[HTML][HTML] The novel 13S, 14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts …

J Dalli, M Zhu, NA Vlasenko, B Deng… - The FASEB …, 2013 - ncbi.nlm.nih.gov
J Dalli, M Zhu, NA Vlasenko, B Deng, JZ Haeggström, NA Petasis, CN Serhan
The FASEB Journal, 2013ncbi.nlm.nih.gov
Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert
potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7R, 14S-dihydroxy-
docosa-4Z, 8E, 10E, 12Z, 16Z, 19Z-hexaenoic acid) is the first identified maresin. Here, we
investigate formation, stereochemistry, and precursor role of 13, 14-epoxy-docosahexaenoic
acid, an intermediate in MaR1 biosynthesis. The 14-lipoxygenation of DHA by human
macrophage 12-lipoxygenase (hm12-LOX) gave 14-hydro (peroxy)-docosahexaenoic acid …
Abstract
Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7R, 14S-dihydroxy-docosa-4Z, 8E, 10E, 12Z, 16Z, 19Z-hexaenoic acid) is the first identified maresin. Here, we investigate formation, stereochemistry, and precursor role of 13, 14-epoxy-docosahexaenoic acid, an intermediate in MaR1 biosynthesis. The 14-lipoxygenation of DHA by human macrophage 12-lipoxygenase (hm12-LOX) gave 14-hydro (peroxy)-docosahexaenoic acid (14-HpDHA), as well as several dihydroxy-docosahexaenoic acids, implicating an epoxide intermediate formation by this enzyme. Using a stereo-controlled synthesis, enantiomerically pure 13S, 14S-epoxy-docosa-4Z, 7Z, 9E, 11E, 16Z, 19Z-hexaenoic acid (13S, 14S-epoxy-DHA) was prepared, and its stereochemistry was confirmed by NMR spectroscopy. When this 13S, 14S-epoxide was incubated with human macrophages, it was converted to MaR1. The synthetic 13S, 14S-epoxide inhibited leukotriene B 4 (LTB 4) formation by human leukotriene A 4 hydrolase (LTA 4 H)∼ 40%(P< 0.05) to a similar extent as LTA 4 (∼ 50%, P< 0.05) but was not converted to MaR1 by this enzyme. 13S, 14S-epoxy-DHA also reduced (∼ 60%; P< 0.05) arachidonic acid conversion by hm12-LOX and promoted conversion of M1 macrophages to M2 phenotype, which produced more MaR1 from the epoxide than M1. Together, these findings establish the biosynthesis of the 13S, 14S-epoxide, its absolute stereochemistry, its precursor role in MaR1 biosynthesis, and its own intrinsic bioactivity. Given its actions and role in MaR1 biosynthesis, this epoxide is now termed 13, 14-epoxy-maresin (13, 14-eMaR) and exhibits new mechanisms in resolution of inflammation in its ability to inhibit proinflammatory mediator production by LTA 4 hydrolase and to block arachidonate conversion by human 12-LOX rather than merely terminating phagocyte involvement.—Dalli, J., Zhu, M., Vlasenko, NA, Deng, B., Haeggström, JZ, Petasis, NA, Serhan, CN The novel 13S, 14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A 4 hydrolase (LTA 4 H) and shifts macrophage phenotype.
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