Structure Dependent Determination of Organophosphate Targets in Mammalian Tissues Using Activity-Based Protein Profiling.
Structure Dependent Determination of Organophosphate Targets in Mammalian Tissues Using Activity-Based Protein Profiling.
复制标题
DOI：
10.1021/acs.chemrestox.9b00344
复制
发表时间：
2020-02-17
影响因子：
4.1
通讯作者：
Wright, Aaron T.
中科院分区：
文献类型：
--
作者：
Lin, Vivian S.;Volk, Regan F.;DeLeon, Adrian J.;Anderson, Lindsey N.;Purvine, Samuel O.;Shukla, Anil K.;Bernstein, Hans C.;Smith, Jordan N.;Wright, Aaron T.
急性和慢性接触有机磷（OP），包括农业杀虫剂，工业化学品和化学战剂，仍然是一个重大的全球健康风险。OP改变暴露个体发育和认知的机制仍然知之甚少，部分原因是大量结构多样的OP和广泛的受影响蛋白质和信号通路。为了研究哺乳动物系统中OP靶标结构的影响，我们开发了一系列用于基于活性的蛋白质谱分析（ABPP）的探针，其具有两个不同的反应基团，模拟OP化学反应性。FOP具有氟膦酸酯部分，PODA和CODA利用二炔基磷酸酯;两种反应基团类型都靶向丝氨酸水解酶活性。由于oxon代表许多OP的高反应性和毒性官能团，本文描述的新探针增强了我们对OP的组织特异性反应性的理解。用探针处理的小鼠组织的化学蛋白质组学分析揭示了不同的蛋白质谱，证明了探针结构对蛋白质靶向的影响。这些靶标对不同OP的敏感性也不同。因此，在ABPP实验中同时使用多个探针可以提供更全面的OP靶点覆盖范围; FOP始终在脑和肝中标记比PODA或CODA更多的靶点，这表明二炔弹头对主要信号传导途径中的酶比更具反应性的氟膦酸酯弹头更具选择性。此外，探针可用于评估N-肟对OP抑制酶的再活化，并可用作在一组蛋白质靶点中筛选治疗候选物的诊断工具。这些应用将有助于澄清乙酰胆碱酯酶抑制以外的OP毒性的短期和长期影响，研究广谱治疗开发的潜在汇聚点，并支持未来在各种模型系统中筛选候选分子的功效。
Acute and chronic exposures to organophosphates (OPs), including agricultural pesticides, industrial chemicals, and chemical warfare agents, remain a significant worldwide health risk. The mechanisms by which OPs alter development and cognition in exposed individuals remain poorly understood, in part due to the large number of structurally diverse OPs and the wide range of affected proteins and signaling pathways. To investigate the influence of structure on OP targets in mammalian systems, we have developed a series of probes for activity-based protein profiling (ABPP) featuring two distinct reactive groups that mimic OP chemical reactivity. FOP features a fluorophosphonate moiety, and PODA and CODA utilize a dialkynyl phosphate ester; both reactive group types target serine hydrolase activity. As the oxon represents the highly reactive and toxic functional group of many OPs, the new probes described herein enhance our understanding of tissue-specific reactivity of OPs. Chemoproteomic analysis of mouse tissues treated with the probes revealed divergent protein profiles, demonstrating the influence of probe structure on protein targeting. These targets also vary in sensitivity toward different OPs. The simultaneous use of multiple probes in ABPP experiments may therefore offer more comprehensive coverage of OP targets; FOP consistently labeled more targets in both brain and liver than PODA or CODA, suggesting the dialkyne warhead is more selective for enzymes in major signaling pathways than the more reactive fluorophosphonate warhead. Additionally, the probes can be used to assess reactivation of OP-inhibited enzymes by N-oximes and may serve as diagnostic tools for screening of therapeutic candidates in a panel of protein targets. These applications will help clarify the short- and long-term effects of OP toxicity beyond acetylcholinesterase inhibition, investigate potential points of convergence for broad spectrum therapeutic development, and support future efforts to screen candidate molecules for efficacy in various model systems.
登录
查看更多内容
影响因子：
4.1
作者：
Hao, Zhengliang;Zhang, Zhijie;Wang, Cui
通讯作者：
Wang, Cui
影响因子：
4.4
作者：
Cho, CMH;Mulchandani, A;Chen, W
通讯作者：
Chen, W
影响因子：
14.9
作者：
Caspi R;Billington R;Ferrer L;Foerster H;Fulcher CA;Keseler IM;Kothari A;Krummenacker M;Latendresse M;Mueller LA;Ong Q;Paley S;Subhraveti P;Weaver DS;Karp PD
通讯作者：
Karp PD
影响因子：
4.1
作者：
BERRY, WK;DAVIES, DR
通讯作者：
DAVIES, DR
影响因子：
168.9
作者：
Eddleston, Michael;Buckley, Nick A.;Eyer, Peter;Dawson, Andrew H.
通讯作者：
Dawson, Andrew H.