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Understanding the cellular role of prolyl oligopeptidase

McQuillan, Karina 2008. Understanding the cellular role of prolyl oligopeptidase. PhD Thesis, Cardiff University.

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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.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
ISBN: 9781303184833
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:33

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