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Revising the structure of a new eicosanoid from human platelets to 8,9-11,12-diepoxy-13- hydroxy-eicosadienoic acid

Kornilov, Andrei, Kennedy, Paul D., Aldrovandi, MacEler, Watson, Andrew J. A., Hinz, Christine, Harless, Bryan, Colombo, Joseph, Maxey, Kirk M., Tyrrell, Victoria J., Simon, Matthew, Aggarwal, Varinder K., Boeglin, William E., Brash, Alan R., Murphy, Robert C. and O'Donnell, Valerie B. 2019. Revising the structure of a new eicosanoid from human platelets to 8,9-11,12-diepoxy-13- hydroxy-eicosadienoic acid. Journal of Biological Chemistry 10.1074/jbc.RA119.008915

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Abstract

Eicosanoids are critical mediators of fever, pain and inflammation generated by immune and tissue cells. We recently described a new bioactive eicosanoid generated by cyclooxygenase-1 (COX-1) during platelet activation that can stimulate human neutrophil integrin expression. Based on mass spectrometry (MS/MS, MS3 ), stable isotope labeling and GC/MS we proposed a structure of 8-hydroxy9,11-dioxolane eicosatetraenoic acid (DXA3). Here, we achieved enzymatic synthesis and 1HNMR characterization of this compound with results in conflict with the proposed structural assignment. Accordingly, by LC-MS we screened autoxidation reactions of 11-HpETE and thereby identified a candidate sharing the precise chromatographic and mass spectral characteristics of the platelet product. The methods were optimized to increase yield, allowing full structural analysis by 1H-NMR. The revised assignment is presented here as 8,9- 11,12-diepoxy-13-hydroxy-eicosadienoic acid, abbreviated to 8,9-11,12-DiEp-13-HEDE or DiEpHEDE, substituted for the previous name DXA3. In platelets, the lipid likely forms via dioxolane ring opening with rearrangement to the diepoxy moieties, followed by oxygen insertion at C13. The enzymatic biosynthetic pathway and MS/MS fragmentation pattern are presented, with demonstration of bioactivity using the synthetic compound. For the platelet lipid, 16 isomers are estimated based on our current knowledge, and determining the exact isomeric structure of the platelet lipid remains to be undertaken.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Date of First Compliant Deposit: 21 May 2019
Date of Acceptance: 6 May 2019
Last Modified: 12 Jun 2019 03:02
URI: http://orca.cf.ac.uk/id/eprint/122733

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