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Title page for ETD etd-12032010-001429


Type of Document Dissertation
Author Zheng, Yuxiang
URN etd-12032010-001429
Title The mechanism and physiological function of epidermal lipoxygenase-3
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Tina M. Iverson Committee Chair
Alan R. Brash Committee Member
Claus Schneider Committee Member
David L. Hachey Committee Member
F. Peter Guengerich Committee Member
Keywords
  • hydroperoxide
  • epoxyalcohol
  • skin
  • lipoxygenase
  • essential fatty acid
Date of Defense 2010-10-08
Availability unrestricted
Abstract
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.
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