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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M900025-JLR200 on March 16, 2009 Originally published In Press as doi:10.1194/jlr.M900025-JLR200 on February 24, 2009

Papers In Press, published online ahead of print July 1, 2009
J. Lipid Res., doi:10.1194/jlr.M900025-JLR200
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Journal of Lipid Research, Vol. 50, 1448-1455, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Biosynthesis of a linoleic acid allylic epoxide: mechanistic comparison with its chemical synthesis and leukotriene A biosynthesisboxs

Katrin Niisuke2,*, William E. Boeglin2,*, John J. Murray*,{dagger},§, Claus Schneider*,** and Alan R. Brash1,*,**

* Department of Pharmacology, Vanderbilt University, Nashville, TN 37232
{dagger} Department of Medicine, Vanderbilt University, Nashville, TN 37232
** Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232
§ Meharry Medical College, Nashville, TN 37208
2 K. Niisuke and W. E. Boeglin contributed equally to this work.

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data.

This work was supported by National Institutes of Health Grant GM-74888.

Published, JLR Papers in Press, March 16, 2009.

1 To whom correspondence should be addressed. e-mail: alan.brash{at}vanderbilt.edu

Biosynthesis of the leukotriene A (LTA) class of epoxide is a lipoxygenase-catalyzed transformation requiring a fatty acid hydroperoxide substrate containing at least three double bonds. Here, we report on biosynthesis of a dienoic analog of LTA epoxides via a different enzymatic mechanism. Beginning with homolytic cleavage of the hydroperoxide moiety, a catalase/peroxidase-related hemoprotein from Anabaena PCC 7120, which occurs in a fusion protein with a linoleic acid 9R-lipoxygenase, dehydrates 9R-hydroperoxylinoleate to a highly unstable epoxide. Using methods we developed for isolating extremely labile compounds, we prepared and purified the epoxide and characterized its structure as 9R,10R-epoxy-octadeca-11E,13E-dienoate. This epoxide hydrolyzes to stable 9,14-diols that were reported before in linoleate autoxidation (Hamberg, M. 1983. Autoxidation of linoleic acid: Isolation and structure of four dihydroxy octadecadienoic acids. Biochim. Biophys. Acta 752: 353–356) and in incubations with the Anabaena enzyme (Lang, I., C. Göbel, A. Porzel, I. Heilmann, and I. Feussner. 2008. A lipoxygenase with linoleate diol synthase activity from Nostoc sp. PCC 7120. Biochem. J. 410: 347–357). We also prepared an equivalent epoxide from 13S-hydroperoxylinoleate using a "biomimetic" chemical method originally described for LTA4 synthesis and showed that like LTA4, the C18.2 epoxide conjugates readily with glutathione, a potential metabolic fate in vivo. We compare and contrast the mechanisms of LTA-type allylic epoxide synthesis by lipoxygenase, catalase/peroxidase, and chemical transformations. These findings provide new insights into the reactions of linoleic acid hydroperoxides and extend the known range of catalytic activities of catalase-related hemoproteins.

Supplementary key words lipoxygenase • biomimetic synthesis • Anabaena • cyanobacterium • catalase • peroxidase • hemoprotein • 1H-nuclear magnetic resonance • gas liquid chromatography-mass spectrometry

Abbreviations: H(P)ETE, hydro(pero)xyeicosatetraenoic acid; H(P)ODE, hydro(pero)xyoctadecadienoic acid; LT, leukotriene; LOX, lipoxygenase; RP-HPLC, reversed-phase high-pressure liquid chromatography; SP-HPLC, straight-phase high-pressure liquid chromatography


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