title: Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex.
abstract: The principal neuropathological feature of Parkinson's disease is the degeneration of melanized dopamine neurons in the substantia nigra pars compacta (SNc). Characteristic pathobiochemical changes in the parkinsonian SNc include a fall of both dopamine (DA) and glutathione levels (GSH), increased activity of gamma-glutamyl transpeptidase, a key enzyme involved in the degradation of GSH to L-cysteine (CySH), together with evidence for elevated intraneuronal superoxide (O2-*), nitric oxide (NO.) and thence peroxynitrite (ONOO-) generation, and accelerated DA oxidation as indicated by a large rise of the 5-S-cysteinyldopamine (5-S-CyS-DA)/DA concentration ratio. The latter effect is consistent with an increased rate of DA oxidation by O2-* and ONOO- forming DA-o-quinone which reacts with CySH forming 5-S-CyS-DA. However, 5-S-CyS-DA is readily further oxidized to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 is rapidly accumulated by isolated intact rat brain mitochondria and selectively inhibits complex I respiration and the alpha-ketoglutarate dehydrogenase (alpha-KGDH) complex. In this study it is demonstrated that DHBT-1 also inhibits the pyruvate dehydrogenase complex (PDHC). The mechanism underlying the inhibition of all of these enzyme complexes involves bioactivation of intramitochondrial DHBT-1 by oxidation to highly electrophilic metabolites that covalently bind to active site cysteine residues. Thus, oxidative metabolites of intraneuronal 5-S-CyS-DA may contribute to impaired mitochondrial complex I and alpha-KGDH activities known to occur in the parkinsonian SNc and suggest that impaired PDHC evoked by the same metabolites may also occur in PD.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Dryhurst
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000201:enzymology* / Q000503:physiopathology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000201:enzymology* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D013843:Thiazines / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C108502:7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid; D011768:Pyruvate Dehydrogenase Complex; D013843:Thiazines; C047408:5-S-cysteinyldopamine; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D001205:Ascorbic Acid; D004298:Dopamine