Document Detail

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase.
MedLine Citation:
PMID:  12881489     Owner:  NLM     Status:  MEDLINE    
Lipoxygenase (LOX) enzymes form fatty acid hydroperoxides used in membrane remodeling and cell signaling. Mammalian epidermal LOX type 3 (eLOX3) is distinctive in totally lacking this typical oxygenase activity. Surprisingly, genetic evidence has linked mutations in eLOX3 or a colocalizing enzyme, 12R-LOX, to disruption of the normal permeability barrier of the skin [Jobard, F., Lefèvre, C., Karaduman, A., Blanchet-Bardon, C., Emre, S., Weissenbach, J., Ozgüc, M., Lathrop, M., Prud'homme, J. F. & Fischer, J. (2002) Hum. Mol. Genet. 11, 107-113]. Herein we identify a logical link of the biochemistry to the genetics. eLOX3 functions as a hydroperoxide isomerase (epoxyalcohol synthase) by using the product of 12R-LOX as the preferred substrate. 12R-Hydroperoxyeicosatetraenoic acid (12R-HPETE) is converted to 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, one of the isomers of hepoxilin A3, and to 12-ketoeicosatetraenoic acid in a 2:1 ratio. Other hydroperoxides, including 8R-HPETE, 12S-HPETE, and 15S-HPETE, as well as the 13S- and 13R-hydroperoxides of linoleic acid are converted less efficiently. Mass spectrometric analysis of the epoxyalcohol formed from [18O]15S-HPETE showed that both hydroperoxy oxygens are retained in the product. We propose that the ferrous form of eLOX3 initiates a redox cycle, unprecedented among LOX in being autocatalytic, in which the hydroperoxy substrate is isomerized to the epoxyalcohol or keto product. Our results provide strong biochemical evidence for a functional linkage of 12R-LOX and eLOX3 and clues into skin biochemistry and the etiology of ichthyosiform diseases in humans.
Zheyong Yu; Claus Schneider; William E Boeglin; Lawrence J Marnett; Alan R Brash
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-07-24
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  100     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-06     Completed Date:  2003-10-03     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9162-7     Citation Subset:  IM    
Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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MeSH Terms
Cell Differentiation
Chromatography, High Pressure Liquid
Circular Dichroism
DNA, Complementary / metabolism
Dose-Response Relationship, Drug
Gas Chromatography-Mass Spectrometry
Hydrogen Peroxide / metabolism*
Intramolecular Oxidoreductases / chemistry*,  genetics*,  physiology*
Keratinocytes / metabolism
Lipoxygenase / chemistry*
Magnetic Resonance Spectroscopy
Mass Spectrometry
Models, Chemical
Nordihydroguaiaretic Acid / chemistry
Signal Transduction
Skin / cytology,  enzymology*
Grant Support
Reg. No./Substance:
0/DNA, Complementary; 500-38-9/Nordihydroguaiaretic Acid; 7722-84-1/Hydrogen Peroxide; EC; EC 5.3.-/Intramolecular Oxidoreductases; EC isomerase

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