Thesis (Ph.D.)--Brown University, 2005. / Vita. Thesis advisor: Christopher T. Seto. Includes bibliographical references (leaves 50-53, 112-114, 156-158). Also available online.

A thesis submitted to the Faculty of Science, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy, Johannesburg, 1996 / The glutathione S-transferases (GST) are a supergene family of h0111o-or heterodimeric Phase II detoxification enzymes which catalyse the S-conjugation between glutathione and an electrophilic substrate. The active site can be divided into two adjacent functional regions; a highly specific Gssite for binding the physiological substrate glutathione and a nonspecific If-site for binding nonpolar electrophilic substrates. Unfolding of porcine class Pi isoenzyme (pGSTPl~l) was monitored under equilibrium conditions using different physicochemical parameters. The coincidence of unfolding curves obtained with functional and structural probes, the absence of thermodynamically stable intermediates such as a folded monomer, and the dependence of pGSTPl··l stability upon protein concentration, indicate a cooperative and concerted two-state unfolding transition between native dimeric pGSTPl-l and unfolded monomeric enzyme. Equilibrium and kinetic unfolding experiments employing tryptophan fluorescence and enzyme activity measurements were preformed to study the effect of ligand binding to the G-site on the unfolding and stability of the porcine class pi glutathione S-transferase against urea. The presence of glutathione caused a shift in the equilibrium-unfolding curves towards lower urea concentrations and enhanced the first-order rate constant for unfolding suggesting a destabilisation of the pGSTPl-l structure against urea. The presence of either glutathione sulphonate or S-hexylglutathione, however, produced the opposite effect in that their binding to the G-site appeared to exert a stabilising effect against urea. The binding of these glutathione analogues also reduced significantly the degree of cooperativity of unfolding indicating a possible change in the protein's unfolding pathway. / MT2017

Peroxisome proliferator-activated receptors (PPARs) are members of a large group of ligand-regulated transcription factors that includes nuclear receptors for steroid and thyroid hormones, retinoids and vitamin D���. Synthetic fibrates and thiazolidinediones that bind to and activate PPARs are used efficaciously in humans to remedy hypertriglyceridemia and non-insulin dependent diabetes mellitus, respectively. The objective of the studies described herein was to elucidate the molecular mechanisms of ligand-dependent PPAR signaling. Several PPAR ligands, including WY-14,643, were demonstrated to directly induce PPAR�� conformational changes as evidenced by a differential protease sensitivity assay. Conformational changes were induced in a dose-dependent manner which paralleled that of ligand to induce transcriptional activation. Direct interaction of ligands with, and the resulting conformational alterations in, PPAR�� may facilitate interaction of the receptor with transcriptional intermediary factors and thus may underlie the molecular basis of ligand-dependent transcriptional activation mediated by PPAR��. The yeast two hybrid screen was utilized to identify downstream components of the PPAR�� signaling pathway. Using this technique, the coactivator proteins, p300 and steroid receptor coactivator-1 (SRC-1), were identified as PPAR��-interacting proteins and WY-14,643 potentiated these interactions. p300 also enhanced the transcriptional activation properties of PPAR�� and, therefore, can be considered a bona fide coactivator for this nuclear receptor. Nuclear receptor corepressor (NCoR) was also isolated as a PPAR��-interacting protein from a yeast two hybrid screen. In contrast to the ligand enhanced PPAR��-coactivator interactions, WY-14,643 inhibited NCoR interaction with PPAR��. NCoR and the coactivators, p300 and SRC-1, were also demonstrated to require distinct receptor regions for efficient interaction with PPAR��. Results described herein demonstrate that ligand induces PPAR�� conformational changes, promotes PPAR��-coactivator (p300 and SRC-1) interactions, and inhibits PPAR��-NCoR interactions. We hypothesize that such molecular events are critical for ligand-dependent transcriptional activation by PPAR��. These results contribute additional knowledge as to the molecular mechanisms of PPAR-dependent signaling and may act as a starting part for the improvement and/or development of therapeutic strategies aimed at manipulating this signaling pathway. / Graduation date: 1999

Thesis (Ph. D.)--University of Delaware, 2006. / Principal faculty advisor: Thomas P. Beebe, Jr., Dept. of Chemistry & Biochemistry. Includes bibliographical references.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

No description available.

Thesis (MScMed)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

Thesis (Ph. D.)--Ohio State University, 2003. / Title from first page of PDF file. Document formatted into pages; contains xv, 189 p.; also includes graphics (some col.) Includes bibliographical references (p. 168-189). Available online via OhioLINK's ETD Center

Thesis (M.Sc.)--York University, 2006. Graduate Programme in Chemistry. / Typescript. Includes bibliographical references. Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR29571

Thesis (M.S.)--Brigham Young University. Dept. of Chemistry and Biochemistry, 2006. / Includes bibliographical references.