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J. Biol. Chem., Vol. 278, Issue 13, 11190-11196, March 28, 2003
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From the Division of Cell Biology, Department of Pediatrics,
National Jewish Medical and Research Center,
Denver, Colorado 80206
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE)
is a metabolite of arachidonic acid shown to possess important
biological activities within different cell types. In the neutrophil, a
specific NADP+-dependent dehydrogenase
utilizes 5-lipoxygenase-derived 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5(S)-HETE) as the required substrate. In the present
study, 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HpETE), rather than 5-HETE, was found to be the biosynthetic precursor of 5-oxo-ETE in
the murine macrophage. The macrophage was not able to convert 5-HETE
into 5-oxo-ETE even when preincubated with phorbol ester or with other
lipid hydroperoxides. The factor responsible for the conversion of
5-HpETE into 5-oxo-ETE was found predominantly in the cytosolic
fraction of the macrophage, with an approximate molecular weight of
50,000-60,000, as assessed by size exclusion chromatography.
Formation of 5-oxo-ETE was rapid and the catalytic protein was found to
have an apparent Km of 5.3 µM for the
eicosanoid. Furthermore, the protein could efficiently utilize 5(R,S)-HpETE as substrate and was heat and
protease labile. This novel pathway of 5-oxo-ETE biosynthesis in the
murine macrophage was consistent with reduction of a 5-hydroperoxy
group to an intermediate alkoxy radical that could be subsequently
oxidized to the 5-oxo product. Such a mechanism would enable racemic
5-HpETE, derived from free radical oxidation of arachidonic acid, to be
efficiently converted into this potent chemotactic eicosanoid.
Biosynthesis of 5-Oxo-6,8,11,14-eicosatetraenoic Acid from
5-Hydroperoxyeicosatetraenoic Acid in the Murine Macrophage*
*
This work was supported in part by National Institutes of
Health Grant HL36577.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 303-398-1849;
Fax: 303-398-1694; E-mail: murphyr@njc.org.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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