title: Esterases hydrolyze phenyl valerate activity as targets of organophosphorus compounds.
abstract: OPs are a large diverse class of chemicals used for several purposes (pesticides, warfare agents, flame retardants, etc.). They can cause several neurotoxic disorders: acute cholinergic toxicity, organophosphorus-induced delayed neuropathy, long-term neurobehavioral and neuropsychological symptoms, and potentiation of neuropathy. Some of these syndromes cannot be fully understood with known molecular targets. Many enzyme systems have the potential to interact with OPs. Since the discovery of neuropathy target esterase (NTE), the esterases that hydrolyze phenyl valerate (PVases) have been of interest. PVase components are analyzed in chicken tissue, the animal model used for testing OP-delayed neurotoxicity. Three enzymatic components have been discriminated in serum, and three in a soluble fraction of peripheral nerve, three in a soluble fraction of brain, and four in a membrane fraction of brain have been established according to inhibitory kinetic properties combined with several inhibitors. The criteria and strategies to differentiate these enzymatic components are shown. In the brain soluble fraction three enzymatic components, namely Eα, Eβ and Eγ, were found. Initial interest focused on Eα activity (highly sensitive to paraoxon and spontaneously reactivated, mipafox and resistant to PMSF). By protein separation methods, a subfraction enriched in Eα activity was obtained and 259 proteins were identified by Tandem Mass Spectrometry. Only one had the criteria for being serine-esterase identified as butyrylcholinesterase, which stresses the relationship between cholinesterases and PVases. The identification and characterization of the whole group of PVases targets of OPs (besides AChE, BuChE and NTE) is necessary to clarify the importance of these other targets in OPs neurotoxicity or on detoxication pathways. A systematic strategy has proven useful for the molecular identification of one enzymatic component, which can be applied to identify them all.
authors.affiliation: Institute of Bioengineering, Miguel Hernández University of Elche, Spain; Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (CAPES 88887.065877/2014-00), Military Institute of Engineering, Rio de Janeiro, Brazil. Electronic address: imangas@umh.es.
authors.forename: Iris
authors.initials: I
authors.lastname: Mangas
authors.affiliation: Institute of Bioengineering, Miguel Hernández University of Elche, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Estévez
authors.affiliation: Institute of Bioengineering, Miguel Hernández University of Elche, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Vilanova
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004950:Esterases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000633:toxicity*; D014631:Valerates / Q000378:metabolism*
chemical_list: D009943:Organophosphorus Compounds; D014631:Valerates; C049867:phenyl valerate; D004950:Esterases; C022635:serine esterase
keywords: Brain; Butyrylcholinesterase; Chicken; Neuropathy target esterase; Phenyl valerate esterase