title: Yeast cells with impaired drug resistance accumulate glycerol and glucose.
abstract: Multiple drug resistance (MDR) in yeast is effected by two major superfamilies of membrane transporters: the major facilitator superfamily (MFS) and the ATP-binding cassette (ABC) superfamily. In the present work, we investigated the cellular responses to disruptions in both MFS (by deleting the transporter gene, QDR3) and ABC (by deleting the gene for the Pdr3 transcription factor) transporter systems by growing diploid homozygous deletion yeast strains in glucose- or ammonium-limited continuous cultures. The transcriptome and the metabolome profiles of these strains, as well as the flux distributions in the optimal solution space, reveal novel insights into the underlying mechanisms of action of QDR3 and PDR3. Our results show how cells rearrange their metabolism to cope with the problems that arise from the loss of these drug-resistance genes, which likely evolved to combat chemical attack from bacterial or fungal competitors. This is achieved through the accumulation of intracellular glucose, glycerol, and inorganic phosphate, as well as by repurposing genes that are known to function in other parts of metabolism in order to minimise the effects of toxic compounds.
authors.affiliation: Cambridge Systems Biology Centre & Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK. sgo24@.cam.ac.uk dd345@cam.ac.uk pnarpir@gmail.com.
authors.forename: Duygu
authors.initials: D
authors.lastname: Dikicioglu
authors.forename: Sebnem
authors.initials: S
authors.lastname: Oc
authors.forename: Bharat M
authors.initials: BM
authors.lastname: Rash
authors.forename: Warwick B
authors.initials: WB
authors.lastname: Dunn
authors.forename: Pınar
authors.initials: P
authors.lastname: Pir
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kell
authors.forename: Betul
authors.initials: B
authors.lastname: Kirdar
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Oliver
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005656:Fungal Proteins / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D055442:Metabolome / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; C089261:PDR3 protein, S cerevisiae; C499245:Qdr3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D005947:Glucose; D005990:Glycerol