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Homotrimeric dUTPases: Principles of Catalysis and Inhibitor Design
University of Kalmar, School of Pure and Applied Natural Sciences. (Biochemistry)
2009 (English)Doctoral thesis, monograph (Other academic)
Abstract [en]

The ubiquitous enzyme dUTPase hydrolyzes dUTP into dUMP and pyrophosphate, preventing DNA fragmentation and cell death due to accumulation of dUTP. Inhibitors of dUTPase could serve as drugs in the treatment of cancers and infectious diseases. This thesis presents five studies. A mutational study on the Escherichia coli dUTPase (S72A) provides new insights about the catalytic principles of the homotrimeric dUTPases. A model is presented in which transition state formation is associated with a rotation of the conserved Ser72 side chain. The model can explain the strict order of deamination and hydrolysis catalyzed by the bifunctional dCTP deaminase:dUTPases. The S72A/D90N double mutant is currently investigated. Preliminary data indicate that this form preserves the binding properties of the S72A mutant but is completely inactive, making it attractive for structural studies. In the remaining studies we compare the binding of substrate analogues to the human, the E. coli and the equine infectious anemia virus (EIAV) homotrimeric dUTPases. One study concerns 2´,3´-dideoxy-UTP (ddUTP) and shows that removal of the 3´-hydroxyl group increases KM, ten times with the cellular dUTPases and fifty times with the viral dUTPase, but does not affect kcat with any of these enzymes. Another study concerns the inhibitory effects of 3´-azido-2´,3´-dideoxy-UTP. This derivative binds to the bacterial dUTPase but not to the other forms making it a potential lead for the development of antibacterial dUTPase inhibitors. Yet another study investigates two uracil derivatives. Both compounds are found to inhibit the human, the bacterial but not the viral dUTPase. The inhibition is shown to be competitive.

Place, publisher, year, edition, pages
Kalmar: Högskolans trykeri i Kalmar , 2009. , p. 145
Series
Dissertation series / University of Kalmar, Faculty of Natural Science, ISSN 1650-2779 ; 64
Keywords [en]
dUTPases, kinetics, ground state destabilization, inhibitors
National Category
Biochemistry and Molecular Biology
Research subject
Natural Science
Identifiers
URN: urn:nbn:se:lnu:diva-6119ISBN: 978-91-85993-19-2 (print)OAI: oai:DiVA.org:lnu-6119DiVA, id: diva2:324134
Public defence
2009-02-27, 10:00 (English)
Opponent
Supervisors
Available from: 2010-07-19 Created: 2010-06-14 Last updated: 2010-07-19Bibliographically approved

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Gonzalez Palmén, Lorena
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CiteExportLink to record
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Citation style
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