有机磷酸酯阻燃剂毒性作用新靶点:对蛋白质糖基转移酶的识别及分子机制研究
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- 英文论文题名：The potential biological target of organophosphate esters:recognition to protein O-GlcNAc transferase and mechanism of toxicity
- 论文作者：谷玉新 ; 杨郁 ; 郭良宏
- 英文论文作者：Yu-Xin Gu ; Yu Yang ; Liang-Hong Guo ; State Key Laboratory of Environmental Chemistry and Ecotoxicology ; Research Center for Eco-Environmental Sciences ; Chinese Academy of Sciences
- 年：2016
- 作者机构：中国科学院生态环境研究中心;
- 论文关键词：有机磷酸酯 ; 蛋白质糖基转移酶 ; 抑制 ; 毒理机制 ; 分子对接
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十六分会：环境化学
- 语种：中文
- 分类号：R114
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十六分会 ; 环境化学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：119k
- 原文格式：D
- 会议级别：全国
摘要
有机磷酸酯(Organophosphate esters,OPEs)作为溴代阻燃剂的主要替代品,其对环境和人类健康的影响日益引起关注。其中神经毒性是OPE最主要的毒性效应,机制尚不清楚。蛋白质糖基化是蛋白质翻译后修饰最重要、最常见的一种共价修饰方式,涉及细胞免疫、蛋白质翻译调控、蛋白降解等多种生物过程,糖基化水平异常会导致疾病的发生。本课题首先建立了一种简单、快速、免标记的蛋白质O-Glc NAc糖基转移酶(OGT)活性的电化学传感检测方法,筛查了12种OPEs(含芳香、氯代和烷基取代)对OGT活性的抑制作用,其中芳香和氯代取代的OPEs对OGT活性表现出明显的抑制效应。进一步在PC12神经细胞内研究了芳香和氯代取代的OPEs对全细胞O-Glc NAcylation水平、热休克蛋白表达、Tau蛋白糖基化水平的影响,结果证实OPEs能够显著降低O-Glc NAcylation水平、热休克表达和Tau蛋白糖基化水平。分子对接结果揭示抑制效应取决于OPEs与OGT的结合模式,我们的研究结果表明OGT可能是OPEs神经毒性的一个潜在生物靶标,且OPEs对OGT的抑制效应也可能与OPEs神经毒性的分子机制相关。
Organophosphate esters(OPEs),as substitutes for brominated flame retardants,have raised concerns about environment and human health effects.Currently,the molecular mechanism of OPEs neurotoxicity is not fully understood.Protein glycosylation is the most important post-translational modification that occurs in the cell.The abnormal glycosylation level results in the occurrence of some diseases.In our work,we have developed a label-free electrochemical biosensor to evaluate the OGT activity and employed it to investigate the inhibition of OGT by twelve OPEs.OPEs substituted with aromatic or chlorinated alkyl groups inhibited OGT activity significantly.Furthermore,these OPEs were found to inhibit the OGT activity in PC12 living cells,and led to a marked loss in the O-Glc NAcylation level.Molecular docking revealed that binding modes contribute to the inhibition difference.Our finding suggested that OGT,as a new potential biological target of OPEs,might be implicated in toxicological and pathogenic mechanism of OPEs.
Organophosphate esters(OPEs),as substitutes for brominated flame retardants,have raised concerns about environment and human health effects.Currently,the molecular mechanism of OPEs neurotoxicity is not fully understood.Protein glycosylation is the most important post-translational modification that occurs in the cell.The abnormal glycosylation level results in the occurrence of some diseases.In our work,we have developed a label-free electrochemical biosensor to evaluate the OGT activity and employed it to investigate the inhibition of OGT by twelve OPEs.OPEs substituted with aromatic or chlorinated alkyl groups inhibited OGT activity significantly.Furthermore,these OPEs were found to inhibit the OGT activity in PC12 living cells,and led to a marked loss in the O-Glc NAcylation level.Molecular docking revealed that binding modes contribute to the inhibition difference.Our finding suggested that OGT,as a new potential biological target of OPEs,might be implicated in toxicological and pathogenic mechanism of OPEs.
引文
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[2]Wong C.H.J.Org.Chem.,2005,70(11):4219-4225.