Li H, Shen X M, Dryhurst G
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
J Neurochem. 1998 Nov;71(5):2049-62. doi: 10.1046/j.1471-4159.1998.71052049.x.
We have proposed that a very early step in the pathogenesis of idiopathic Parkinson's disease is the elevated translocation of L-cysteine into neuromelanin-pigmented dopaminergic neurons in the substantia nigra. This influx of L-cysteine was proposed to divert the normal neuromelanin pathway by scavenging dopamine-o-quinone, formed by autoxidation of cytoplasmic dopamine, to give initially 5-S-cysteinyldopamine, which is further oxidized to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). In a recent report, it was demonstrated that DHBT-1 evokes inhibition of complex I respiration when incubated with intact rat brain mitochondria and a time-dependent irreversible inhibition of NADH-coenzyme Q1 (CoQ1) reductase when incubated with mitochondrial membranes. In this study, it is established that the time dependence of NADH-CoQ1 reductase inhibition reflects the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an o-quinone imine intermediate that rearranges to 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (BT-1) and decarboxylates to 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine (BT-2), which are further catalytically oxidized to o-quinone imine intermediates. The electrophilic o-quinone imine intermediates formed in these mitochondria-catalyzed oxidations of DHBT-1, BT-1, and BT-2 are proposed to bind covalently to key sulfhydryl residues at the complex I site, thus evoking irreversible inhibition of NADH-CoQ1 reductase. Evidence for this mechanism derives from the fact that greater than equimolar concentrations of glutathione completely block inhibition of NADH-CoQ1 reductase by DHBT-1, BT-1, and BT-2 by scavenging their electrophilic o-quinone imine metabolites to form glutathionyl conjugates. The results of this investigation may provide insights into the irreversible loss of glutathione and decreased mitochondrial complex I activity, which are both anatomically specific to the substantia nigra and exclusive to Parkinson's disease.
我们曾提出，特发性帕金森病发病机制中一个非常早期的步骤是L-半胱氨酸向黑质中神经黑色素沉着的多巴胺能神经元的转运增加。有人提出，L-半胱氨酸的这种流入会通过清除由细胞质多巴胺自氧化形成的多巴胺邻醌来改变正常的神经黑色素途径，最初生成5-S-半胱氨酰多巴胺，其进一步氧化为7-(2-氨基乙基)-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸（DHBT-1）。在最近的一份报告中，已证明当与完整的大鼠脑线粒体一起孵育时，DHBT-1会引起复合体I呼吸的抑制，而当与线粒体膜一起孵育时，会引起NADH-辅酶Q1（CoQ1）还原酶的时间依赖性不可逆抑制。在本研究中，已确定NADH-CoQ1还原酶抑制的时间依赖性反映了DHBT-1由线粒体内膜的未知成分催化氧化为邻醌亚胺中间体，该中间体重排为7-(2-氨基乙基)-5-羟基-1,4-苯并噻嗪-3-羧酸（BT-1）并脱羧为7-(2-氨基乙基)-5-羟基-1,4-苯并噻嗪（BT-2），它们进一步被催化氧化为邻醌亚胺中间体。在这些线粒体催化的DHBT-1、BT-1和BT-2氧化过程中形成的亲电子邻醌亚胺中间体被认为会与复合体I位点的关键巯基残基共价结合，从而引起NADH-CoQ1还原酶的不可逆抑制。这一机制的证据来自于这样一个事实，即大于等摩尔浓度的谷胱甘肽通过清除其亲电子邻醌亚胺代谢产物以形成谷胱甘肽共轭物，完全阻断了DHBT-1、BT-1和BT-2对NADH-CoQ1还原酶的抑制。本研究结果可能为谷胱甘肽的不可逆丧失和线粒体复合体I活性降低提供见解，这两者在解剖学上均特定于黑质且为帕金森病所特有。
