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Forward Chemical Genetics in Yeast for Discovery of Chemical Probes Targeting Metabolism
Department of Biochemistry, Stanford Genome Technology Center, Stanford University, Stanford, CA 94305, USA
Molecular Diagnostics and Cancer Cell Biology, Genentech, Inc., South San Francisco, CA 94080, USA
* Author to whom correspondence should be addressed.
Received: 5 September 2012; in revised form: 5 October 2012 / Accepted: 30 October 2012 / Published: 5 November 2012
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.
Keywords: yeast; forward chemical genetics; chemogenomic profiling; glycolysis; cancer metabolism; Warburg effect; mitochondria; methotrexate; leucovorin
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St.Onge, R.; Schlecht, U.; Scharfe, C.; Evangelista, M. Forward Chemical Genetics in Yeast for Discovery of Chemical Probes Targeting Metabolism. Molecules 2012, 17, 13098-13115.
St.Onge R, Schlecht U, Scharfe C, Evangelista M. Forward Chemical Genetics in Yeast for Discovery of Chemical Probes Targeting Metabolism. Molecules. 2012; 17(11):13098-13115.
St.Onge, Robert; Schlecht, Ulrich; Scharfe, Curt; Evangelista, Marie. 2012. "Forward Chemical Genetics in Yeast for Discovery of Chemical Probes Targeting Metabolism." Molecules 17, no. 11: 13098-13115.