title: Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.
abstract: In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP.
authors: Department of Genetics, Institute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland.
authors: Paweł
authors: P
authors: Lis
authors: Department of Genetics, Institute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland.
authors: Paweł
authors: P
authors: Jurkiewicz
authors: Department of Genetics, Institute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland.
authors: Magdalena
authors: M
authors: Cal-Bąkowska
authors: KoDiscovery LLC, UM BioPark, Innovation Center, Baltimore, MD, USA.
authors: Young H
authors: YH
authors: Ko
authors: Departments of Biological Chemistry and Oncology, Sydney Kimmel Comprehensive Cancer Center and Center for Obesity Research and Metabolism, John Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Peter L
authors: PL
authors: Pedersen
authors: Unité de Biochimie Physiologique, Institut des Sciences de la Vie, Université Catholique de Louvain-la-Neuve, Louvain-la-Neuve, Belgium.
authors: Andre
authors: A
authors: Goffeau
authors: Department of Genetics, Institute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland.
authors: Stanisław
authors: S
authors: Ułaszewski
mesh_terms: D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016681:Genome, Fungal / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000235:genetics; D011773:Pyruvates / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D011773:Pyruvates; D029701:Saccharomyces cerevisiae Proteins; C470937:Whi2 protein, S cerevisiae; C017092:bromopyruvate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: 3-bromopyruvate (3-BP); Saccharomyces cerevisiae; Whi2; energetic metabolism; genomic screen