INHIBITION OF ENZYMES 655 



(Peters et al., 1946), acetyl-CoA carboxylase (Hatch and Stumpf, 1961), 

 maltase (Rona et al., 1922), and choline oxidase (Rothschild et al., 1954). 

 In these cases, lewisite or phenylarsenoxide is 50-1000 times more potent 

 than arsenite. In many cases it is difficult to accurately compare the relative 

 potencies, since the data are not sufficient; e. g., arsenite does not inhibit 

 trypanosomal o; -glycerophosphate dehydrogenase at 0.5 mM while oxo- 

 phenarsine and Melarsen inhibit 38% at 0.01 mM (Grant and Sargent, 

 1961), and all we can say is that the inhibitory difference must be over 100. 

 We have already speculated that this may be due in part to the small size 

 of the arsenite, steric interference with substrate attachment being minimal, 

 but it is unlikely that this is a very important reason. Likewise, electro- 

 static repulsion by negatively charged enzymes is not tenable, because 

 arsenite is probably not mainly ionic and this could not account for the 

 very great differences observed. One then seeks the answer in the abilities 

 of the arsenicals to react with SH groups, and what evidence there is 

 indicates that arsenite reacts with simple thiols less readily than do the 

 phenylarsenoxides, but we cannot explain easily why this is so. Although 

 arsenite doesn't react well with glutathione, it reacts very readily with 

 dimercaprol (Table 6-2). It may well be that arsenite does not form a 

 stable mercaptide with a single SH group, i. e., a complex such as (H0)2As — 

 S — E may be unstable. If arsenite and cysteine are mixed, one cannot isolate 

 the monothioarsinite since the dithioarsinite is the immediate product; in 

 the case of an enzyme, if two SH groups are not available, the reaction would 

 proceed with difficulty. Such differences between arsenite and the organic 

 arsenoxides are not observed with the so-called dithiol enzymes. 



Specificity of Arsenical Inhibition 



Can one use the monosubstituted trivalent arsenicals to block specifi- 

 cally the a-keto acid oxidases? Evidence will be presented later (page 668) 

 that these arsenicals can often cause the accumulation of pyruvate or 

 a-ketoglutarate without appreciably inhibiting the glycolytic pathway or 

 the reactions involved in the metabolism of amino acids and lipids. Here we 

 shall look only at the relative sensitivities of the various enzymes. There 

 are certain enzymes which are generally as inhibitable as the a-keto acid 

 oxidases, but most of these would not play a very significant role in the 

 usual metabolic studies; such sensitive enzymes are glutathione reduc- 

 tase, glycine reductase, thioesterases, protein thiol dehydrogenase, certain 

 pyrophosphatases, m?/o-inositol oxygenase, gulonate dehydrogenase, D-ami- 

 no acid oxidase, formate transacetylase, and choline oxidase. Occasionally 

 one must take into account the possible inhibition of acetyl-CoA carboxy- 

 lase or the various aldehyde dehydrogenases or oxidases. The only other 

 cycle enzyme which might be affected is succinate dehydrogenase. It is 

 difficult to make a universally valid statement about the relative sensi- 



