Thesis

Analysis of the regulation mechanism of LmxMPK1, a Leishmania mexicana MAP kinase homologue

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Awarding institution
  • University of Strathclyde
Date of award
  • 2012
Thesis identifier
  • T13608
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Abstract
  • Leishmaniasis is a disfiguring tropical disease, caused by various species of the protozoan parasite Leishmania. Two million new infections and 50,000 deaths occur annually. Currently 350 million people live in areas where leishmaniasis is endemic and are at risk of infection - a number that will increase with global warming. Access to treatment is inconsistent across the affected regions, moreover, the available treatments for leishmaniasis have changed little in the past century and are often toxic with resistance becoming more prevalent, thus underscoring the need for new treatment regimens. LmxMPK1 is an essential MAP kinase homologue in Leishmania mexicana.;Previous work had suggested that it might be regulated in a novel manner that differed from that of MAP kinases in higher eukaryotes. This study found evidence to support this theory, although a definitive mechanism of regulation of kinase activity was not established. A residue outside of the MAPK phosphorylation lip was shown to be essential for regulation of kinase localisation in vivo, whilst invitro results showed that it was a target for kinase autophosphorylation. The in vitro results also hinted that at least one other residue might also be subject to autophosphorylation, although to a lesser degree.;An inhibitor-sensitised system for studying LmxMPK1 was optimised, with the phenylalanine-93 to glycine mutation shown to be optimal for retaining kinase activity in the absence of inhibitor and diminishing kinase activity when the inhibitor was present. The in vivo localisation of a novel L. mexicana phosphatase homologue, LmxPTP, was studied and evidence of endoplasmic reticulum localisation was found. Work was carried out to determine the essentiality of LmxPTP by attempting to delete the gene encoding it. However, this was not achieved and whether it was due to the phosphatase being essential, chromosome aneuploidy or unsuccessful transfection of the deletion fragments was not determined.
Advisor / supervisor
  • Wiese, Martin
Resource Type
Note
  • This thesis was previously held under moratorium from 18th December 2013 to 18th December 2017
DOI
Date Created
  • 2012
Former identifier
  • 9910020933402996

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