INHIBITION OF ENZYMES 645 



ketogliitarate by rat liver mitochondria is stimulated around 10% by 

 0.033 mM arsenite (Corwin and Schwarz, 1963). Possible mechanisms 

 for such stimulation were discussed in connection with the mercurials 

 (page 11-815) but, aside from the reduction of inactive oxidized papain by 

 arsenoxides (Bersin, 1934), the nature of the stimulations observed is 

 unknown. J. S. Roth (1958) postulated that the activation of ribonuclease 

 by phenylarsenoxide may be related to the removal of a naturally occurring 

 inhibitor that is bound to the enzyme during extraction, but it is also pos- 

 sible that active ribonuclease is released from lysosomes. It is interesting 

 that the oxidation of glutathione by mouse kidney homogenate is stimulated 

 by 2 milf arsenite (Ames et al., 1946). Since it is generally assumed that ar- 

 senite does not react with glutathione, one must conclude that the action 

 is on the enzyme or on a natural inhibitor. 



The activation of myosin ATPase by butarsen may be especially impor- 

 tant because it relates this enzyme to mitochondrial ATPase and oxidative 

 phosphorylation (Blum and Sanadi, 1964). When butarsen is added to 

 myosin ATPase along with ATP there is no effect at 0.33 mM, but in the 

 absence of ATP there is a rapid activation, the rate approximately doubling 

 in 200 sec. This effect is potentiated by 2-mercaptoethanol, which has no 

 action of its own, while cysteine and thioglycolate prevent the activating 

 action of butarsen. The ITPase activity, on the other hand, is inhibited 

 by butarsen. Dimercaprol abolishes the action of butarsen on both ATPase 

 and ITPase. Blum and Sanadi suggest that the 2-mercaptoethanol may 

 react with the butarsen and that this complex penetrates to the site of 

 ATPase activity to combine with an SH group there (see page 659), but 

 the reason for the activation is not clear. Possibly structural changes near 

 the active center of myosin are induced and facilitate access of ATP to 

 its hydrolytic site, as has been postulated for the stimulation by 2,4- 

 dinitrophenol. 



Potentiation of Arsenical Inhibition by Thiols 



Thiols usually reduce the actions of SH reagents on enzymes, but quite 

 often the opposite happens in the case of the arsenicals, as we have already 

 seen for succinic semialdehyde dehydrogenase and thiol transacylase 

 (page 620), and in the activation of myosin ATPase in the preceding par- 

 agraph. Some further examples will illustrate the nature of this phenom- 

 enon. The aldehyde dehydrogenases from yeast and liver are unaffected 

 by arsenite alone, but inhibition occurs readily when 2-mercaptoethanol 

 is present (Jakoby, 1957, 1958). The enzymes are somewhat stimulated 

 by the thiol alone, but arsenite brings the activity far below the control 

 level without the thiol. The pyruvate oxidase from Acetobacter melanogenum 

 is depressed very little by 1 mM arsenite, but in the presence of glutathione 

 the inhibition is almost complete (Bone and Hochster, 1960). If /^-hydroxy- 



