Human lipoxygenase isoforms form complex patterns of double and triple oxygenated compounds from eicosapentaenoic acid

Item Type:	Article
Title:	Human lipoxygenase isoforms form complex patterns of double and triple oxygenated compounds from eicosapentaenoic acid
Creators Name:	Kutzner, L. and Goloshchapova, K. and Rund, K.M. and Jübermann, M. and Blum, M. and Rothe, M. and Kirsch, S.F. and Schunck, W.H. and Kühn, H. and Schebb, N.H.
Abstract:	Lipoxygenases (ALOX) are lipid peroxidizing enzymes that catalyze the biosynthesis of pro- and anti-inflammatory lipid mediators and have been implicated in (patho-)physiological processes. In humans, six functional ALOX isoforms exist and their arachidonic acid oxygenation products have been characterized. Products include leukotrienes and lipoxins which are involved in the regulation of inflammation and resolution. Oxygenation of n3-polyunsaturated fatty acids gives rise to specialized pro-resolving mediators, e.g. resolvins. However, the catalytic activity of different ALOX isoforms can lead to a multitude of potentially bioactive products. Here, we characterized the patterns of oxygenation products formed by human recombinant ALOX5, ALOX15, ALOX15B and ALOX12 from eicosapentaenoic acid (EPA) and its 18-hydroxy derivative 18-HEPE with particular emphasis on double and triple oxygenation products. ALOX15 and ALOX5 formed a complex mixture of various double oxygenation products from EPA, which include 5,15-diHEPE and various 8,15-diHEPE isomers. Their biosynthetic mechanisms were explored using heavy oxygen isotopes (H(2)(18)O, (18)O(2) gas) and three catalytic activities contributed to product formation: i) fatty acid oxygenase activity, ii) leukotriene synthase activity, iii) lipohydroperoxidase activity. For ALOX15B and ALOX12 more specific product patterns were identified, which was also the case when these enzymes reacted in concert with ALOX5. Several double oxygenated compounds were formed from 18-HEPE by ALOX5, ALOX15B and ALOX12 including previously identified resolvins (RvE2, RvE3), while formation of triple oxygenation products, e.g. 5,17,18-triHEPE, required ALOX5. Taken together our data show that EPA can be converted by human ALOX isoforms to a large number of secondary oxygenation products, which might exhibit bioactivity.
Keywords:	Eicosanoids, Oxylipins, Reaction Specificity, Catalytic Activity, Leukotrienes, Specialized Pro-Resolving Mediators
Source:	Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
ISSN:	1388-1981
Publisher:	Elsevier
Volume:	1865
Number:	12
Page Range:	158806
Date:	December 2020
Official Publication:	https://doi.org/10.1016/j.bbalip.2020.158806
PubMed:	View item in PubMed

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