Thesis (Ph.D.)--University of Nebraska-Lincoln, 2007. / Title from title screen (site viewed June 17, 2008). PDF text: 73 p. : ill. ; 3 Mb. UMI publication number: AAT 3290780. Includes bibliographical references. Also available in microfilm and microfiche formats.

Thesis (M.S.)--University of Missouri-Columbia, 2004. / Typescript. Includes bibliographical references. Also available on the Internet.

Thesis (doctoral)--Rijksuniversiteit te Groningen.

Thesis (Ph. D.)--Columbia University, 1944. / Vita. eContent provider-neutral record in process. Description based on print version record. Bibliography: p. 19-20.

The work described herein is concerned with the [3+2] dipolar cycloaddition of amino acid derived azomethine ylids. Such cycloadditions are a highly efficient technique for the construction of proline derivatives, and may potentially be employed in other areas of asymmetric synthesis. Chapter 1 commences with a brief review of natural and synthetic, proline containing, molecules. Approaches to the synthesis of the proline moiety are described, focusing on previously developed methods for performing the [3+2] dipolar cycloaddition in a chiral manner. The methodology employed in this thesis is subsequently detailed, along with a brief description of the aims of the work. This is followed by a review of α-amino acid synthesis via chiral template technology. The potential application of chiral [3+2] dipolar cycloadditions to such syntheses is introduced. Chapter 2 describes the cycloaddition of carboxylate substituted chiral azomethine ylids with a range of dipolarophiles under both thermal and Lewis acid catalysed conditions. The effect on the stereoselectivity and yield caused by changing the conditions is discussed. Subsequent removal of the chiral template allows the synthesis of some tetra-substituted proline derivatives. Chapter 3 details the intramolecular variant of the cycloaddition. Further functionalisation of the cycloadducts via insertion of alternative chain links and sulfone alkylation was attempted. The Pummerer rearrangement of the related sulfoxide was shown to proceed smoothly and with total regio- and stereocontrol. Application of the methodology to the synthesis of a simple proline derivative and a symmetric pyrrolidine is described. Chapter 4 reports the attempted application of [3+2] dipolar cycloadditions to the synthesis of α-amino acids. The synthesis and subsequent cycloaddition of a new, α-amino acid derived, chiral template is described. Subsequent deprotection of the cycloadducts generated allows the synthesis of some α-phenyl substituted prolines. Unsuccessful attempts to incorporate additional substituents and perform the cycloaddition in an intramolecular manner are described. Chapter 5 contains a description of the techniques employed, together with spectroscopic data for the compounds described in this thesis.

The common eastern bumblebee queens (Bombus impatiens) endure cold winter months by entering a diapausal state post-fertilization. During this overwintering period, these animals use stored energy reserves while maintaining a low metabolic rate. Bumblebees are thought to use primarily lipids to fuel this critical overwintering period, despite the fact that bee mitochondria do not appear equipped to break down this metabolic fuel. For some insects, lipids stored in the fat body can be converted to the amino acid proline, and this metabolic fuel has recently been discovered to be readily oxidized by bumblebee workers. My research, therefore, investigates the role of proline during overwintering in bumblebee queens. Using cellular respirometry, I determined the metabolic capacity of the muscle cells of queens to use various fuels, and if this capacity changes throughout overwintering. Surprisingly, the tested queens showed a much lower potential to oxidize proline than workers, and their capacity did not change during a four-month overwintering period. The metabolic properties of muscle tissue were further characterized using metabolic enzymes activity profile. These results further demonstrate the low potential for proline metabolism and the limitations of bumblebee queens’ capacity to oxidize lipids. Body composition was measured to determine how the various energy stores (lipid, glycogen, protein) change during overwintering; however, no decrease in concentration was observed. Overall, this work clarifies the constraints of B. impatiens metabolism during overwintering.

Hydroxyproline as a modified amino acid can serve as a carbon and nitrogen source for certain microorganisms. Its primary isomer trans-4-hydroxy-L-proline is found in the root nodule of legume plants. Hydroxyproline (Hyp) catabolism has been characterized in bacteria and animal cells. In bacteria, trans-4-hydroxy-L-proline (trans-4-L-proline) is converted to the central metabolite α-ketoglutarate (α-KG) by four reactions. The Hyp catabolism pathway has been identified in the nitrogen-fixing legume endosymbiont Sinorhizobium meliloti. hypS is one of the transcripts in the 14 hyp gene cluster on the pSymB megaplasmid, and was annotated to encode a putative malate/L-lactate dehydrogenase. In this study, purified HypS was assayed on different substrates and the reaction products were characterized. It was demonstrated that HypS can oxidize L-proline and reduce Δ1-pyrroline-2-carboxylate, but not on L-malate. Noticeably unlike the wild type strain, a hypS- mutant strain failed to grow on D-proline. The ability of D-proline to support grow of an L-proline auxotroph, together with the substrate specificity of HypS, strongly suggests that hypS is involved in the metabolism of D-proline to L-proline in S. meliloti. The possible role of HypS in the catabolism of Hyp or related compounds remains to be determined. / Thesis / Master of Science (MSc)

The original publication is available at www.springerlink.com.

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / During early embryogenesis pluripotent cells of the inner cell mass (ICM) give rise to a second pluripotent cell population known as the primitive ectoderm an obligate developmental intermediate and the substrate for gastrulation. The ICM and primitive ectoderm are distinguished on the basis of morphology, gene expression and differentiation potential. However, the signals and mechanisms involved in the transition form ICM to primitive ectoderm are not understood. Culture of ES cells in the presence of a conditioned medium MEDII leads to a transition of ES cells to a population of pluripotent primitive ectoderm-like (EPL) cells that are the in vitro equivalent of the primitive ectoderm. In terms of EPL cell formation the bioactive component of MEDII was identified as L-proline. In this thesis the molecular mechanism by which L-proline induces EPL-cell formation was elucidated. As well as L-proline, short L-proline containing peptides were also shown to induce EPL-cell formation but different peptides displayed different abilities to induce the transition with some inducing the complete transition and others inducing morphology changes only. The mechanism of L-proline induced EPL-cell formation was shown to be independent of NK receptors. The mechanism of L-proline induced EPL-cell formation, as deduced from the results presented in this thesis, was suggested to involve the internalisation of L-proline via the SAT2 amino acid transporter into ES cells as competitive inhibitors of SAT2 prevented EPL-cell formation. MAPK signalling via the action of MEK1 was implicated in L-proline induced EPL-cell formation as inhibitors of MEK1 prevented EPL-cell morphology, gene expression and differentiation potential in the presence of Lproline. PI3K signalling was implicated in L-proline-induced EPL-cell morphology since PI3K inhibitor L Y294002 maintained domed colonies in the presence of L-proline but failed to maintain an ES-cell gene expression profile and differentiation potential. Both MAPK and PI3K signalling were suggested to lie down-stream of L-proline action since treatment of ES cells with L-proline induced the activation of ERK1/2 and Akt down-stream effectors of MAPK and PI3K signalling respectively. A gene potentially involved in the Pl3K-rnediated rnorphology change was Lefty2. Therefore, the mechanism of L-proline induced EPL-cell formation appears to involve internalisation of L-proline and at least two signalling pathways down-stream of L-proline, which regulate different components of the transition. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1281009 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

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