The cross-linking action of organophosphorus poisons; Implications for chronic neurotoxicity

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1 Scopus citations

Abstract

Treatment of pure proteins with organophosphorus toxicants caused proteins to form nonreducible high-molecular-weight multimers. Tubulin was a particularly good example of a protein sensitive to modification by chlorpyrifos oxon. The chemical bonds responsible for the multimer structure were analyzed by mass spectrometry. It was found that chlorpyrifos oxon and other organophosphorus toxicants made covalent adducts on the ε-amino group of lysine, thus activating lysine for reaction with a nearby γ-carboxyl of glutamic or β-carboxyl of aspartic acid. A stable isopeptide bond between proteins was formed, explaining the high-molecular-weight protein multimers. We hypothesize that chemically induced, cross-linked tubulin and other proteins in the brain disrupt microtubule function leading to neurotoxicity.

Original languageEnglish (US)
Title of host publicationHandbook of Toxicology of Chemical Warfare Agents
PublisherElsevier
Pages1027-1033
Number of pages7
ISBN (Electronic)9780128190906
DOIs
StatePublished - Jan 1 2020

Keywords

  • Brady hypothesis
  • Isopeptide bonds
  • Neurotoxicity
  • Organophosphorus toxicants
  • Protein aggregation
  • Tubulin

ASJC Scopus subject areas

  • Environmental Science(all)

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