Oxidative metabolites of 5-S-cysteinyldopamine inhibit the alpha-ketoglutarate dehydrogenase complex: possible relevance to the pathogenesis of Parkinson's disease.
Oxidative metabolites of 5-S-cysteinyldopamine inhibit the alpha-ketoglutarate dehydrogenase complex: possible relevance to the pathogenesis of Parkinson's disease.
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5-S-半胱氨酰多巴胺的氧化代谢物抑制α-酮戊二酸脱氢酶复合物：可能与帕金森病的发病机制有关。
DOI：
10.1007/s007020070045
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Dryhurst,G
中科院分区：
文献类型：
--
作者：
Shen,XM;Li,H;Dryhurst,G
帕金森病患者黑质的特征性变化是多巴胺氧化的明显加速速率，如通过增加的5-S-CyS-DA与多巴胺的比率所证明的。然而，5-S-CyS-DA比多巴胺更容易被氧化成7-（2-氨乙基）-3，4-二氢-5-羟基-2H-1，4-苯并噻嗪-3-羧酸（DHBT-1）。先前的研究表明，DHBT-1可以被完整的大鼠脑线粒体积累，并抑制复合物I而不是复合物II呼吸。在这项研究中，显示DHBT-1也抑制α-酮戊二酸脱氢酶复合物（α-KGDH），但不抑制细胞色素c氧化酶（复合物IV）。α-KGDH的抑制依赖于DHBT-1的氧化，由线粒体内膜的未知成分催化，生成亲电子邻醌亚胺，共价修饰活性位点巯基残基。后一个结论是基于三倍等摩尔谷胱甘肽能够阻断DHBT-1对α-KGDH的抑制作用，而不改变其线粒体膜催化氧化的速率，通过清除亲电邻醌中间体形成谷胱甘肽结合物（已分离和光谱表征）。在帕金森病黑质中，线粒体α-KGDH和复合物I的活性降低，但其他呼吸复合物的活性不降低。这些变化以及加速多巴胺氧化、增加5-S-CyS-DA形成以及这种缀合物易于氧化成DHBT-1（其抑制α-KGDH和复合物I，而不影响其他呼吸酶复合物）的证据表明，后一种推定的代谢物可能是导致帕金森病中α-KGDH和复合物I缺陷的内毒素。
A characteristic change in the substantia nigra of Parkinson's disease patients 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). Previous studies have demonstrated that DHBT-1 can be accumulated by intact rat brain mitochondria and inhibits complex I but not complex II respiration. In this study, it is shown that DHBT-1 also inhibits the α-ketoglutarate dehydrogenase complex (α-KGDH) but not cytochrome c oxidase (complex IV). The inhibition of α-KGDH is dependent on the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an electrophilic o-quinone imine that covalently modifies active site sulfhydryl residues. The latter conclusion is based on the ability of ≧ equimolar glutathione to block the inhibition of α-KGDH by DHBT-1, without altering its rate of mitochondrial membrane-catalyzed oxidation, by scavenging the electrophilic o-quinone intermediate forming glutathionyl conjugates which have been isolated and spectroscopically characterized. Activities of mitochondrial α-KGDH and complex I, but not other respiratory complexes, are decreased in the parkinsonian substantia nigra. Such changes together with evidence for accelerated dopamine oxidation, increased formation of 5-S-CyS-DA and the ease of oxidation of this conjugate to DHBT-1 which inhibits α-KGDH and complex I, without affecting other respiratory enzyme complexes, suggests that the latter putative metabolite might be an endotoxin that contributes to the α-KGDH and complex I defects in Parkinson's disease.