Alan Brash
Last active: 3/22/2018

Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: a potential P450 and lipoxygenase interaction.

Teder T, Boeglin WE, Brash AR
J Lipid Res. 2014 55 (12): 2587-96

PMID: 25293588 · PMCID: PMC4242451 · DOI:10.1194/jlr.M054072

Herein, we characterize a generally applicable transformation of fatty acid epoxides by lipoxygenase (LOX) enzymes that results in the formation of a five-membered endoperoxide ring in the end product. We demonstrated this transformation using soybean LOX-1 in the metabolism of 15,16-epoxy-α-linolenic acid, and murine platelet-type 12-LOX and human 15-LOX-1 in the metabolism of 14,15-epoxyeicosatrienoic acid (14,15-EET). A detailed examination of the transformation of the two enantiomers of 15,16-epoxy-α-linolenic acid by soybean LOX-1 revealed that the expected primary product, a 13S-hydroperoxy-15,16-epoxide, underwent a nonenzymatic transformation in buffer into a new derivative that was purified by HPLC and identified by UV, LC-MS, and ¹H-NMR as a 13,15-endoperoxy-16-hydroxy-octadeca-9,11-dienoic acid. The configuration of the endoperoxide (cis or trans side chains) depended on the steric relationship of the new hydroperoxy moiety to the enantiomeric configuration of the fatty acid epoxide. The reaction mechanism involves intramolecular nucleophilic substitution (SNi) between the hydroperoxy (nucleophile) and epoxy group (electrophile). Equivalent transformations were documented in metabolism of the enantiomers of 14,15-EET by the two mammalian LOX enzymes, 15-LOX-1 and platelet-type 12-LOX. We conclude that this type of transformation could occur naturally with the co-occurrence of LOX and cytochrome P450 or peroxygenase enzymes, and it could also contribute to the complexity of products formed in the autoxidation reactions of polyunsaturated fatty acids.

Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (23)

8,11,14-Eicosatrienoic Acid Animals Arachidonate 12-Lipoxygenase Arachidonate 15-Lipoxygenase Biocatalysis Blood Platelets Chromatography, High Pressure Liquid Eicosanoids Epoxy Compounds Gas Chromatography-Mass Spectrometry Humans Hydroxylation Linolenic Acids Lipid Peroxides Lipoxygenase Mice Molecular Structure Nuclear Magnetic Resonance, Biomolecular Oxidation-Reduction Recombinant Proteins Soybean Proteins Spectrometry, Mass, Electrospray Ionization Stereoisomerism

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