J. Mol. Microbiol. Biotechnol. (2001) 3(2): 207-214. Drug ABC TransportersJMMB from S. Symposium cerevisiae 207 The Pleitropic Drug ABC Transporters from Saccharomyces cerevisiae Bruce Rogers1,3, Anabelle Decottignies2,4, The Discovery of the Yeast ABC Transporters and of Marcin Kolaczkowski2,5, Elvira Carvajal2,6, their Major Regulators Elisabetta Balzi2,7and André Goffeau2,8,* The first ABC transporter gene discovered in 1Phytera Inc, Worcester, MA, USA Saccharomyces cerevisiae was shown to encode the full- 2Unité de biochimie physiologique, Louvain-la-Neuve, size Ste6p plasma membrane protein exporting the a- Belgium mating pheromone (Mcgrath and Varshafsky, 1989; Kuchler 3Present address: Genetics Institute, Inc., Cambridge, MA, et al., 1989,). The first half-size ABC transporter gene, USA ADP1, was unravelled by the systematic sequencing of 4Present address: Imperial Cancer Research Fund, chromosome III (Purnelle et al., 1991). Adp1p belongs to London, U.K. the historic “white” family determining the eye color of 5Present address: University of Medicine Wroclaw, Drosophila. Its function in yeast is still unknown today. Department of Biophysics, Wroclaw, Poland During the next few “pregenomic” years, four additional 6Present address: State University of Rio de Janeiro, transporters were reported. The SNQ2 gene was Dept. Cell Biology and Genetics., Rio Janeiro, Brazil discovered in a screen for mutants resistant to 7Present address: European Commission, Research nitroxiquinoline oxides and other mutagens (Servos et al., Directorate, Brussels, Belgium 1993). The overexpressed PDR5 gene was found to confer 8Present address: Chaire Internationale de Recherche resistance to cycloheximide and many other drugs (Balzi Blaise Pascal, Laboratoire de Biologie Moléculaire, Ecole et al., 1994; Bissinger et al., 1994; Hirata et al., 1994). The Normale Supérieure, Paris, France YCF1 gene was detected as responsible for a cadmium resistance phenotype due to accumulation of glutathione- heavy metal conjugates in vacuole (Szczypka et al.,1994, Abstract Li et al., 1996 ). The mutated YOR1 gene was reported as conferring oligomycin and anionic drugs sensitivity The Saccharomyces cerevisiae genome contains 16 (Katzmann et al., 1995, Cui et al., 1996). genes encoding full-size ABC transporters. Each comprises two nucleotide binding folds (NBF) alternating with transmembrane domains (TM). We have studied in detail three plasma membrane multidrug exporters: Pdr5p (TC3.A.1.205.1) and Snq2p Table 1. The yeast ABC transporters according to the Transporter (TC3.A.1.205.2) which share NBF-TM-NBF-TM topology Classification (TC) system (Saier, 2000) as well as Yor1p (TC3.A.1.208.3) which exhibits the 3.A.1.203 The Peroxysomal Fatty Acyl CoA Transporter (FAT) reciprocal TM-NBF-TM-NBF topology. The substrate Family specificity of Pdr5p, Snq2p and Yor1p are largely, but 3.A.1.203.2 PAT1/PAL1/PXA1 and PAT2/PAL2/PXA2: long chain not totally, overlapping as shown by screening the fatty acyl COA importer 3.A.1.204 The Eye Pigment Precursor Transporter (EPP) Family growth inhibition by 349 toxic compounds of undetermined ADP1: unknown substrate combinatorial deletants of these three ABC genes. 3.A.1.205 The Pleiotropic Drug Resistance (PDR) Family Multiple deletion of 7 ABC genes (YOR1, SNQ2, PDR5, 3.A.1.205.1 PDR5: cycloheximide/pleiotropic drug exporter 3.A.1.205.2 SNQ2: mutagen/pleiotropic drug exporter YCF1, PDR10, PDR11 and PDR15) and of two 3.A.1.205.3 PDR12: weak acid exporter. transcription activation factors (PDR1 and PDR3) undetermined PDR10, PDR15 and YOR011: unknown substrates. renders the cell from 2 to 200 times more sensitive to 3.A.1.206 The Sex Pheromone Exporter (STE) Family numerous toxic coumpounds including antifungals 3.A.1.206.1 STE6: a-factor sex pheromone exporter 3.A.1.207 The Conjugate Transporter (CT1) Family used in agriculture or medicine. The use of the pdr1-3 3.A.1.207.1 YCF1: vacuolar metal resistance factor activating mutation and when necessary of the PDR5 3.A.1.207.2 BAT1: vacuolar bile acid transporter promoter in appropriate multideleted hosts allow high 3.A.1.207.3 BPT1: vacuolar bilirubin transporter undetermined YHL035: unknown substrate levels of expression of Pdr5p, Snq2p or Yor1p. These 3.A.1.208 The Conjugate Transporter (CT2) Family overexpressed proteins exhibit ATPase activity in vitro 3.A.1.208.3 YOR1: oligomycin/pleiotropic drug exporter and confer considerable multiple drug resistance in 3.A.1.209 The Major Histocompatibility Peptide Transporter vivo. The latter property can be used for screening (TAP) Family undetermined TAP1/TAP2: unknown substrate specific inhibitors of fungal and other ABC 3.A.1.212 The Mitochondrial Fe/S Protein Exporter (MPE) transporters. Family 3.A.1.212.1 ATM1: mitochondrial putative iron transporter 3.A.1.213 The Putative Transporter Family of Unknown Function 3.A.1.213.1 PDR11 and YOR011: unknown function 3.A.1.213.2 YOL075: unknown function *For correspondence. Email [email protected]. 3.A.1.213.3 MDL1 and MDL2: unknown function © 2001 Horizon Scientific Press Further Reading Caister Academic Press is a leading academic publisher of advanced texts in microbiology, molecular biology and medical research. 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Drug Sensitivity of ABC and PDR Deletants ANTICANCER daunorubicin + - - + + + ∆PDR5 ∆SNQ2 ∆YOR1 ∆PDR5 ∆PDR5 ∆PDR1 doxorubicin + - + + + + ∆SNQ2 ∆SNQ2 ∆PDR3 trifluoperazine + - - - - - ∆YOR1 FLAVONOIDS baicalein + + + + + + FUNGICIDES fisetin - - + - + + Azoles myricetin - - + - + + bitertanol + - - + + + quercetin - - + - + + diclobutrazol + - - + + + IONOPHORES flusilazole + - - + + + FCCP - +/- + - + - imazalil nitrate + + + + + + A23187 + + - + + + itraconazole + +/- - + + + monensin + - - - + + ketoconazole + +/- - + + + nigericin + - - +/- + + prochloraz + - - + + + valinomycin + - + - - + tebuconazole + - - + + + ANILINES triadimenol + - - + + + aniline +/- - + + + +/- miconyole +/- +/- + + + +/- p-aminopdiphenylamine - - - + + - expoxiconyole + - + + + + p-amino-p-methoxy- - +/- - - + - triadimylonb + +/- - + + + diphenylamine Imidothiazole phenylhydrazine