Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex
Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex
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DOI：
10.1007/s007020100013
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发表时间：
2001-01-01
影响因子：
3.3
通讯作者：
Dryhurst, G
中科院分区：
文献类型：
--
作者：
Li, H;Dryhurst, G
帕金森病的主要神经病理特征是黑质致密部（SNc）黑化多巴胺神经元的变性。帕金森SNc的特征性病理生化变化包括多巴胺（DA）和谷胱甘肽（GSH）水平下降，γ -谷氨酰转肽酶（GSH降解为l -半胱氨酸（CySH）的关键酶）活性增加，以及神经元内超氧化物（O-2）升高的证据。)，一氧化氮（NO .）和随后的过氧亚硝酸盐（ONOO-）生成，并加速DA氧化，这表明5- s -半胱氨酸多巴胺(5-S-CyS-DA)/DA浓度比大幅上升。后一种效应与O-2（-）和ONOO-生成的DA-o-醌与CySH反应生成5-S-CyS-DA的氧化速率增加一致。然而，5-S-CyS-DA很容易进一步氧化为7-（2-氨基乙基）-3,4-二羟基-5-羟基-1,4-苯并噻嗪-3-羧酸（DHBT-1）。先前的研究表明，DHBT-1在分离的完整大鼠脑线粒体中迅速积累，并选择性地抑制复合体呼吸和α -酮戊二酸脱氢酶（α -KGDH）复合体。在这项研究中，DHBT-1也抑制丙酮酸脱氢酶复合物（PDHC）。抑制所有这些酶复合物的机制涉及线粒体内DHBT-1的生物活化，氧化成高度亲电代谢物，共价结合活性位点半胱氨酸残基。因此，神经元内5-S-CyS-DA的氧化代谢物可能导致帕金森SNc中已知的线粒体复合物I和α -KGDH活性受损，并提示由相同代谢物引起的PDHC受损也可能发生在PD中。
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 (O-2(-.)), 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 O-2(-.) 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-diliydro-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 if 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.