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CHARACTERIZATION OF PROTEIN PRENYLTRANSFERASES AND PROTEIN PRENYLATION IN PLASMODIUM FALCIPARUM
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TitleCHARACTERIZATION OF PROTEIN PRENYLTRANSFERASES AND PROTEIN PRENYLATION IN PLASMODIUM FALCIPARUM
AuthorDaSilva, Thiago Gaspar
KeywordsDissertations, Academic -- Health and Public Affairs
Health and Public Affairs -- Dissertations, Academic
Farnesylation
Farnesyltransferase
Geranylgeranylation
Inhibitors
Malaria
Peptidomimetic
Prenylation
AbstractMalaria kills at least one million people each year, mostly children - a death every 30 seconds. Almost one half of the world population is at risk from malaria. Antimalarial drugs are the only means for the treatment of about 500 million annual global malaria cases. Because of prevalent drug-resistance it is extremely urgent to identify new drug targets. Many proteins involved in eukaryotic signal transduction and cell cycle progression undergo post-translational lipid modification by a prenyl group. Protein prenyltransferases, which catalyze the post-translational prenyl modification, have been established as a target for anticancer therapy. Research done in our laboratory has demonstrated recently that prenyl modification of proteins could be a novel target for the development of antimalarial drugs.The goal of this study is to understand the molecular mechanism of protein prenylation in Plasmodium. The key to use of prenyltransferase inhibitors for the pharmacological intervention is a thorough understanding of the in vivo prenylation pathways in the malaria parasite. Knowledge of the physiological functions of the cellular protein substrates of malarial prenyltransferases is an important first step in the elucidation of the mechanism of antimalarial action of inhibitors of protein prenylation. The research described in this thesis revealed the evidence for the existence of farnesylated and geranylgeranylated malaria parasite proteins. The study shows that the dynamics of protein prenylation changes with the intraerythrocytic development cycle of the parasite. We detected that prenylated proteins in the 50 kDa range were mostly farnesylated and that the proteins in the 22-25 kDa range were mostly geranylgeranylated. The prenylation of P. falciparum proteins is inhibited by prenyltransferase inhibitors. We have also demonstrated unique features of protein prenylation in P. falciparum compared to the human host such as farnesylation of proteins are sensitive to inhibition by geranylgeranyltransferase inhibitors.. In-silico search of the malarial genome sequence identified potential protein prenyltransferase substrates. One of these substrates is a SNARE protein Ykt6 homologue. The malarial Ykt6 was recombinantly expressed and subjected to an in-vitro prenylation assay. We showed that the recombinant Ykt6 was indeed a substrate for the malarial prenyltransferase.
AdviserChakrabarti, Dobopam
PublisherUniversity of Central Florida
DegreeM.S.
Degree DisciplineDepartment of Molecular Biology and Microbiology
Degree GrantorHealth and Public Affairs
Degree ProgramMolecular Biology and Microbiology
Graduation Date2004-08-01
TypeMaster's thesis
Access LevelPublic - Allow Worldwide Access
Release Date2004-08-01
RepositoryUniversity Archives
Repository CollectionElectronic Theses and Dissertations
IdentifierCFE0000100
Access Linkhttp://purl.fcla.edu/fcla/etd/CFE0000100

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