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Title page for ETD etd-08232013-110456


Type of Document Dissertation
Author Jin, Jing
Author's Email Address jing.jin@vanderbilt.edu
URN etd-08232013-110456
Title Biosynthetic Mechanisms of LTA-type Epoxides and Novel Bioactive Lipid Mediators
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Claus Schneider Committee Chair
Alan R. Brash Committee Member
David L. Hachey Committee Member
Ned A. Porter Committee Member
Sean S. Davies Committee Member
Keywords
  • leukotriene
  • lipoxygenase
Date of Defense 2013-08-09
Availability unrestricted
Abstract
Biosynthesis of lipid mediators including the leukotrienes, lipoxins, eoxins, resolvins, and protectins entails the lipoxygenase (LOX) catalyzed synthesis of an allylic epoxide intermediate, designated as leukotriene A4 (LTA4) and LTA analogues, and heretofore considered too unstable for direct structural characterization. In this dissertation I developed methods involving biphasic reaction conditions for the LOX-catalyzed synthesis of LTA epoxides and their structural analysis by NMR. As proof of concept, human 15-LOX-1 was shown to convert 15S-hydroperoxyeicosatetraenoic acid (15S-HPETE) to the LTA analogue, 14,15-LTA4 (thus identifying eoxin A4). Using this methodology I then showed that recombinant Arabidopsis AtLOX1, an arachidonate 5-LOX, converts 5S-HPETE to the trans epoxide LTA4, and 5R-HPETE to the cis epoxide 5-epi-LTA4. The results are reconciled with a mechanism based on a dual role of the LOX non-heme iron in LTA epoxide biosynthesis. The same methodology was used to structurally characterize the LTA-related epoxides from omega-3 fatty acids, including identification of the proposed epoxide intermediate in protectin biosynthesis.
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