title: Arginine decarboxylase: A novel biological target of mercury compounds identified in PC12 cells.
abstract: 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=7.96nM). 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 neuromodulatory 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.
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China; College of Environmental Science and Engineering, Taiyuan University of Technology, Taiyuan 030024, China.
authors: Sufang
authors: S
authors: Wang
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China.
authors: Qiyan
authors: Q
authors: Lv
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China. Electronic address: yuyang@rcees.ac.cn.
authors: Yu
authors: Y
authors: Yang
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China; Institute of Environment and Health, Jianghan University, Wuhan 430056, China. Electronic address: LHGuo@rcees.ac.cn.
authors: Liang-Hong
authors: LH
authors: Guo
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China.
authors: Bin
authors: B
authors: Wan
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China.
authors: Xiaomin
authors: X
authors: Ren
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085, China.
authors: Hui
authors: H
authors: Zhang
mesh_terms: D065567:Absorption, Physiological; D000376:Agmatine / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003653:Decarboxylation / Q000187:drug effects; D004785:Environmental Pollutants / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D005034:Ethylmercuric Chloride / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008627:Mercuric Chloride / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010663:Phenylmercury Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D051381:Rats
chemical_list: D056831:Coordination Complexes; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D008767:Methylmercury Compounds; D009419:Nerve Tissue Proteins; D010663:Phenylmercury Compounds; D008627:Mercuric Chloride; D000376:Agmatine; D001120:Arginine; D002262:Carboxy-Lyases; C019722:arginine decarboxylase; D005034:Ethylmercuric Chloride; C004925:methylmercuric chloride; C008859:phenylmercuric chloride
keywords: Arginine decarboxylase; Inhibition; Mercury; Molecular dynamics simulation; Neurotoxicity