Thesis (Ph. D.)--University of Wisconsin--Madison, 1960. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

viii, 181 leaves : ill., appendix / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.1972) from the Dept. of Agricultural Biochemistry, University of Adelaide

Thesis (Ph.D. 1972) from the Dept. of Agricultural Biochemistry, University of Adelaide.

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2009 / N3-substituted pyrimidine nucleoside derivatives containing either an iodovinyl moiety or an allyl group, i.e. [121]-N3-(3-iodoprop-2-en- l -yl)thymidine, (1~-711 and e21]-N3-(prop-2-enl- yl)-5-iodo-Z'-deoxyuridine, (1~_10, were synthesised and preliminarily evaluated by determining their uptake into CHO-Kl cells. Compound e~-711 was designed to be a delivery vector of 121: into the DNA of the cells, while (1~_10 was designed to serve as a control. Compound (1231]-711 was also intended to have a higher metabolic radiochemical stability than 5-iodo-Z'-deoxyuridine ([123I]_IUdR) for the therapeutic use in cancer. The synthesis of the N3-substituted intermediate precursors 411, 5 and 9 was achieved by Nalkylation of suitably' protected thymidine and 5-iodo-Z'-deoxywidine analogues, respectively. The intmediate precursors for radiolabelling, 411 and 11, were obtained by incorporating a trialkylstannyl group at the respective labelling positions prior to radioidination. (1~1-711 was recovered from (1~_6G after acid-hydrolysis of the protecting groups and 10 was obtained from direct oxidative iodination of11. The radiochemical yields ranged from 73% to 91% at the end ofthe synthesis and radiochemical purities were in excess of99"10 after HPLC purification. The cell-uptakes ofthe radiotracers were carried out and assessed by a direct comparison with the gold standard e23I]-IUdR, which is known to bephosphorylated and incorporated into the DNA of cells during the cells S-phase. The cell-uptake results of (1~_711 and (1~-10 were roughly 4% and 3% relative to [123I]-IUdR, respectively. The poor cell-uptake of (1~_10 suggested thatthe uptake into the cells is not influenced by the position of the iodine atom in the molecule, but most probably by the availability of the N3-position in its non-substituted form. As a result of its poor incorporation into cells, it was concluded that the synthesised radiotracer (1231]_711 would be a poor candidate for use in the eradication ofmalignant cells.

Thymidine kinase is a key enzyme in the nucleotide salvage pathway, catalyzing the production of dTMP from thymidine and ATP. In order to identify the structural features of the TK protein and/or primary amino acid sequences which contribute to the catalytic and regulatory activities of this enzyme, an in vitro transcription and translation system has been used in concert with protein engineering techniques for the production and phenotypic characterization of mutant and wild-type TK enzymes. Because of discrepancies in the literature regarding the quaternary structure of the VVTK, the native molecular weight and quaternary structure was determined to be an 80kDa homotetrameric enzyme by glycerol gradient fractionation, gel filtration and glutaraldehyde cross-linking analyses. Computer-assisted alignment of the predicted amino acid sequences derived from cellular and poxvirus TK genes identified seven highly-conserved domains distributed throughout the VVTK polypeptide (domains I-VII). Domain I (amino acid residues 11-18 ) exhibits a high degree of similarity to both ATP and GTP binding site consensus sequences, although the VVTK utilizes only ATP as a phosphate donor. Site directed mutagenesis and ATP-agarose affinity chromatography techniques were employed to confirm that this region was responsible for ATP binding and to determine which amino acids were essential for efficient binding. The TK gene (tdk) from E. coli was isolated and sequenced to serve as a prokaryotic enzyme with which to compare VVTK. The alignment revealed only 23% shared identity with VVTK and, interestingly, the identical and similar residues were clustered into three of the seven domains identified previously (domains I, III and VII). Preliminary evidence supports domain III (residues 78-90) as a putative magnesium binding site and that a highly conserved cysteine residue (cysteine 170) within domain VII (residues 168-171) may be a component of the catalytic site. Secondary structure alignment between Herpes Simplex Virus (HSV) TK and monkeypox TK (a close relative of VVTK) revealed that the putative nucleoside binding site of HSVTK aligns with residues within domain IV. Replacement of a VVTK residue (Q114) with the corresponding residue of HSVTK (an aspartic acid) greatly alters the substrate specificity and dTTP sensitivity of VVTK. / Graduation date: 1991

Written for the Dept. of Chemistry. Title from title page of PDF (viewed 2009/06/25). Includes bibliographical references.

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 215-242).

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvii, 179 p.; also includes graphics. Includes bibliographical references (p. 155-179). Available online via OhioLINK's ETD Center

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