Polyhydroxy, Epoxy & Oxo Fatty Acid

Scientists have reported dozens of polyhydroxy fatty acids. Some, such as Lipoxin A4, have been thoroughly characterized structurally and have been implicated as conserved endogenous mediators. Others are of unknown absolute configuration and uncertain biological relevance.

Two representative polydydroxy fatty acids

Products in this group include the epoxides and corresponding vicinal diols derived from linoleic and arachidonic acids. These products of the cytochrome P450 system have been reported to be racemic by some authors, while others report enrichment in particular enantiomers. All of our epoxides (EpETrEs and EpOMEs) are provided as racemic mixtures.

Of these, only 5,6-EpETrE requires special handling. The proximity of the epoxide in this molecule to the C-1 carboxyl group facilitates decomposition through the formation of the ?-lactone. The free acid form of the molecule should be protected from acidic conditions and stored at -80°C. Alternatively, the methyl ester of 5,6-EpETrE may be purchased, and small quantities hydrolyzed to the free acid as needed.

The products of multiple lipoxygenation reactions include the DiHETEs, such as 5(S),12(S)-DiHETE. This molecule is not a member of the Leukotriene B4 biosynthetic pathway, although it bears hydroxyl groups at C-5 and C-12. In addition to having the opposite configuration at C-12, 5(S),12(S)-DiHETE contains a conjugated triene that is trans-cis-trans, reflecting its double-lipoxygenation origins. The lipoxins are also molecules created from polyunsaturated fatty acids by the sequential action of two lipoxygenase enzymes - in this case, it is usually 5- and 15-lipoxygen-ases. The lipoxins contain a conjugated tetraene, making them relatively unstable to oxygen, elevated temperatures and light. Suggested storage for lipoxins is therefore at -80°C in the dark in an argon-flushed vial. In general, the handling precautions given for fatty acids should be followed for all products in this group. Significant biological activity was recently reported for hydroxy fatty acids that had undergone oxidation to form conjugated dienones, or OxoETEs. We have included the oxo metabolites of 5-, 12-, and 15-HETE, as well as 9- and 13-HODE. All of these oxo metabolites are relatively unstable and should be handled with care.

Suggestions for further reading

Falgueyret, J-P., Leblanc, Y., and Riendeau, D. Stereoselective carbonyl reductases from rat skin and leukocyte microsomes converting 12-ketoeicosatetraenoic acid to 12(S)-HETE. FEBS Lett. 262, 197-200 (1990).
Muller, A., Rechencq, E., Kugel, C., et al. Comparative biological activities of the four synthetic (5,6)-diHETE isomers. Prostaglandins 38, 635-644 (1989).
Fitzpatrick, F.A. and Murphy, R.C. Cytochrome P-450 metabolism of arachidonic acid: formation and biological actions of "epoxygenase"-derived eicosanoids. Pharmacol. Rev. 40, 229-241 (1989).

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