UBC Theses and Dissertations
Inhibition studies of the tubulin detyrosination/tyrosination cycle Griffith, Jennifer Kristine
Microtubules are a highly dynamic component of the cytoskeleton, which are crucial for many cellular processes. Microtubules are comprised of α/β-tubulin heterodimers, which are subject to multiple post-translational modifications including the detyrosination/tyrosination cycle. This cycle involves the removal of an RNA-encoded C-terminal α-tubulin tyrosine residue by tubulin carboxypeptidase, followed by the reattachment of the tyrosine residue by tubulin tyrosine ligase. This research project is focused on the development of an inhibitor against tubulin tyrosine ligase and tubulin carboxypeptidase. The precise function of this cycle has yet to be determined; an inhibitor could function as a chemical biology tool that could be used to study the physiological effects of the detyrosination/tyrosination cycle. This thesis details the design and synthesis of phosphinic acid and phosphonic acid peptide analogue inhibitors. Progress towards the synthesis of a dipeptide phosphinic acid is reported; due to complications in phosphorus-carbon bond forming reactions the total synthesis was not completed. The focus of the research project changed to the synthesis of phosphonic acid peptide analogue inhibitors. A dipeptide phosphonic acid inhibitor was successfully synthesized, but was inactive against tubulin tyrosine ligase. Progress towards the synthesis of a tripeptide phosphonic acid inhibitor is reported; due to complications in the final deprotection steps the total synthesis was not completed. A pentapeptide phosphonic acid inhibitor was successfully synthesized, and it showed moderate inhibitor activity against tubulin tyrosine ligase.
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