Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex

Summary.

The principal neuropathological feature of Parkinson's disease is the degeneration of melanized dopamine neurons in the substantia nigra pars compacta (SN_c). Characteristic pathobiochemical changes in the parkinsonian SN_c include a fall of both dopamine (DA) and glutathione levels (GSH), increased activity of γ-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 α-ketoglutarate dehydrogenase (α-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 α-KGDH activities known to occur in the parkinsonian SN_c and suggest that impaired PDHC evoked by the same metabolites may also occur in PD.