The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype.

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 B4 (LTB4) formation by human leukotriene A4 hydrolase (LTA4H) ∼40% (P<0.05) to a similar extent as LTA4 (∼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 LTA4 hydrolase and to block arachidonate conversion by human 12-LOX rather than merely terminating phagocyte involvement.

• Authors: Jesmond Dalli, Min Zhu, Nikita A Vlasenko, Bin Deng, Jesper Z Haeggström, Nicos A Petasis, Charles N Serhan
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 7 Pg. 2573-83 (Jul 2013) ISSN: 1530-6860 [Electronic] United States
• PMID: 23504711 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid
• Leukotriene B4
• Docosahexaenoic Acids
• Arachidonic Acid
• Arachidonate 12-Lipoxygenase
• Epoxide Hydrolases
• leukotriene A4 hydrolase

Topics

• Arachidonate 12-Lipoxygenase (metabolism)
• Arachidonic Acid (chemistry, metabolism)
• Biocatalysis (drug effects)
• Cells, Cultured
• Docosahexaenoic Acids (chemistry, metabolism, pharmacology)
• Epoxide Hydrolases (metabolism)
• Humans
• Leukotriene B4 (biosynthesis, chemistry)
• Macrophages (drug effects, metabolism)
• Magnetic Resonance Spectroscopy
• Models, Chemical
• Molecular Structure