616 6. ARSENICALS 



there was no definite concept of mechanism, although occasionally the idea 

 was expressed that the inhibition might involve oxidation-reduction reac- 

 tions. Meanwhile the importance of thiols and their reaction with arsenicals 

 were being established, so when certain enzymes were found to have SH 

 groups it was natural to examine inhibition in this light. The first impli- 

 cation of the role of SH groups in enzyme inhibition was apparently made 

 by Bersin (1934) using papain. It was shown that inactive oxidized papain 

 is activated by various arsenoxides, this presumably being due to a re- 

 duction of the S — S groups to SH groups (Bersin and Koster, 1935): 



S SH 



+ R— As=0 + 2H2O ^ E + R— AsO(OH)2 



\ 

 S SH 



However, when fully active reduced papain is treated with the arsenoxides 

 an inhibition is observed (see accompanying tabulation). Actually, no 



... % of full 



Form of papain Arsenical Activity ,. ., 



activity 



Oxidized — 0.09 9.6 



P-NH2-99-ASO (1 mM) 0.37 39.4 



Reduced — 0.94 100 



p-NB..-<p-AsO (1 mM) 0.G6 70.2 



direct evidence that the inhibition is due to mercaptide formation was 

 provided, but Maschmann (1935 b) showed that the inhibition of liver 

 cathepsin is associated with a reduction in the nitroprusside reaction, 

 indicating that the enzyme SH groups react with the arsenical. Although 

 it has generally been assumed since then that most enzyme inhibitions are 

 the result of a reaction of the arsenical with a necessary enzyme SH group, 

 in very, few cases has this been conclusively demonstrated by titration of 

 the SH groups. 



Possible Mechanisms of Inhibition 



Arsenical inhibition may or may not involve SH groups. If it does, the 

 SH groups do not have to be on the apoenzyme, but can be on the substrate, 

 a cofactor, or some intermediate. The inhibition of cysteine desulfhydrase 

 by arsenite (Lawrence and Smythe, 1943; Powning, 1954) might be due 

 in part to the reaction with cysteine, but it was also postulated that mer- 

 captopyruvate is an intermediate in the reaction: 



