Arginine decarboxylase: A novel biological target of mercury compounds identified in PC12 cells
Authors: Liang-Hong Guo
Qiyan Lv
Bin Wan
Hui Zhang
Yu Yang
Sufang Wang
Xiaomin Ren
Journal: Biochemical Pharmacology (2016)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Arginine decarboxylase; Inhibition; Mercury; Molecular dynamics simulation; Neurotoxicity.
Affiliations: 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., 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., 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: ., 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: .

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&gt;EtHg&gt;PhHg&gt;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. 

Retracted: No

PubPeer comments:
 No arginine decarboxylase even exists in human or mammal(PMID: 19956990, PMID: 17900240, https: www.ncbi.nlm.nih.gov gene ?term=AY325129). How does the authors detect the ADC activity and even found an inhibitor? ,