Print Email Facebook Twitter Activity-based protein profiling reveals broad reactivity of the nerve agent sarin Title Activity-based protein profiling reveals broad reactivity of the nerve agent sarin Author TNO Defensie en Veiligheid Tuin, A.W. Mol, M.A.E. van den Berg, R.M. Fidder, A. van der Marel, G.A. Overkleeft, H.S. Noort, D. Publication year 2009 Abstract Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which contains a phosphonofluoridate moiety, a P-Me moiety, and a biotinylated O-alkyl group, and its use in activity-based protein profiling with two relevant biological samples, that is, rhesus monkey liver and cultured human A549 lung cells. In this way, we have unearthed eight serine hydrolases (fatty acid synthase, acylpeptide hydrolase, dipeptidyl peptidase 9, prolyl oligopeptidase, carboxylesterase, long-chain acyl coenzyme A thioesterase, PAF acetylhydrolase 1b, and esterase D/S-formyl glutathione hydrolase) as targets that are modified by the nerve agent sarin. It is also shown that the newly developed probe 3 might find its way into the development of alternative, less laborious purification protocols for human butyrylcholinesterase, a potent bioscavenger currently under clinical investigation as a prophylactic/therapeutic for nerve agent intoxications. © 2009 American Chemical Society. Subject 1 alkyl 2 acetylglycerophosphocholine esteraseAcylamino acid releasing enzymeCarboxylesteraseDipeptidyl peptidaseDipeptidyl peptidase 9Fatty acid synthaseMethylphosphonofluoridic acidOrganophosphatePalmitoyl coenzyme A hydrolaseProlyl endopeptidaseUnclassified drugAnimal cellBiotinylationChemical structureControlled studyHumanHuman cellMatrix assisted laser desorption ionization time of flight mass spectrometryNonhumanProtein analysisQuantitative analysisSensitivity analysisMacaca mulattaCarboxylesterase, 59536-71-9, 83380-83-0, 9016-18-6, 9028-01-7Dipeptidyl peptidase, 9032-67-1Fatty acid synthese, 9045-77-6Palmitoyl coenzyme A hydrolase, 37270-64-7, 78689-76-6, 9025-87-0Prolyl endopeptidase, 72162-84-6Sarin, 107-44-8Cholinesterase, 9001-08-5Hydrolase, 9027-41-2ButyrylcholinesteraseCholinesterase inhibitorsNerve agentAnimalAntagonists and inhibitorsBloodChemistryLiverMetabolismRhesus monkeyStructure activity relationSynthesisTumor cell cultureHydrolasesMolecular StructureNerve agentsStructure-activity relationship To reference this document use: http://resolver.tudelft.nl/uuid:2ad7bce2-36f8-490a-af36-183d6b0dec16 DOI https://doi.org/10.1021/tx8004218 TNO identifier 183522 ISSN 0893-228X Source Chemical Research in Toxicology, 22 (22), 683-689 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.