Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.584474
Title: Understanding the cellular role of prolyl oligopeptidase
Author: McQuillan, Karina
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2008
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Abstract:
Prolyl oligopeptidase (PO, Prolyl Endopeptidase, PE, PEP) is a member of the serine protease family and shares a good structural homology with other a/p hydrolase fold enzymes. PO specifically cleaves oligopeptides after a proline residue. The PO homologue, DpoA, was identified in the cellular slime mould Dictyostelium Discoideum following a lithium screen. Loss of DpoA confers resistance to both lithium and valproic acid (VPA), through regulation of inositol phosphate pathways. The intracellular substrate and cellular role of PO remain uncertain. However, it is known to inhibit dephosphorylation of the higher order inositol phosphates IP5 and IP4 to IP3, a reaction catalysed by Multiple Inositol Polyphosphate Phosphatase (MIPP), by an unknown mechanism. In this study it has been determined that DpoA is highly similar to the mammalian enzyme. It has also been demonstrated that while some variation was observed at the sequence level there is clear homology around the active site and the catalytic triad is conserved. Enzyme activity and inhibition studies reveal similar KM and Kt values in the presence of known specific inhibitors. Thus making it a relevant model for the mammalian enzyme. Characterisation of the direct effects of three mood stabilisers on PO activity has revealed no effect of lithium, carbamazapine or valproic acid at therapeutic concentrations. However, VPA while exerting no clear effect in vivo was able to inhibit PO in vitro at increased concentrations. This inhibition was also seen using VPA analogues lacking either the carboxylic acid domain or branching structure. Significant to the elusive intracellular role for PO is the identification of a clear inhibitory effect of PO on MIPP activity in vitro. While identification of PO presence within the nucleus as well as distributed throughout the cytoplasm may also be significant to its role in inositol signalling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.584474  DOI: Not available
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