Oxidative metabolites of 5-S-cysteinyldopamine inhibit the alpha-ketoglutarate dehydrogenase complex: possible relevance to the pathogenesis of Parkinson's disease

A characteristic change in the substantia nigra of Parkinson's disease pati ents is an apparent accelerated rate of dopamine oxidation as evidenced by an increased 5-S-cysteinyldopamine (5-S-CyS-DA) to dopamine ratio. However, 5-S-CyS-DA is more easily oxidized than dopamine to give 7-(2-aminoethyl)- 3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (DHBT-1). Pre vious studies have demonstrated that DHBT-1 can be accumulated by intact ra t brain mitochondria and inhibits complex I but not complex II respiration. In this study, it is shown that DHBT-1 also inhibits the alpha-ketoglutara te dehydrogenase complex (alpha-KGDH) but not cytochrome c oxidase (complex IV). The inhibition of alpha-KGDH is dependent on the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, t o an electrophilic o-quinone imine that covalently modifies active site sul fhydryl residues. The latter conclusion is based on the ability of greater than or equal to equimolar glutathione to block the inhibition of alpha-KGD H by DHBT-1, without altering its rate of mitochondrial membrane-catalyzed oxidation, by scavenging the electrophilic o-quinone intermediate forming g lutathionyl conjugates which have been isolated and spectroscopically chara cterized. Activities of mitochondrial alpha-KGDH and complex I. but not oth er respiratory complexes, are decreased in the parkinsonian substantia nigr a. Such changes together with evidence for accelerated dopamine oxidation, increased formation of 5-S-CyS-DA and the ease of oxidation of this conjuga te to DHBT-1 which inhibits alpha-KGDH and complex I, without affecting oth er respiratory enzyme complexes, suggests that the latter putative metaboli te might be an endotoxin that contributes to the alpha-KGDH and complex I d efects in Parkinson's disease.