INHIBITION OF ENZYMES 615 



indicate the latter. There is some evidence the arsenite can react with 

 keratin under appropriate conditions by first reducing the disulfide groups 

 to SH groups, as might occur in the binding of arsenite to hair, a phe- 

 nomenon known for many years. 



The reactivity of a particular SH group on a protein undoubtedly varies 

 with the location of the SH group. The larger arsenicals might be steri- 

 cally prevented from reaching certain SH groups, and electric fields around 

 SH groups would influence the approach of charged arsenicals. The question 

 whether two appropriately spaced SH groups must be present to ensure 

 a tight binding of monosubstituted arsenicals, enabling a ring to be formed, 

 cannot be definitely answered, although this is assumed in much work 

 on enzyme inhibition. It seems to be true that arsenicals are generally 

 more selective SH reagents, compared for example to the mercurials, and 

 they are not useful substances for the titration of all reactive SH groups. 

 This point will be taken up again in the section on enzyme inhibition, but 

 it is likely that monosubstituted arsenicals do not usually react readily or 

 strongly with single SH groups on proteins, although the evidence for this 

 is not as convincing as one would like. Furthermore, it is doubtful if the 

 organic arsenicals can react with SH groups from different protein mole- 

 cules, since the bond angles, steric factors, and electrostatic repulsion would 

 in most cases be unfavorable. Possibly two SH groups on the same protein, 

 not normally adjacent, might react with a single arsenical molecule if the 

 protein structure is flexible, and this would perhaps alter the protein struc- 

 ture. Indeed, there is evidence that certain enzymes are not reactivated 

 even though all of the arsenical is removed, and this could be the result 

 of irreversible structural alterations. 



INHIBITION OF ENZYMES 



The earliest workers to examine the effects of the arsenicals on enzymes 

 unfortunately had only insensitive enzymes at their disposal. Thus emulsin, 

 myrosin, pepsin, trypsin, diastase, and similar enzymes were found to be 

 unaffected by arsenite (Boehm and Johannsohn, 1874), and this appar- 

 ently supressed further work on enzymes for many years and led tO state- 

 ments that the actions of the arsenicals could not be explained on the basis 

 of interference with enzymes. Several reports from 1904 to 1915 did not 

 clarify the problem, since enzymes such as catalase (Senter, 1904; Santesson, 

 1915), "zymase" (Harden and Young, 1911), and succinate oxidase (Bat- 

 telli and Stern, 1911) were found to be inhibited only by high concentrations 

 of arsenite; low concentrations either had no effect or actually stimulated. 

 More susceptible enzymes were found in the 1920's — e. g., lipase (Rona 

 and Bach, 1920), urease (Rona and Gyorgy, 1920), maltase (Rona et al., 

 1922), and xanthine oxidase (Barry et al, 1928), but throughout this work 



