The goal of my thesis research is to elucidate the catalytic mechanism and physiological function of the atypical mammalian lipoxygenase, epidermal lipoxygenase-3. Although named as a lipoxygenase based on sequence homology to other lipoxygenases, epidermal lipoxygenase-3 appears to be devoid of dioxygenase activity with natural polyunsaturated fatty acids and shows instead a prominent hydroperoxide isomerase activity with fatty acid hydroperoxides. Epidermal lipoxygenase-3, together with 12R-lipoxygenase, is implicated through genetics in skin barrier formation, yet the mechanism of action of these two lipoxygenases in the physiological setting is poorly understood. During my research I uncovered dioxygenase activity in epidermal lipoxygenase-3, elucidated its mechanism, and developed a novel model to explain the in vivo action of epidermal lipoxygenase-3 and 12R-lipoxygenase. The mechanistic study of eLOX3 led to a better understanding of the catalysis of epidermal lipoxygenase-3 and lipoxygenases in general, particularly regarding how lipoxygenase is activated by fatty acid hydroperoxides and the role of active site O2 in this activation process. The study on the physiological function of epidermal lipoxygenase-3 led to elucidation of a novel biochemical pathway whereby 12R-lipoxygenase and epidermal lipoxygenase-3 mediate at least part of the long-known and not well-understood effect of essential fatty acids on skin health by oxygenating linoleate-enriched ceramides and allowing subsequent hydrolysis and covalent coupling of the ceramides to proteins, thus providing an explanation for the skin barrier defects exhibited when the gene encoding either epidermal lipoxygenase-3 or 12R-lipoxygenase is deleted, or when essential fatty acids are excluded from the diet.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12032010-001429 |
| Date | 10 December 2010 |
| Creators | Zheng, Yuxiang |
| Contributors | Alan R. Brash, Tina M. Iverson, F. Peter Guengerich, David L. Hachey, Claus Schneider |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-12032010-001429/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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