470 CHEMICAL AGENTS 



of uranyl ion on yeast (p. 454). Increases in respiratory rate are in- 

 duced by sublethal concentrations of metals (247); the explanation 

 may lie in an increased permeability to exogenous substrate or, less 

 likely, in inactivation of regulatory enzyme systems (20). 



Present theories of the ultimate action of heavy metals visualize them 

 as enzyme poisons and admit only the question of whether they are 

 primarily effective against sulfhydryl enzymes or generally inhibitory 

 to enzymes of all types. 



The reaction of a divalent metal with a sulfhydryl enzyme is depicted 

 conventionally as mercaptide formation: 



SH S 



/ /\ 



En 4- HgCl 2 -+ En Hg 4- 2HC1 (3) 



\ \/ 



SH S 



The resemblance to a five-membered chelate complex — there are two 

 points of attachment on the enzyme — is obvious. A monovalent metal 

 or an organic mercurial like p-chloromercuribenzoic acid reacting as 

 such presumably forms a mercaptide with only a single sulfhydryl 

 group. The argument for the importance of this reaction is based 

 primarily on the observation that heavy-metal poisoning of both bac- 

 teria and fungi can be prevented or, within certain time limits, re- 

 versed by such thiol compounds as cysteine, glutathione, and 2,3-di- 

 mercaptopropanol (107, 185). In addition, it can be shown that 

 mercaptide-forming reagents react stoichiometrically with free sulfhy- 

 dryl groups of proteins (13, 316). 



Shaw (373) proposes a model for the inhibition of vital processes that 

 is based on these considerations and the added assumption that the 

 sulfhydryl groups with which cations combine are part of the catalyt- 

 ically active site of the inhibited enzyme. The driving force of Equa- 

 tion 3 is regarded as proportional to the free energy of the simple reac- 

 tion: 



Me++ 4- S— ±=; MeS (4) 



That is, toxicity should be correlated with the insolubility of the metal 

 sulfides (MeS). The order of insolubility is in fact very much like the 

 order of toxicity: Hg = Ag > Cu > Pb > Cd > Zn. This is also the 

 order of affinity of metals for the sulfhydryl group of purified serum 

 albumin (204). 



Emphasis on reaction with sulfhydryl groups may, however, divert 

 attention from other possibilities. In particular, the simple demon- 

 stration that thiol compounds antagonize the toxicity of metals to in- 



