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Title page for ETD etd-11072011-164315


Type of Document Dissertation
Author Selvy, Paige Elizabeth
URN etd-11072011-164315
Title Mechanistic characterization of isoform selective inhibitors of mammalian phospholipase D
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Craig W. Lindsley Committee Chair
Ethan Lee Committee Member
H. Alex Brown Committee Member
Tina M. Iverson Committee Member
Vsevolod Gurevich Committee Member
Keywords
  • small molecule inhibitor
  • phospholipase D
  • mechanism
  • interfacial kinetics
  • enzyme kinetics
  • lipids
Date of Defense 2011-10-28
Availability unrestricted
Abstract
Increasing evidence supports an integral role for the lipid second messenger phosphatidic acid (PtdOH) in cell signaling. In addition to altering curvature of biological membranes, PtdOH lies at the intersection between metabolism and signaling pathways and is involved in cell survival as well as proliferation pathways. Phospholipase D (PLD), an evolutionarily conserved phosphodiesterase that hydrolyzes phosphatidylcholine, is involved in generating signal-mediated PtdOH molecular species. Aberrant PLD expression and activity have been implicated in metastatic cancers, neurological disorders, and microbial pathogenesis, making this enzyme a potential therapeutic target for which we recently developed potent and isoform-selective pharmacological inhibitors. Here we define the mechanism of action for these novel small molecule inhibitors. Using backscattering interferometry (BSI), a novel method for measuring protein-small molecule and protein-lipid binding, we demonstrate that these compounds directly interact with PLD to allosterically block interfacial lipid binding and catalytic activity. This unanticipated finding represents a unique mechanism of phospholipase inhibition and a new paradigm for modulation of signaling pathways.
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