Further insights into the influence of L-cysteine on the oxidation chemistry of dopamine: reaction pathways of potential relevance to Parkinson's disease.
Further insights into the influence of L-cysteine on the oxidation chemistry of dopamine: reaction pathways of potential relevance to Parkinson's disease.
复制标题
进一步了解 L-半胱氨酸对多巴胺氧化化学的影响：与帕金森病潜在相关的反应途径。
DOI：
10.1021/tx960008f
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发表时间：
1996
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;Dryhurst,G
神经黑色素是一种黑色聚合色素，通常存在于黑质（SN）多巴胺能细胞体的细胞质中，多巴胺（DA）自氧化为DA-o-醌(1)。在这项研究中，发现在半胱氨酸（CySH）存在的情况下，邻醌1被清除产生5- s -半胱氨酸多巴胺（5-S-CyS-DA，主要产物）和2- s -半胱氨酸多巴胺（2-S-CyS-DA，次要产物）。这些半胱氨酸缀合物比DA更容易被氧化。所得产物的相对产率取决于游离CySH的浓度。这些产物包括2,5-双- s -半胱氨酸多巴胺（2,5-双- s -cys - da）和2,5,6-三- s -半胱氨酸多巴胺（2,5,6-三- s -cys - da）， 7-（2-氨基乙基）-3,4-二氢-5-羟基- 2h -1,4-苯并噻吩-3-羧酸（DHBT-1）， 8-（2-氨基乙基）-3,4-二氢-5-羟基- 2h -1,4-苯并噻吩-3-羧酸（DHBT-5），以及这些二氢苯并噻吩的一些半胱氨酸偶联物（dhbt）。2,5- bi - s -cys - da, DHBT-1， DHBT-1的6- s -半胱氨酸缀合物，DHBT-5和DHBT-5的6- s -半胱氨酸缀合物在给药到实验室小鼠的大脑时是致命的，并引起非常典型的多动综合征和严重震颤发作。这些及相关结果支持了帕金森病（PD）中出现的大量不可逆的谷胱甘肽（GSH）损失、5-S-CyS-DA/DA浓度比升高以及SN中多巴胺能神经元色素脱色可能是由γ-谷氨酰转肽酶介导的CySH（和/或GSH）转运到这些细胞中引起的假设。此外，由此产生的半胱氨酸多巴胺和dhbt可能包括内毒代谢物，负责黑质纹状体多巴胺能神经元和PD的选择性变性。
The initial step in the genesis of neuromelanin, a black polymeric pigment normally found in the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN), is the autoxidation of dopamine (DA) to DA-o-quninone (1). In this investigation, it is demonstrated that in the presence ofl-cysteine (CySH)o-quinone1is scavenged to give 5-S-cysteinyldopamine (5-S-CyS-DA, major product) and 2-S-cysteinyldopamine (2-S-CyS-DA, minor product). These cysteinyl conjugates are more easily oxidized than DA. The relative yields of the resulting products are dependent on the concentration of free CySH. These products include 2,5-bi-S-cysteinyldopamine (2,5-bi-S-CyS-DA) and 2,5,6-tri-S-cysteinyldopamine (2,5,6-tri-S-CyS-DA), 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5), and a number of cysteinyl conjugates of these dihydrobenzothiazines (DHBTs). 2,5-Bi-S-CyS-DA, DHBT-1, the 6-S-cysteinyl conjugate of DHBT-1, DHBT-5, and the 6-S-cysteinyl conjugate of DHBT-5 were lethal when administered into the brains of laboratory mice and evoke a very characteristic hyperactivity syndrome and episodes of sever tremor. These and related results provide support for the hypothesis that the massive, irreversible loss of glutathione (GSH), increased 5-S-CyS-DA/DA concentration ratio, and depigmentation of dopaminergic neurons in the SN that all occur in Parkinson's disease (PD) might be caused by the γ-glutamyl transpeptidase-mediated translocation of CySH (and/or GSH) into these cells. Furthermore, the resulting cysteinyldopamines and DHBTs might include endotoxic metabolites responsible for the selective degeneration of nigrostriatal dopaminergic neurons and PD.