CHEMICAL PROPERTIES 599 



It was evident that the oxidation of keto acids is rather specifically blocked 

 by the arsenicals and this has been substantiated in many tissues and under 

 a variety of conditions, so that today the keto acid oxidases are generally 

 considered to be the key sites for the actions of the arsenicals. Many enzymes 

 had been tested since 1870 but few had been found to be clearly sensitive 

 to arsenicals, but the keto acid oxidases had not been available for investi- 

 gation. World War II initiated intensive study of the arsenicals, par- 

 ticularly in the laboratory of Sir Rudolph Peters at Oxford, and it was 

 demonstrated without question that pyruvate oxidase and the oxidation 

 of pyruvate generally are extremely susceptible to arsenicals, this presum- 

 ably being associated with the participation of the dithiol, lipoic acid, in 

 the transfer of acyl groups and electron transport by these oxidases. One 

 of the major purposes of this chapter is to provide evidence for this site 

 of action and to examine critically the role of keto acid oxidase inhibition 

 in the effects exerted by the arsenicals on cellular function and growth. 

 The arsenicals today are a commonly used group of SH reagents for the 

 inhibition of enzymes and metabolic reactions. In some respects they 

 may be as specific for SH groups as any inhibitor available; but we shall 

 see that they differ markedly from most other SH reagents in the types 

 of SH group reacted, and so can provide much information on the compo- 

 sition of active sites and the participation of certain thiols. The usefulness 

 of the mercurials to the biochemist was increased when simple organic 

 mercurials were introduced. Likewise, the organic arsenicals have occa- 

 sionally been used to good advantage; however, they are perhaps not 

 used as routinely, relative to arsenite, in metabolic work as they should 

 be, and there has not been a concerted effort to investigate the relative 

 activities of these compounds on enzyme systems. One must emphasize 

 at the beginning that there is a paucity of good delineation of the over-all 

 effects of the arsenicals on the metabolism of any organism or tissue, and 

 essentially no studies bearing on the specificity of action in living tissue 

 have been made. It is for this reason that one must make the regrettable 

 statement that, despite what has been written to the contrary, we are not 

 able confidently today to explain satisfactorily any action of the arsenicals 

 in detail. It is an excellent field for the correlation of structure with action, 

 and thorough studies of the effects of hundreds of compounds on microor- 

 ganisms have been made, but these investigations have not been extended 

 to enzymes or metabolism and thus are complicated by many factors, such 

 as permeability. 



CHEMICAL PROPERTIES 



Discussion of the chemistry of the arsenicals is complicated by the fact 

 that many different types of compound have been used in biological work. 

 The nomenclature of the arsenicals has been confusing and lacks uniformity. 



