title: Forward chemical genetics in yeast for discovery of  chemical probes targeting metabolism.
abstract: The many virtues that made the yeast Saccharomyces cerevisiae a dominant model organism for genetics and molecular biology, are now establishing its role in chemical genetics. Its experimental tractability (i.e., rapid doubling time, simple culture conditions) and the availability of powerful tools for drug-target identification, make yeast an ideal organism for high-throughput phenotypic screening. It may be especially applicable for the discovery of chemical probes targeting highly conserved cellular processes, such as metabolism and bioenergetics, because these probes would likely inhibit the same processes in higher eukaryotes (including man). Importantly, changes in normal cellular metabolism are associated with a variety of diseased states (including neurological disorders and cancer), and exploiting these changes for therapeutic purposes has accordingly gained considerable attention. Here, we review progress and challenges associated with forward chemical genetic screening in yeast. We also discuss evidence supporting these screens as a useful strategy for discovery of new chemical probes and new druggable targets related to cellular metabolism.
authors.affiliation: Department of Biochemistry, Stanford Genome Technology Center, Stanford University, Stanford, CA 94305, USA. bstonge@stanford.edu
authors.forename: Robert
authors.initials: R
authors.lastname: St Onge
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schlecht
authors.forename: Curt
authors.initials: C
authors.lastname: Scharfe
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D016296:Mutagenesis; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D008727:Methotrexate