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题名: Arginine decarboxylase: A novel biological target of mercury compounds identified in PC12 cells
作者: Wang, Sufang; Lv, Qiyan; Yang, Yu; Guo, Liang-Hong; Wan, Bin; Ren, Xiaomin; Zhang, Hui
刊名: BIOCHEMICAL PHARMACOLOGY
出版日期: 2016-10-15
卷号: 118, 期号:0, 页码:109-120
关键词: Mercury ; Neurotoxicity ; Arginine decarboxylase ; Inhibition ; Molecular dynamics simulation
DOI: 10.1016/j.bcp.2016.08.019
部门归属: 环境化学与生态毒理学国家重点实验室
英文摘要: Mercury compounds are well-known toxic environmental pollutants and potently induce severe neurotoxicological effects in human and experimental animals. Previous studies showed that one of the mechanisms of mercury compounds neurotoxicity arose from the over-activation of the N-methyl D-aspartate (NMDA)-type glutamate receptor induced by increased glutamate release. In this work, we aimed to investigate the molecular mechanisms of Hg compounds neurotoxicities by identifying their biological targets in cells. Firstly, the inhibitory effects of four Hg compounds, including three organic (methyl-, ethyl- and phenyl-mercury) and one inorganic (Hg2+) Hg compounds, on the activity of arginine decarboxylase (ADC), a key enzyme in the central agmatinergic system, were evaluated. They were found to inhibit the ADC activity significantly with methylmercury (MeHg) being the strongest (IC50 = 7.96 nM). Furthermore, they showed remarkable inhibitory effects on ADC activity in PC12 cells (MeHg > EtHg > PhHg > HgCl2), and led to a marked loss in the level of agmatine, an endogenous neuro-modulatory and neuroprotective agent that selectively blocks the activation of NMDA receptors. MeHg was detected in the immunoprecipitated ADC from the cells, providing unequivocal evidence for the direct binding of MeHg with ADC in the cell. Molecular dynamics simulation revealed that Hg compounds could form the coordination bond not only with cofactor PLP of ADC, but also with substrate arginine. Our finding indicated that MeHg could attenuate the neuroprotective effects of agmatine by the inhibition of ADC, a new cellular target of MeHg, which might be implicated in molecular mechanism of MeHg neurotoxicity. (C) 2016 Elsevier Inc. All rights reserved.
收录类别: SCI
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内容类型: 期刊论文
URI标识: http://ir.rcees.ac.cn/handle/311016/35803
Appears in Collections:环境化学与生态毒理学国家重点实验室_期刊论文

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Recommended Citation:
Wang, Sufang,Lv, Qiyan,Yang, Yu,et al. Arginine decarboxylase: A novel biological target of mercury compounds identified in PC12 cells[J]. BIOCHEMICAL PHARMACOLOGY,2016,118(0):109-120.
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