15-Lipoxygenase metabolism of 2-arachidonylglycerol: Generation of a peroxisome proliferator-activated receptor α agonist

Kevin R. Kozak, Rajnish A. Gupta, John S. Moody, Chuan Ji, William E. Boeglin, Raymond N. Dubois, Alan R. Brash, Lawrence J. Marnett

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

The recent demonstrations that cyclooxygenase-2 and leukocyte-type 12-lipoxygenase (LOX) efficiently oxygenate 2-arachidonylglycerol (2-AG) prompted an investigation into related oxygenases capable of metabolizing this endogenous cannabinoid receptor ligand. We evaluated the ability of six LOXs to catalyze the hydroperoxidation of 2-AG. Soybean 15-LOX, rabbit reticulocyte 15-LOX, human 15-LOX-1, and human 15-LOX-2 oxygenate 2-AG, providing 15(S)-hydroperoxyeicosatetraenoic acid glyceryl ester. In contrast, potato and human 5-LOXs do not efficiently metabolize this endocannabinoid. Among a series of structurally related arachidonyl esters, arachidonylglycerols serve as the preferred substrates for 15-LOXs. Steady-state kinetic analysis demonstrates that both 15-LOX-1 and 15-LOX-2 oxygenate 2-AG comparably or preferably to arachidonic acid. Furthermore, 2-AG treatment of COS-7 cells transiently transfected with human 15-LOX expression vectors or normal human epidermal keratinocytes results in the production and extracellular release of 15-hydroxyeico-satetraenoic acid glyceryl ester (15-HETE-G), establishing that lipoxygenase metabolism of 2-AG occurs in an eukaryotic cellular environment. Investigations into the potential biological actions of 15-HETE-G indicate that this lipid, in contrast to its free-acid counterpart, acts as a peroxisome proliferator-activated receptor α agonist. The results demonstrate that 15-LOXs are capable of acting on 2-AG to provide 15-HETE-G and elucidate a potential role for endocannabinoid oxygenation in the generation of peroxisome proliferator-activated receptor α agonists.

Original languageEnglish (US)
Pages (from-to)23278-23286
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number26
DOIs
StatePublished - Jun 28 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kozak, K. R., Gupta, R. A., Moody, J. S., Ji, C., Boeglin, W. E., Dubois, R. N., Brash, A. R., & Marnett, L. J. (2002). 15-Lipoxygenase metabolism of 2-arachidonylglycerol: Generation of a peroxisome proliferator-activated receptor α agonist. Journal of Biological Chemistry, 277(26), 23278-23286. https://doi.org/10.1074/jbc.M201084200