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Design and Synthesis of alpha-Bromo Phosphonates as Analogues of Glucose-6-Phosphate

  • Author / Creator
    Downey, A. Michael
  • Protein phosphorylation is a crucial component in physiological signal transduction pathways. It is estimated that one-third of all cellular proteins are modified through phosphorylation, and these pathways are regulated by kinase and phosphatase enzymes. Glucose-6-phosphatase (G6Pase) is an essential enzyme that catalyzes the last step in both glycogenolysis and gluconeogenesis by converting glucose-6-phosphate (G6P) into glucose. As a result, aberrant G6Pase signaling has been implicated in diabetes. The active site of G6Pase contains a nucleophilic histidine residue, and two arginine residues that stabilize binding through hydrogen bonding to the phosphate moiety. In this thesis we present novel synthetic methodology to install -bromophosphonate moieties on G6P analogues to test as irreversible inhibitors of G6Pase, which could serve as a valuable tool in the study of glucose metabolism. We describe our efforts towards the synthesis of a panel of phosphonate-based G6P analogues which were tested for in vitro activity against the enzyme.

  • Subjects / Keywords
  • Graduation date
    2013-06
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R30K26K8F
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Cairo, Christopher W. (Chemistry)
  • Examining committee members and their departments
    • Lowary, Todd L. (Chemistry)
    • West, Frederick G. (Chemistry)