The yeast plasma membrane proton pumping ATPase is a viable antifungal target. I. Effects of the cysteine-modifying reagent omeprazole

Biochim Biophys Acta. 1995 Oct 4;1239(1):81-90. doi: 10.1016/0005-2736(95)00133-n.


The yeast plasma membrane proton pumping ATPase (H(+)-ATPase) was investigated as a potential molecular target for antifungal drug therapy by examining the inhibitory effects of the sulfhydryl-reactive reagent omeprazole on cell growth, glucose-induced medium acidification and H(+)-ATPase activity. Omeprazole inhibits the growth of Saccharomyces cerevisiae and the human pathogenic yeast Candida albicans in a pH dependent manner. Omeprazole action is closely correlated with inhibition of the H(+)-ATPase and is fungicidal. Glucose-dependent medium acidification is correspondingly blocked by omeprazole and appears to require the H(+)-ATPase to proceed through its reaction cycle. A strong correlation is observed between inhibition of medium acidification and H(+)-ATPase activity in plasma membranes isolated from treated cells. The inhibitory properties of omeprazole are blocked by pre-treatment of activated drug with beta-mercaptoethanol, which is consistent with the expected formation of a sulfhydryl-reactive sulfenamide derivative. Mutagenesis of the three putative membrane sector cysteine residues (C148S, C312S, C867A) in the S. cerevisiae H(+)-ATPase suggests that covalent modification of the conserved C148 residue may be important for inhibition of ATPase activity and cell growth. Other mutations (M128C and G158D/G156C) mapping near C148 support the importance of this region by modulating omeprazole inhibition of the H(+)-ATPase. These findings suggest that the plasma membrane H(+)-ATPase may serve as an important molecular target for antifungal intervention.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Candida albicans / drug effects*
  • Candida albicans / enzymology
  • Cell Membrane / enzymology
  • Cysteine / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Glucose / physiology
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Mercaptoethanol / pharmacology
  • Mutation
  • Omeprazole / pharmacology*
  • Proton Pump Inhibitors
  • Proton Pumps / metabolism
  • Proton-Translocating ATPases / antagonists & inhibitors*
  • Proton-Translocating ATPases / genetics
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae Proteins*
  • Sulfhydryl Reagents / pharmacology*


  • Enzyme Inhibitors
  • PMA2 protein, S cerevisiae
  • Proton Pump Inhibitors
  • Proton Pumps
  • Saccharomyces cerevisiae Proteins
  • Sulfhydryl Reagents
  • Mercaptoethanol
  • PMA1 protein, S cerevisiae
  • Proton-Translocating ATPases
  • Glucose
  • Cysteine
  • Omeprazole