-nitrophenyl phosphates are shown in Fig. 13-9. The inhibition 



0-Me 



0,N-^~\-0-P=0 

 0-Me 

 Dimethyl-7;-nitrophpnyl phosphate 



0-Et 



0-Et 



Diethyl-p-?iitrophenyl phosphate 



TIME (MIN) 



120 



Fig. 13-9. Inhibition of rabbit erythrocyte chohnesterase by 

 p-nitrophenyl phosphates and its spontaneous reversal. (From 

 Aldridge, 1953 b.) Curve A: diethyl-j9-nitrophenyl phosphate 

 (4.1 X 10^4 mM); curve B: dimethyl-j)-nitrophenyl phosphate 

 (2.4 X 10-3 mM); curve C: dimethyl-p-nitrophenyl phosphate 

 (4.7 X 10-4 milf). 



produced by the diethyl compound is stable but that by the dimethyl analog 

 is slowly and spontaneously reversible. The reversal follows first-order 

 kinetics as is shown by the linear relationship between log (per cent inhi- 

 bition) and time (Fig. 13-10). The first-order rate constant for the reversal 

 reaction was found to be 1.68 X 10-^ min-^ at 17°, 4.29 X 10" =* min-^ at 28°, 

 and 8.55x10-3 min-^ at 37o, giving an energy of activation of 14.4 kcal/ 

 mole. Aldridge postulated the following sequence to explain the inhibition 

 reversal: 



