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  2. Elucidating the potential neurotoxicity of chiral phenthoate: Molecular insight from experimental and computational studies

Elucidating the potential neurotoxicity of chiral phenthoate: Molecular insight from experimental and computational studies

  • Chemosphere. 2020 Sep;255:127007. doi: 10.1016/j.chemosphere.2020.127007.
Fei Ding 1 Wei Peng 2 Yu-Kui Peng 3 Bing-Qi Liu 4
Affiliations

Affiliations

  • 1 Department of Environmental Science and Engineering, School of Water and Environment, Chang'an University, Xi'an, 710054, China; Key Laboratory of Subsurface Hydrology and Ecological Effect in Arid Region of Ministry of Education, Chang'an University, No. 126 Yanta Road, Yanta District, Xi'an, 710054, China.
  • 2 State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China. Electronic address: weipeng@cau.edu.cn.
  • 3 Center for Food Quality Supervision, Inspection & Testing, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, 712100, China.
  • 4 Department of Agricultural Chemistry, Qingdao Agricultural University, Qingdao, 266109, China.
Abstract

Chiral organophosphorus pollutants are existed ubiquitously in the ecological environment, but the enantioselective toxicities of these nerve agents to humans and their molecular bases have not been fully elucidated. Using experimental and computational approaches, this story was to explore the neurotoxic response process of the target acetylcholinesterase (AChE) to chiral phenthoate and further decipher the microscopic mechanism of such toxicological effect at the enantiomeric level. The results showed that the toxic reaction of AChE with chiral phenthoate exhibited significant enantioselectivity, and (R)-phenthoate (K=1.486 × 105 M-1) has a bioaffinity for the nerve Enzyme nearly three times that of (S)-phenthoate (K=4.503 × 104 M-1). Dynamic research outcomes interpreted the wet experiments, and the inherent conformational flexibility of the target Enzyme has a great influence on the enantioselective neurotoxicological action processes, especially reflected in the conformational changes of the three key loop regions (i.e. residues His-447, Gly-448, and Tyr-449; residues Gly-122, Phe-123, and Tyr-124; and residues Thr-75, Leu-76, and Tyr-77) around the reaction patch. This was supported by the quantitative results of conformational studies derived from circular dichroism spectroscopy (α-helix: 34.7%→30.2%/31.6%; β-sheet: 23.6%→19.5%/20.7%; turn: 19.2%→22.4%/21.9%; and random coil: 22.5%→27.9%/25.8%). Meanwhile, via analyzing the modes of toxic action and free energies, we can find that (R)-phenthoate has a strong inhibitory effect on the enzymatic activity of AChE, as compared with (S)-phenthoate, and electrostatic energy (-23.79/-17.77 kJ mol-1) played a critical role in toxicological reactions. These points were the underlying causes of chiral phenthoate displaying different degrees of enantioselective neurotoxicity.

Keywords

Acetylcholinesterase; Chiral pollutant; Enantioselective neurotoxicity; Phenthoate; Risk assessment; Toxicological pattern.

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