Toxicity of copper, cobalt, and nickel salts is dependent on histidine metabolism in the yeast Saccharomyces cerevisiae

The pH-dependent inhibition of 22 metal salts have been systematically inve stigated for the yeast Saccharomyces cerevisiae. We have established that t he inhibition of growth by Cu, Co, or Ni salts is markedly enhanced by hist idine auxotrophy and by increasing the pH of the medium. Each of the his1-h is7 mutant strains were unable to grow in the presence of elevated levels o f Cu, Co, or Ni at nearly neutral pHs, in contrast to His(+) strains, which grew under these conditions. The Cu, Co, or Ni inhibition was reversed by the addition of histidine to the medium. Deletion of the high-affinity hist idine permease Hip1p in His(-) strains resulted in even greater sensitivity to Cu, Co, and Ni and the requirement of an even higher level of histidine to reverse the inhibition. These results suggest that intracellular histid ine, most likely in the vacuole, diminishes the pH-dependent toxicity of Cu , Co, and Ni. Furthermore, the toxicity of many salts is exacerbated in str ains with a defective vacuolar H+-ATPase, which abolishes the ability of ye ast to maintain an acidic vacuole, a compartment known to sequester metal c ompounds. We suggest that the accumulation of histidine in the vacuole is a normal process used to detoxify Cu, Co, and Ni.