title: Methionine Metabolism Alters Oxidative Stress Resistance via the Pentose Phosphate Pathway.
abstract: Nutrient uptake and metabolism have a significant impact on the way cells respond to stress. The amino acid methionine is, in particular, a key player in the oxidative stress response, and acting as a reactive oxygen species scavenger, methionine is implicated in caloric restriction phenotypes and aging. We here provide evidence that some effects of methionine in stress situations are indirect and caused by altered activity of the nicotinamide adenine dinucleotide phosphate (NADPH) producing oxidative part of the pentose phosphate pathway (PPP). In Saccharomyces cerevisiae, both methionine prototrophic (MET15) and auxotrophic (met15Δ) cells supplemented with methionine showed an increase in PPP metabolite concentrations downstream of the NADPH producing enzyme, 6-phosphogluconate dehydrogenase. Proteomics revealed this enzyme to also increase in expression compared to methionine self-synthesizing cells. Oxidant tolerance was increased in cells preincubated with methionine; however, this effect was abolished when flux through the oxidative PPP was prevented by deletion of its rate limiting enzyme, ZWF1. Stress resistance phenotypes that follow methionine supplementation hence involve the oxidative PPP. Effects of methionine on oxidative metabolism, stress signaling, and aging have thus to be seen in the context of an altered activity of this NADP reducing pathway.
authors.affiliation: 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Kate
authors.initials: K
authors.lastname: Campbell
authors.affiliation: 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Jakob
authors.initials: J
authors.lastname: Vowinckel
authors.affiliation: 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Markus A
authors.initials: MA
authors.lastname: Keller
authors.affiliation: 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , Cambridge, United Kingdom .|2 The Francis Crick Institute Mill Hill Laboratory , London, United Kingdom .
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
mesh_terms: D002853:Chromatography, Liquid; D006019:Glycolysis; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008715:Methionine / Q000378:metabolism*; D009154:Mutation; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D008715:Methionine