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Challenge NaCl Concentration Type 1.4M Cation stress Galactose 2% Carbon source (replaces glucose) Cellular effect Extracellular Na+ exposes yeast to hyperosmosis, and requires intracellular glycerol accumulation and cell wall and cytoskeleton strengthening (Hohmann 2002). Na+ enters cells through the K+ transporters Trk1 and Trk2, and potentially through Pho89 and Nsc1. Intracellularly, it displaces K+, challenging cell volume regulation, intracellular pH and membrane potentials, protein synthesis, and enzyme activation (Arino et al. 2010). At acidic pH, Na+ is exported by Nha1 (Banuelos et al. 1998). At higher pH, Na+ efflux is mediated by the Ena proteins, encoded in a single gene in most natural strains but in Wine/European strains a different gene variant introgressed from S. paradoxus has been amplified into 3-5 similar paralogs (Warringer et al. 2011). This introgression/duplication largely defines natural yeast variation in salt tolerance. The Ena1 variant plays the critical role in Na+ tolerance (Haro et al. 1991). Regulation of salt tolerance genes is complex, involving the HOG1, Calcineurin pathway, TOR pathway, RIM101 and glucose repression pathways. Galactose well supports yeast growth as only energy and carbon source. It enters cells through the Gal2 permease in a process that also requires Gal1. Intracellular galactose is converted into glucose-1-phosphate by three sequential reactions that are catalyzed by Gal10, Gal1 and Gal7 respectively, with Gal10 also being required for re-cycling of a pathway intermediate. All the galactose structural genes are coordinately regulated at the level of transcription in response to galactose by Gal4p, Gal80p, and Gal3p (Johnston and Davis 1984; Lohr et al. 1995). All seven GAL genes are spatially co-localized in a gene cluster (Slot and Rokas 2010). Large natural variations in galactose use is largely accounted for by loss-of-function mutations in Gal2, Gal3 (Warringer et al. Caffeine 2.25mg/mL Toxin Rapamycin 0.024µg/ml Toxin Phleomycin 2µg/ml Toxin Hydroxyurea 2.5mg/ml Toxin 2011) or loss of the whole GAL cluster (Slot and Rokas 2010). A purine, similar to adenine and guanine, that binds multiple enzymatic targets. In yeast, caffeine targets the TORC1 complex (Reinke et al. 2006), caffeine prevents gene conversion by displacing Rad51 (Tsabar et al. 2015), impairs DNA repair 26019182, and may interfere with cell wall generation. Mutations in very diverse cellular components modulate caffeine sensitivity. Caffeine trafficking is not well understood. A polyketide macrolide produced by Streptomyces hygroscopicus. Rapamycin binds the Fpr1 protein (Koltin et al. 1991). This protein-drug complex binds to and inhibits Tor1 (Heitman et al. 1991), but not Tor2 12408816. Tor1p is a component of TORC1, a protein complex regulating nutrient availability and stress responses (Loewith & Hall 2011). Mutations in Fpr1 or Tor1 confer resistance to the drug (Heitman et al. 1991). Loss of non-essential TORC1 components (e.g. Kog1 and Tco089), or in TORC1 interactors (e.g. Rrd1) confer rapamycin sensitivity. Rapamycin binds to the Fpr1 paralog Fpr2 without known toxic effects 1380159. Rapamycin trafficking is not well understood. A 12 component drug complex isolated from Streptomyces. Binds to DNA, impedes DNA polymerase and induces DNA damage and breakdown, potentially via an oxidative mechanism (Moore, 1988). Arrests cells before entry into Sphase (Nakada et al. 2003) (Weinert et al. 1994). Loss of DNA repair components, such as Rad6, 9 or 17 cause phleomycin hypersensitivity (7785323, 8989864). Phleomycin trafficking is not well understood. Hydroxyurea inhibits reduction of ribonucleotides to deoxidized ribonucleotides (Krakoff et al. 1968), by binding to and inhibiting the four component RNR (ribonucleotide reductase) complex. dNTP depletion impedes synthesis and repair of DNA Glycine 30mg N/L Nitrogen source (replaces ammonium) Isoleucine 30mg N/L Nitrogen source (replaces ammonium) Allantoin 30mg N/L Nitrogen source (replaces ammonium) (Yao et al. 2003) (Koç et al. 2004), arresting cells in early S-phase. The RNR complex consists of four proteins, RNR1, 2, 3, and 4, of which RNR1 and 2 are essential, and RNR4’s essentiality depends on the genetic background (Elledge and Davis, 1987; Elledge and Davis, 1990; Huang and Elledge, 1997). Natural variation in hydroxyurea resistance is partially mediated via the Hur1 protein (Warringer et al. 2011). Glycine is generally a very poor nitrogen source for yeast, but the growth delays, rates and efficiencies vary between strains (Ibstedt et al. 2015). Glycine has no dedicated high affinity permease but is taken up by the broad specificity amino acid permeases Gap1 (Jauniaux and Grenson 1990) and Agp1 and the more specialized Dip5 and Put4 (Regenberg et al. 1999). Intracellular glycine is catabolized into ammonium in three sequential mitochondrial reactions. These are catalyzed by a single glycine cleavage complex with four components: Gcv3, Gcv1, Gcv2 and Lpd1. Cleavage reactions requires a folic acid derivative. Isoleucine is generally a poor nitrogen source for yeast, but growth delays, rates and efficiencies vary between strains (Ibstedt et al. 2015). Isoleucine is take up by the paralogous high affinity permeases Bap2 (Grauslund et al. 1995) and Bap3 (Regenberg et al. 1999) as well the low affinity general amino acid permease Gap1 (Jauniaux and Grenson 1990). Isoleucine is catabolized in a single step reaction to glutamate, using the mitochondrial Bat1 or the cytoplasmic Bat2 (Kispal et al. 1996), with Bat1 expressed during exponential growth and Bat2 in stationary phase. Allantoin is the primary nitrogen secretion product of higher mammals, excluding apes. Yeast utilizes allantoin as sole nitrogen source, but with varying delays, rates and efficiencies that largely maps to variation in Dal4 and Dal1 (Ibstedt et al. 2015). The Dal4 permease is the only known entrance mechanism for allantoin. Intracellular allantoin is catabolized to urea in three sequential reactions catalyzed by Dal1, Dal2 and Dal3 respectively (Buckholz and Cooper 1991; Yoo and Cooper 1991a; Yoo and Cooper 1991b). Urea is converted into ammonium by the multi-step enzyme Dur1,2 (Cooper et al. 1980). The allantoin catabolic genes are regulated by both general and specific signals that involve Gln3, Gat1, Dal80, Dal81, and Dal82 (Magasanik and Kaiser 2002). 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