Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

A brain detoxifying enzyme for organophosphorus nerve poisons

Academic Article
uri icon
  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

related to degree

  • Chiang, Kyle Ping, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2001 - 2006

authors

  • Nomura, D. K.
  • Leungt, D.
  • Chiang, Kyle Ping
  • Quistad, G. B.
  • Cravatt, Benjamin
  • Casida, J. E.

publication date

  • April 2005

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Organophosphorus (OP) insecticides and chemical warfare agents act primarily by inhibiting acetylcholinesterase. There are many secondary targets for OP toxicants as observed for example with the major insecticide chlorpyrifos and its bioactivated metabolite chlorpyrifos oxon (CPO). Therefore, it was surprising that the predominant mouse brain protein labeled in vitro by [(3)H-ethyl]CPO (1 nM) (designated CPO-binding protein or CPO-BP) is not one of these known OP toxicant targets. CPO-BP is a 50-kDa membrane-bound serine hydrolase measured by derivatization with [(3)H]CPO and SDS/PAGE or filtration binding assay. It appears to undergo rapid diethylphosphorylation by [(3)H]CPO followed by either dephosphorylation and reactivation or aging on loss of an ethyl group. CPO and several other OP toxicants potently inhibit CPO-BP in vivo (i.p., 2 h) (50% inhibition at 2-25 mg/kg) and in vitro (50% inhibition at 8-68 nM). Using three chemical labeling reagents, i.e., [(3)H]CPO and the activity-based proteomic probes fluorophosphonate-biotin and fluorophosphonate-rhodamine, mouse brain CPO-BP is identified as serine hydrolase KIAA1363 of unknown function. Brains from KIAA1363(-/-) mice show greatly reduced levels of CPO labeling and hydrolytic metabolism compared to brains from wild-type mice. KIAA1363 therefore is the principal enzyme for metabolizing low levels of CPO in brain and may play a more general role in detoxification of OP nerve poisons.

subject areas

  • Animals
  • Brain
  • Cell Membrane
  • Chlorpyrifos
  • Hydrolysis
  • Inactivation, Metabolic
  • Kinetics
  • Male
  • Mice
  • Neurotoxins
  • Serine Endopeptidases
  • Serine Proteases
  • Sterol Esterase
  • Tritium
scroll to property group menus

Research

keywords

  • detoxification
  • insecticide
  • phosphorylation
  • serine hydrolase KIAA1363
scroll to property group menus

Identity

PubMed Central ID

  • PMC1087944

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0501915102

PubMed ID

  • 15840715
scroll to property group menus

Additional Document Info

start page

  • 6195

end page

  • 6200

volume

  • 102

issue

  • 17

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support