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

Brian C. Monk, A. Brett Mason, Georgi Abramochkin, James E. Haber, Donna Seto-Young, David S. Perlin

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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 β-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.

Original languageEnglish (US)
Pages (from-to)81-90
Number of pages10
JournalBBA - Biomembranes
Volume1239
Issue number1
DOIs
StatePublished - Oct 4 1995
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Cell Biology

Keywords

  • (Yeast)
  • ATPase, H-
  • Drug targeting
  • Omeprazole
  • Plasma membrane

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