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Regulation of kinases by synthetic imidazoles, nucleotides and their deuterated analogues

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dc.contributor.advisor Myer, M. S.
dc.contributor.advisor Kenyon, C.
dc.contributor.advisor Van der Westhuyzen, C. Nkosi, Thokozani Clement 2016-04-19T09:39:26Z 2016-04-19T09:39:26Z 2015-02 2016-04-19
dc.identifier.citation Nkosi, Thokozani Clement (2015) Regulation of kinases by synthetic imidazoles, nucleotides and their deuterated analogues, University of South Africa, Pretoria, <> en
dc.description.abstract Deuteration is the replacement of a hydrogen atom by deuterium atom in a molecule. The replacement begins at the most acidic hydrogen in the molecule. In ATP, the deshielded hydrogen is C8-H which is the first replaced during deuteration. During ATP deuteration some of the ATP is hydrolysed to ADP concurrently. Using kinetic analysis, it was confirmed that the ATP hydrolysis that occurs is 1st order in ATP concentration, while the hydrogen replacement is 2nd order. The ATP and its C8 deuterated analogue were tested against three enzymes shikimate kinase (SK), acetate kinase (AK) and glutamine synthetase (GS) to determine if a kinetic isotope effect (KIE) exists in these systems. With AK and GS, the KIED increased as the KIEH decreased, while with SK the KIED decreased as the KIEH increased as the concentration of the ATP or deuterated analogue increased. Deuteration of imidazole and purine compounds reduced the specific activity of AK or SK at low concentrations in an enzyme-catalysed reaction. From a library of imidazole-containing compounds that inhibited SK, three compounds were selected and their IC50 values were determined on the SK-catalysed reaction. These compounds show a differential potency and efficiency between their protonated and deuterated analogues when compared in a 1:1 mixture. Synthesized purines incorporating three different substituents at N-9 were tested against AK or SK for their ability to lower the specific activity of the enzymes used en
dc.format.extent 1 online resource (147 leaves) : illustrations
dc.language.iso en en
dc.subject Acetate kinase en
dc.subject Glutamine synthetase en
dc.subject Shikimate kinase en
dc.subject Adenosine triphosphate rate order en
dc.subject Proton nuclear magnetic resonance en
dc.subject Enzyme activity and kinetics en
dc.subject Imidazole and purine deuteration en
dc.subject.ddc 572.744
dc.subject.lcsh Deuterium
dc.subject.lcsh Acetates
dc.subject.lcsh Glutamine synthetase
dc.subject.lcsh Adenosine triphosphate
dc.subject.lcsh Proton magnetic resonance
dc.subject.lcsh Enzyme activation
dc.subject.lcsh Enzyme kinetics
dc.title Regulation of kinases by synthetic imidazoles, nucleotides and their deuterated analogues en
dc.type Dissertation en
dc.description.department Physics en M. Sc. (Physics)

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