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dc.contributor.advisorGates, Kent S. (Kent Stephen), 1962-eng
dc.contributor.authorPunthasee, Puminaneng
dc.date.issued2016eng
dc.date.submitted2016 Springeng
dc.descriptionAbstract from short.pdf file.eng
dc.descriptionDissertation supervisor: Dr. Kent Gates.eng
dc.descriptionIncludes vita.eng
dc.description.abstractThe phosphorylation of a tyrosine substrate is one of the most crucial reactions that regulate numerous biological processes. The phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Malfunctions of either class of enzymes resulted in pathological diseases. Despite an equal importance of both classes of enzymes, the development of PTK inhibitors is advanced, while that of PTPs is lagging. Therefore, we provide a mini-review of inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme in PTP superfamily, aiming to gain an attention to the development of PTP inhibitors. PTP1B is a PTP that has been fully characterized and proved as a drug target for type 2 diabetes and obesity treatment. In the past few decades, the development of effective PTP1B inhibitors by pharmaceutical industries has been unsuccessful and remained challenging due to the difficulty in balancing drug properties, i.e. potency, selectivity, and cell permeability of the inhibitors. In this dissertation, we present a novel strategy called "exo-affinity-labeling" to modulate PTP1B activity. The exo-affinity labeling agent covalently inhibits PTP1B in a unique way and this, so called, inactivator might be able to provide the desired drug properties. We report a series of inhibitors of PTP1B. A short-linker TDZ 8a and long-linker TDZs 11a, and 11b exhibit time- and concentration-dependent loss of PTP1B activity. Mass spectrometry analysis shows that 8a covalently modifies Cys121. However, the inactivation reaction is second-order with the rate constant (kinact) of 168 ± 25 M-1min-1 and we did not observe saturation kinetics in a re-plot of observed pseudo-first order rate constant (kobs) versus concentrations. This suggests that the inactivation by 8a is not an affinity-labeling agent. The absence of the saturation kinetics is also observed in the inactivation by 11a. On the other hand, 11b is the only inactivator that exhibits the saturation kinetics, suggesting the affinity-labeling mechanism. Fitting a curve to a hyperbolic equation for affinity-labeling agent gives a rate constant (kinact) of 4.7 ± 0.6 x 102 M-1min-1 and a dissociation constant (KI) = 17±4 [mu]M. However, further study is needed to reveal an insight of the inactivation mechanism.eng
dc.description.bibrefIncludes bibliographical references.eng
dc.format.extent1 online resource (131 pages) : illustrationseng
dc.identifier.merlinb118909885eng
dc.identifier.oclc992170217eng
dc.identifier.urihttps://hdl.handle.net/10355/56831
dc.identifier.urihttps://doi.org/10.32469/10355/56831eng
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcollectionUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsOpenAccesseng
dc.rights.licenseThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.eng
dc.subject.FASTPhosphorylationeng
dc.subject.FASTProtein-tyrosine phosphataseeng
dc.titleThe development of exo-affinity labeling agents, inactivators of protein tyrosine phosphatase 1Beng
dc.typeThesiseng
thesis.degree.disciplineChemistry (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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