title: Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress.
abstract: BACKGROUND
  Eukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. Among these processes, metabolic alterations seem to play an important role.
  
  
  RESULTS
  We recently discovered that yeast cells with reduced activity of the key glycolytic enzyme triosephosphate isomerase exhibit an increased resistance to the thiol-oxidizing reagent diamide. Here we show that this phenotype is conserved in Caenorhabditis elegans and that the underlying mechanism is based on a redirection of the metabolic flux from glycolysis to the pentose phosphate pathway, altering the redox equilibrium of the cytoplasmic NADP(H) pool. Remarkably, another key glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is known to be inactivated in response to various oxidant treatments, and we show that this provokes a similar redirection of the metabolic flux.
  
  
  CONCLUSIONS
  The naturally occurring inactivation of GAPDH functions as a metabolic switch for rerouting the carbohydrate flux to counteract oxidative stress. As a consequence, altering the homoeostasis of cytoplasmic metabolites is a fundamental mechanism for balancing the redox state of eukaryotic cells under stress conditions.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany. ralser@molgen.mpg.de
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
authors.forename: Mirjam M
authors.initials: MM
authors.lastname: Wamelink
authors.forename: Axel
authors.initials: A
authors.lastname: Kowald
authors.forename: Birgit
authors.initials: B
authors.lastname: Gerisch
authors.forename: Gino
authors.initials: G
authors.lastname: Heeren
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Edda
authors.initials: E
authors.lastname: Klipp
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Michael
authors.initials: M
authors.lastname: Breitenbach
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Sylvia
authors.initials: S
authors.lastname: Krobitsch
mesh_terms: D000375:Aging / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D050260:Carbohydrate Metabolism / Q000187:drug effects; D003198:Computer Simulation; D004351:Drug Resistance; D055785:Gene Knockdown Techniques; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007716:Kluyveromyces / Q000201:enzymology / Q000235:genetics; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014305:Triose-Phosphate Isomerase / Q000235:genetics / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D016877:Oxidants; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D013481:Superoxides; D009249:NADP; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D014305:Triose-Phosphate Isomerase