title: In vitro inhibition of lysine decarboxylase activity by organophosphate esters.
abstract: Organophosphate esters (OPEs), a major group of organophosphorus flame retardants, are regarded as emerging environmental contaminants of health concern. Amino acid decarboxylases catalyze the conversion of amino acids into polyamines that are essential for cell proliferation, hypertrophy and tissue growth. In this paper, inhibitory effect of twelve OPEs with aromatic, alkyl or chlorinated alkyl substituents on the activity of lysine decarboxylase (LDC) was assessed quantitatively with an economic and label-free fluorescence sensor and cell assay. The sensor comprises a macrocyclic host (cucurbit[7]uril) and a fluorescent dye (acridine orange) reporter. The twelve OPEs were found to vary in their capacity to inhibit LDC activity. Alkyl group substituted OPEs had no inhibitory effect. By contrast, six OPEs substituted with aromatic or chlorinated alkyl groups inhibited LDC activity significantly with IC50 ranging from 1.32 μM to 9.07 μM. Among them, the inhibitory effect of tri-m-cresyl phosphate (TCrP) was even more effective as an inhibitor than guanosine 5'-diphosphate-3'-diphosphate (ppGpp) (1.60 μM), an LDC natural inhibitor in vivo. Moreover, at non-cytotoxic concentrations, these six OPEs showed perceptible inhibitory effects on LDC activity in PC12 living cells, and led to a marked loss in the cadaverine content. Molecular docking analysis of the LDC/OPE complexes revealed that different binding modes contribute to the difference in their inhibitory effect. Our finding suggested that LDC, as a new potential biological target of OPEs, might be implicated in toxicological and pathogenic mechanism of OPEs.
authors.affiliation: 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.forename: Sufang
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.forename: Bin
authors.initials: B
authors.lastname: Wan
authors.affiliation: 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.forename: Lianying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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: LHGuo@rcees.ac.cn.
authors.forename: Liang-Hong
authors.initials: LH
authors.lastname: Guo
mesh_terms: D000818:Animals; D002103:Cadaverine / Q000378:metabolism; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000494:pharmacology; D005453:Fluorescence; D062105:Molecular Docking Simulation; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004952:Esters; D010755:Organophosphates; D002262:Carboxy-Lyases; C021520:lysine decarboxylase; D002103:Cadaverine
keywords: Inhibition; Lysine decarboxylase; Molecular docking; Organophosphate esters; Toxicity