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Permanent link (DOI): https://doi.org/10.7939/R30K26K8F

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

Descriptions

Other title
Subject/Keyword
Phosphonate
Glucose-6-phoshatase
Phosphate
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Downey, A. Michael
Supervisor and department
Cairo, Christopher W. (Chemistry)
Examining committee member and department
Lowary, Todd L. (Chemistry)
West, Frederick G. (Chemistry)
Department
Department of Chemistry
Specialization

Date accepted
2012-10-24T14:16:23Z
Graduation date
2013-06
Degree
Master of Science
Degree level
Master's
Abstract
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.
Language
English
DOI
doi:10.7939/R30K26K8F
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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