title: The antifungal eugenol perturbs dual aromatic and branched-chain amino acid permeases in the cytoplasmic membrane of yeast.
abstract: Eugenol is an aromatic component of clove oil that has therapeutic potential as an antifungal drug, although its mode of action and precise cellular target(s) remain ambiguous. To address this knowledge gap, a chemical-genetic profile analysis of eugenol was done using ∼4700 haploid Saccharomyces cerevisiae gene deletion mutants to reveal 21 deletion mutants with the greatest degree of susceptibility. Cellular roles of deleted genes in the most susceptible mutants indicate that the main targets for eugenol include pathways involved in biosynthesis and transport of aromatic and branched-chain amino acids. Follow-up analyses showed inhibitory effects of eugenol on amino acid permeases in the yeast cytoplasmic membrane. Furthermore, phenotypic suppression analysis revealed that eugenol interferes with two permeases, Tat1p and Gap1p, which are both involved in dual transport of aromatic and branched-chain amino acids through the yeast cytoplasmic membrane. Perturbation of cytoplasmic permeases represents a novel antifungal target and may explain previous observations that exposure to eugenol results in leakage of cell contents. Eugenol exposure may also contribute to amino acid starvation and thus holds promise as an anticancer therapeutic drug. Finally, this study provides further evidence of the usefulness of the yeast Gene Deletion Array approach in uncovering the mode of action of natural health products.
authors.affiliation: Department of Agronomy and Plant Breeding, University of Tehran, Karaj, Iran ; Biology Department, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Emad
authors.initials: E
authors.lastname: Darvishi
authors.forename: Mansoor
authors.initials: M
authors.lastname: Omidi
authors.forename: Ali Akbar Shahnejat
authors.initials: AA
authors.lastname: Bushehri
authors.forename: Ashkan
authors.initials: A
authors.lastname: Golshani
authors.forename: Myron L
authors.initials: ML
authors.lastname: Smith
mesh_terms: D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors*; D024322:Amino Acids, Aromatic / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism*; D005054:Eugenol / Q000494:pharmacology*; D017353:Gene Deletion; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D026905:Amino Acid Transport Systems; D024322:Amino Acids, Aromatic; D000597:Amino Acids, Branched-Chain; D000935:Antifungal Agents; D005054:Eugenol