HEAVY METALS 



471 



tact cells cannot by itself prove that the primary effect of metals in vivo 

 is on sulfhydryl enzymes. Thiols form stable covalent compounds with 

 metals and would be expected, therefore, to compete successfully with 

 almost any bond formed between enzyme and metal. 



That the sulfhydryl hypothesis may be too limited is indicated above 

 all by the observation that many enzymes which are not apparently 

 dependent upon sulfhydryl groups for their activity are inhibited in 

 vitro by one or more of the heavy metals. These include sucrase, /3-glu- 

 cosidase, arginase, asparaginase, carbonic anhydrase, catalase, and cyto- 

 chrome oxidase (319, 388, 405). As already mentioned, inhibition of 

 respiration and spore germination at approximately the same concen- 

 tration by heavy metals is also suggestive of a general poisoning of many 

 different enzymes. 



If we grant that heavy metals are general enzyme poisons, we may 

 inquire about the sites at which they might act on an enzyme. Obvi- 

 ously, as Horsfall (174) emphasizes, the order of toxicity closely resem- 

 bles the order of stability of metal chelate complexes. From this, it is 

 apparent that the heavy metals might act by displacing from an enzyme 

 a metal like magnesium which is essential to its activity and which is 

 bound normally in a coordination complex. However, the order of 

 stability of chelate complexes is, for obvious reasons, much the same as 

 the order of insolubility of metal sulfides just described, and either 

 series may with equal probability be considered the more important. 



Several potential binding sites are available on proteins to react with 

 transition metals like mercury, silver, and copper. These include car- 

 boxyl, phosphoric, imidazolium, ammonium, and phenolic hydroxyl 

 groups (204). The primary carboxyls and the a-amino groups of the 

 amino acids are, of course, tied up in peptide bonds, and such side 

 chains as the guanidine and amide groups cannot be expected to bind 

 metals at biological pH values. 



In principle at least, inactivation of enzymes by metals is not limited 

 as to location; the enzyme or enzymes may just as well be at the surface 

 of the cell as in the interior. However, it seems more probable that the 

 metals reach the interior of the cell and are not confined in their action 

 at fungistatic concentrations to the surface. 



This discussion of toxicity of the heavy metals makes it clear that 

 there are numerous unsolved problems, especially with regard to the 

 penetration of heavy-metal ions into the cell. Some of the more im- 

 portant points may be listed in conclusion: 



1. Differences in toxicity between various compounds of a given 

 metal are ascribed to differences in the rate at which the toxic metal 



