title: Modifications of glyceraldehyde-3-phosphate dehydrogenase induced by increasing concentrations of peroxynitrite: early recognition by 20S proteasome.
abstract: Peroxynitrite, a potent oxidizing and nitrating species, induces covalent modifications of biomolecules in a number of pathological conditions. In previous studies with S. cerevisiae, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as being especially susceptible to nitration by peroxynitrite. The activity of this enzyme was strongly inhibited by low doses of peroxynitrite in yeast and in cultured rat astrocytes. Here, the sequence of modifications of isolated mammalian GAPDH induced by increasing concentrations of peroxynitrite is demonstrated to be as follows: (i) oxidation, leading to inactivation and to enhanced susceptibility of GAPDH for proteasomal degradation, (ii) oligomer formation, and (iii) nitration. In our study the susceptibility for degradation by isolated 20S proteasome was by far the most sensitive parameter for peroxynitrite-induced damage to GAPDH, implying that this might also occur under pathological conditions where peroxynitrite is generated at low concentrations in vivo.
authors.affiliation: Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, Postfach 101007, D-40001 Düsseldorf, Germany.
authors.forename: Darius P
authors.initials: DP
authors.lastname: Buchczyk
authors.forename: Tilman
authors.initials: T
authors.lastname: Grune
authors.forename: Helmut
authors.initials: H
authors.lastname: Sies
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Klotz
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex
chemical_list: D009097:Multienzyme Complexes; D030421:Peroxynitrous Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases