| The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase. | |
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MedLine Citation:
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PMID: 12881489 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Zheyong Yu; Claus Schneider; William E Boeglin; Lawrence J Marnett; Alan R Brash |
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Publication Detail:
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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:
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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:
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Created Date: 2003-08-06 Completed Date: 2003-10-03 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 9162-7 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Catalysis Cell Differentiation Chromatography, High Pressure Liquid Circular Dichroism DNA, Complementary / metabolism Dose-Response Relationship, Drug Gas Chromatography-Mass Spectrometry Humans Hydrogen Peroxide / metabolism* Intramolecular Oxidoreductases / chemistry*, genetics*, physiology* Keratinocytes / metabolism Kinetics Lipoxygenase / chemistry* Magnetic Resonance Spectroscopy Mass Spectrometry Models, Chemical Mutation Nordihydroguaiaretic Acid / chemistry Oxidation-Reduction Signal Transduction Skin / cytology, enzymology* |
| Grant Support | |
ID/Acronym/Agency:
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AR-41943/AR/NIAMS NIH HHS; AR-45943/AR/NIAMS NIH HHS; CA-89450/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA, Complementary; 500-38-9/Nordihydroguaiaretic Acid; 7722-84-1/Hydrogen Peroxide; EC 1.13.11.12/Lipoxygenase; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.6/hydroperoxide isomerase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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