title: The yeast Saccharomyces cerevisiae Pdr16p restricts changes in ergosterol biosynthesis caused by the presence of azole antifungals.
abstract: Pdr16p belongs to the family of phosphatidylinositol transfer proteins in yeast. The absence of Pdr16p results in enhanced susceptibility to azole antifungals in Saccharomyces cerevisiae. In the major fungal human pathogen Candida albicans, CaPDR16 is a contributing factor to clinical azole resistance. The current study was aimed at better understanding the function of Pdr16p, especially in relation to azole resistance in S. cerevisiae. We show that deletion of the PDR16 gene increased susceptibility of S. cerevisiae to azole antifungals that are used in clinical medicine and agriculture. Significant differences in the inhibition of the sterol biosynthetic pathway were observed between the pdr16Δ strain and its corresponding wild-type (wt) strain when yeast cells were challenged by sub-inhibitory concentrations of the azoles miconazole or fluconazole. The increased susceptibility to azoles, and enhanced changes in sterol biosynthesis upon exposure to azoles of the pdr16Δ strain compared to wt strain, are not the results of increased intracellular concentration of azoles in the pdr16Δ cells. We also show that overexpression of PDR17 complemented the azole susceptible phenotype of the pdr16Δ strain and corrected the enhanced sterol alterations in pdr16Δ cells in the presence of azoles. Pdr17p was found previously to be an essential part of a complex required for intermembrane transport of phosphatidylserine at regions of membrane apposition. Based on these observations, we propose a hypothesis that Pdr16p assists in shuttling sterols or their intermediates between membranes or, alternatively, between sterol biosynthetic enzymes or complexes.
authors.affiliation: Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Ivanka pri Dunaji, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Šimová
authors.forename: Katarína
authors.initials: K
authors.lastname: Poloncová
authors.forename: Dana
authors.initials: D
authors.lastname: Tahotná
authors.forename: Roman
authors.initials: R
authors.lastname: Holič
authors.forename: Ivan
authors.initials: I
authors.lastname: Hapala
authors.forename: Adam R
authors.initials: AR
authors.lastname: Smith
authors.forename: Theodore C
authors.initials: TC
authors.lastname: White
authors.forename: Peter
authors.initials: P
authors.lastname: Griač
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D025141:Drug Resistance, Fungal; D004875:Ergosterol / Q000378:metabolism*; D005816:Genetic Complementation Test; D010641:Phenotype; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: D000935:Antifungal Agents; D001393:Azoles; C483431:PDR16 protein, S cerevisiae; C492205:PDR17 protein, S cerevisiae; D049294:Phospholipid Transfer Proteins; D029701:Saccharomyces cerevisiae Proteins; D004875:Ergosterol