Primary saturation of α, β-unsaturated carbonyl containing fatty acids does not abolish electrophilicity.

Autor: Snyder NW; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA., O'Brien J; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA., Singh B; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA., Buchan G; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA., Arroyo AD; Department of Systems Pharmacology and Translational Therapeutics, Center for Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Liu X; Department of Molecular and Structural Biochemistry, NC State University, Raleigh, NC, 27695, USA., Bostwick A; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA., Varner EL; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA., Angajala A; Department of Pharmacology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36688, USA., Sobol RW; Department of Pharmacology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36688, USA., Blair IA; Department of Systems Pharmacology and Translational Therapeutics, Center for Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Mesaros C; Department of Systems Pharmacology and Translational Therapeutics, Center for Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Wendell SG; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA. Electronic address: gstacy@pitt.edu.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2021 Dec 01; Vol. 350, pp. 109689. Date of Electronic Publication: 2021 Oct 08.
DOI: 10.1016/j.cbi.2021.109689
Abstrakt: Metabolism of polyunsaturated fatty acids results in the formation of hydroxylated fatty acids that can be further oxidized by dehydrogenases, often resulting in the formation of electrophilic, α,β-unsaturated ketone containing fatty acids. As electrophiles are associated with redox signaling, we sought to investigate the metabolism of the oxo-fatty acid products in relation to their double bond architecture. Using an untargeted liquid chromatography mass spectrometry approach, we identified mono- and di-saturated products of the arachidonic acid-derived 11-oxoeicosatetraenoic acid (11-oxoETE) and mono-saturated metabolites of 15-oxoETE and docosahexaenoic acid-derived 17-oxodocosahexaenoinc acid (17-oxoDHA) in both human A549 lung carcinoma and umbilical vein endothelial cells. Notably, mono-saturated oxo-fatty acids maintained their electrophilicity as determined by nucleophilic conjugation to glutathione while a second saturation of 11-oxoETE resulted in a loss of electrophilicity. These results would suggest that prostaglandin reductase 1 (PTGR1), known only for its reduction of the α,β-unsaturated double bond, was not responsible for the saturation of oxo-fatty acids at alternative double bonds. Surprisingly, knockdown of PTGR1 expression by shRNA confirmed its participation in the formation of 15-oxoETE and 17-oxoDHA mono-saturated metabolites. Furthermore, overexpression of PTGR1 in A549 cells increased the rate and total amount of oxo-fatty acid saturation. These findings will further facilitate the study of electrophilic fatty acid metabolism and signaling in the context of inflammatory diseases and cancer where they have been shown to have anti-inflammatory and anti-proliferative signaling properties.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: