Review: Organophosphorus toxicants, in addition to inhibiting acetylcholinesterase activity, make covalent adducts on multiple proteins and promote protein crosslinking into high molecular weight aggregates.

Autor: Lockridge O; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: olockrid@unmc.edu., Schopfer LM; Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: lmschopf@unmc.edu.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2023 May 01; Vol. 376, pp. 110460. Date of Electronic Publication: 2023 Mar 23.
DOI: 10.1016/j.cbi.2023.110460
Abstrakt: The acute effects of exposure to organophosphorus toxicants are explained by inhibition of acetylcholinesterase activity. However, the mechanisms that explain long term illness associated with organophosphorus exposure are still under investigation. We find that organophosphorus nerve agents and organophosphorus pesticides make covalent adducts not only on the serine from acetylcholinesterase, but also on tyrosine, lysine, glutamate, serine and threonine from a variety of proteins. Almost any protein can be modified by a high dose of organophosphorus toxicant. A low dose of 10 μM chlorpyrifos oxon added to the serum-free culture medium of human neuroblastoma SH-SY5Y cells resulted in tyrosine adducts on 48 proteins immunopurified from the cell lysate. We identified the adducted proteins by mass spectrometry after immunopurifying modified proteins with a rabbit anti-diethoxyphospho-tyrosine monoclonal antibody which biased this study for tyrosine adducts. In cultured cells, the primary organophosphate targets are abundant proteins. Organophosphate-modified proteins may disrupt physiological processes. In separate experiments we identified organophosphate adducts on lysine. Organophosphylation activates the lysine for protein crosslinking. The activated lysine reacts with glutamic acid or aspartic acid protein side chains to form an isopeptide bond between proteins, resulting in high molecular weight crosslinked proteins. Crosslinked proteins form insoluble aggregates that may lead to neurogenerative disease.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Oksana Lockridge reports financial support was provided by National Institutes of Health. Oksana Lockridge reports a relationship with National Institutes of Health that includes: funding grants.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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