INHIBITION OF ENZYMES 



651 



Inhibition of a-Keto Acid Oxidases 



The discovery by Krebs in 1933 that arsenite causes accumulation of 

 a-keto acids in kidney slices led to the postulate that the site of block 

 is on the oxidases for these acids, and such inhibition was confirmed by 

 workers using different tissue preparations (see Table 6-3). Peters et al. 

 (1946) particularly emphasized the sensitivity of these oxidases and felt 

 that the arsenicals can, under the proper circumstances, exert quite specific 



Fig. 6-2. Inhibitions of cholinesterases by 

 arsenite at 0.5 mM as influenced by the 

 pH. (From Mounter and Whittaker, 1953.) 



effects on pyruvate and a-ketoglutarate oxidation. Most of this early work 

 was done with various breis and dispersions, and it was not until the 

 a-keto acid oxidases were more highly purified and their components 

 elucidated around 1951-1952 that the mechanism of the inhibition could 

 be approached. At first it was thought that the enzyme SH groups are the 

 site of attack; when coenzyme A was found to be involved, it was suggested 

 as the site of inhibition (Sanadi et al., 1952); when the role of lipoate was 

 established, it was evident that the adjacent SH groups would allow the 

 formation of a stable cyclic thioarsinite (Gunsalus, 1953). It has been gener- 

 ally assumed since that time that arsenicals inactivate the lipoate, and 

 hence prevent the transfer of the acyl groups to coenzyme A as well as 

 the uptake of oxygen for reoxidation of reduced lipoate. 



The detailed mechanism of the complex a-keto acid oxidases has not 

 yet been elucidated and the schemes presented do not completely explain 



