A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation
Autor: | Koen Van Laer, Agnieszka K. Bronowska, Frauke Gräter, David Peralta, Éva Dóka, Tobias P. Dick, Bruce A. Morgan, Péter Nagy |
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Rok vydání: | 2015 |
Předmět: |
Saccharomyces cerevisiae Proteins
Mutant Adaptation Biological Dehydrogenase Biológiai tudományok Saccharomyces cerevisiae Oxidative phosphorylation Enzyme activator chemistry.chemical_compound Természettudományok stomatognathic system Glyceraldehyde Humans Glycolysis Cysteine Molecular Biology Glyceraldehyde 3-phosphate dehydrogenase biology Active site Hydrogen Peroxide Cell Biology Enzyme Activation Biochemistry chemistry Mutation biology.protein Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) Protons Oxidation-Reduction |
Zdroj: | Nature Chemical Biology. 11:156-163 |
ISSN: | 1552-4469 1552-4450 |
DOI: | 10.1038/nchembio.1720 |
Popis: | Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is sensitive to reversible oxidative inactivation by hydrogen peroxide (H2O2). Here we show that H2O2 reactivity of the active site thiolate (C152) is catalyzed by a previously unrecognized mechanism based on a dedicated proton relay promoting leaving group departure. Disruption of the peroxidatic reaction mechanism does not affect the glycolytic activity of GAPDH. Therefore, specific and separate mechanisms mediate the reactivity of the same thiolate nucleophile toward H2O2 and glyceraldehyde 3-phosphate, respectively. The generation of mutants in which the glycolytic and peroxidatic activities of GAPDH are comprehensively uncoupled allowed for a direct assessment of the physiological relevance of GAPDH H2O2 sensitivity. Using yeast strains in which wild-type GAPDH was replaced with H2O2-insensitive mutants retaining full glycolytic activity, we demonstrate that H2O2 sensitivity of GAPDH is a key component of the cellular adaptive response to increased H2O2 levels. |
Databáze: | OpenAIRE |
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