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dc.contributor.authorLinn, Vivian S
dc.contributor.authorVolk, Regan F
dc.contributor.authorDeLeon, Adrian J
dc.contributor.authorAnderson, Lindsey N
dc.contributor.authorPurvine, Samuel Owen
dc.contributor.authorShukla, Anil K
dc.contributor.authorBernstein, Hans Christopher
dc.contributor.authorSmith, Jordan N
dc.contributor.authorWright, Aaron T
dc.date.accessioned2020-03-11T16:14:50Z
dc.date.available2020-03-11T16:14:50Z
dc.date.issued2019-12-24
dc.description.abstractAcute and chronic exposure 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 towards 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.en_US
dc.identifier.citationLinn, V., Volk, R.F., DeLeon, Anderson, L.N., Purvine, S.O., Shukla, A.K., Bernstein, H.C., Smith, J.N., Wright, A.T. (2019) Structure dependent determination of organophosphate targets in mammalian tissues using activity-based protein profiling. <i>Chemical Research in Toxicology, 2019</i>en_US
dc.identifier.cristinIDFRIDAID 1766451
dc.identifier.doi10.1021/acs.chemrestox.9b00344
dc.identifier.issn0893-228X
dc.identifier.issn1520-5010
dc.identifier.urihttps://hdl.handle.net/10037/17719
dc.language.isoengen_US
dc.publisherAmerican Chemical Society (ACS)en_US
dc.relation.journalChemical Research in Toxicology
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright © American Chemical Societyen_US
dc.subjectVDP::Mathematics and natural science: 400::Basic biosciences: 470::Biochemistry: 476en_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Biokjemi: 476en_US
dc.titleStructure dependent determination of organophosphate targets in mammalian tissues using activity-based protein profilingen_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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