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Title: Chlorpyrifos oxon activates glutamate and lysine for protein cross-linking
Author: Muñoz-Torrero López-Ibarra, Diego
Schopfer, Lawrence M.
Lockridge, Oksana
Keywords: Malalties neurodegeneratives
Àcids nucleics
Neurodegenerative Diseases
Nucleic acids
Issue Date: 2023
Publisher: American Chemical Society
Abstract: Chronic low-dose exposure to organophosphorus (OP) toxicants is correlated with an increase in the risk of impaired cognition and neurodegenerative diseases. A mechanism to explain this relationship is needed. We suggest that the formation of organophosphate-induced high-molecular-weight protein aggregates that disrupt cell function may be the missing link. It has been demonstrated that such aggregation can be promoted by OP-labeled lysine. Alternatively, OP-labeled glutamate may be the initiator. To test this hypothesis, we treated MAP-rich tubulin Sus scrofa and human transglutaminase with chlorpyrifos oxon. Trypsin-digested proteins were subjected to liquid chromatography−tandem mass spectrometry followed by Protein Prospector searches to identify diethyl phosphate adducts and cross-linked peptides. We report the presence of diethyl phosphate adducts on the side chains of glutamate, lysine, and tyrosine, as well as cross-links between glutamate and lysine. Glutamate-lysine cross-linking could be initiated either by diethyl phosphate-activated glutamate or by diethyl phosphate-activated lysine to form stable isopeptide bonds between and within proteins. It was concluded that organophosphate-induced high-molecular-weight protein aggregates could promote brain dysfunction.
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It is part of: Chemical Research in Toxicology, 2023, vol. 36, num. 1, p. 112-121
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ISSN: 0893-228X
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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