Thesis (M.S.)--University of Louisville, 2003. / Department of Chemistry. Vita. "December 2003." Includes bibliographical references (leaves 135-144).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1956. / Typescript. Abstracted in Dissertation abstracts, v. 16 (1956) no. 11, p. 2021-2022. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 119-122).

It is known that humoral mechanisms for the inhibition of gastric secretion and motor activity operate from the duodenum. The gastrointestinal hormones cholecystokinin-pancreozymin (CCK-PZ) and secretin have been implicated as the hormones released in some of these proposed mechanisms. Despite the fact that CCK-PZ and secretin are probably involved in gastric inhibitory mechanisms, they fall short of fulfilling the original definition of enterogastrone as the inhibitory principle released from the duodenum by the presence there of fat. Impure preparations of CCK-PZ are known to stimulate H⁺ secretion in the dog when given alone and to inhibit H⁺ secretion stimulated by gastrin. Initial studies in this thesis comparing the effects of 2 purities of CCK-PZ on gastric secretion provided evidence for the existence of a gastric inhibitor distinct from CCK-PZ and secretin in partially purified CCK-PZ preparations. It was concluded from these studies that in partially purifying CCK-PZ, an inhibitory material could have been removed. This conclusion Was supported by the finding that a side fraction from the purification of CCK-PZ, with no significant CCK or secretin activity, possessed potent inhibitory activity for gastrin pentapeptide-stimulated H⁺ and pepsin secretion in the dog. The side fraction referred to in this these as EG Stage I became the starting point for several purification procedures. Purification of the inhibitory material led to the discovery that it was a polypeptide distinct in its chemical features from CCK-PZ, notably by the absence of the amino acid proline. The pure inhibitory material, gastric inhibitory polypeptide (G.I.P.), when available, was shown to possess no secretin activity, negligible CCK activity, and to have no pyrogenic or vasodepressor effects. G.I.P. was used in studies to determine its potency as an inhibitor of gastric sectretion and motor activity in the dog. Studies were carried out in which.G.I.P. was shown to be a highly potent inhibitor of H⁺ and pepsin secretion from bickel pouches and motor activity from vagally denervated antral pouches stimulated by gastrin pentapeptide and the whole gastrin molecule. Another objective was to determine if G.I.P. was effective as an inhibitor of gastric secretion against stimulants that were resistant to inhibition by CCK-PZ and secretin, e.g. histamine. Results of these experiments proved G.I.P. to be about half as effective an inhibitor of H⁺, pepsin and fundic motor activity during histamine infusion as compared with experiments in which gastrin pentapeptide was the stimulant. The range of effectiveness of G.I.P. as a gastric inhibitor was extended to vagally stimulated H⁺ and pepsin secretion with potency of inhibition equaling that found in histamine studies. As a result of structural similarities between G.I.P. and glucagon, studies were carried out to determine if G.I.P. mimicked the hyperglycemic or pancreatic inhibitory actions known to be possessed by glucagon. This was found not to be the case. In addition to inhibiting stimulated gastric secretion and motor activity, G.I.P. was shown to inhibit fundic pouch H⁺ secretion, pepsin secretion and motor activity in the unstimulated condition. It is concluded that since G.I.P. fulfills the physiological Requirements as an efficient gastric inhibitor and mimics the actions of fat in the duodenum, it is an excellent candidate for the humoral agent released from the duodenum by fat and perhaps by hydrochloric acid and hypertonic solutions. However, reservations must be held as to its status as a hormone until it is detected in blood and tissues. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Dans la présente thèse, nous rapportons l'étude de la dissociation induite par collision (CID) de biomolécules. La CID est une technique de spectrométrie de masse (MS) bien connue, dont le but est la dissociation d’ions par l'impact avec un gaz inerte. L'énergie de translation collisionnelle est convertie en énergie interne de l’ion qui peut ainsi se dissocier. La CID est donc une technique largement utilisée en MS qui permet d'identifier, ou de quantifier, une ou plusieurs espèces par la détection des fragments générés.La réactivité et la cinétique des réactions chimiques sont généralement étudiées théoriquement par la recherche des points stationnaires sur la coordonnée de réaction. Il est ainsi possible d'identifier le chemin d'énergie minimum de réaction ou la surface d'énergie potentielle (PES). Une autre possibilité est d'effectuer des simulations de dynamique chimique, qui permettent d'explorer la réactivité d'une espèce sans connaitre les produits, ce qui est un point crucial pour des molécules plus grosses. En plus, pour interpréter la MS il est important d'avoir une compréhension fondamentale de la dynamique de la fragmentation de l’ion, et des informations importantes peuvent être récupérées avec des simulations. Dans le présent travail, nous avons étudié et développé des modèles physiques pour étudier des biomolécules complexes et flexibles, comme les acides aminés et les peptides.Une fois que l'ion est excité par une seule collision, le transfert d'énergie peut être suivi d'une redistribution statistique interne de l'énergie vibrationnelle (IVR) de l'ion et des produits statistiques sont typiquement obtenus. D'autre part, la collision peut causer une localisation de l'énergie et une excitation rapide, donnant des produits différents de ceux observés après une IVR. En particulier, une situation limite est celle où l'ion se fragmente juste après la collision avec le gaz. Afin de récupérer ces fragmentations moins statistiques, il est important de modéliser la collision, ce qui peut être fait par une dynamique chimique de collision explicite. Cependant, ce type de simulation est limité dans le temps (~ 10-15 ps). La dynamique chimique par activation statistique interne (ou thermique) peut être utilisée pour obtenir une échelle de temps plus longue et une réactivité statistique. De plus, en observent le déclin de la population par rapport au temps, il est possible d'obtenir les constantes de vitesse globales et individuelles. Les deux modes d'activation ont été appliqués pour étudier la réactivité de l'anion di-proline, les deux tripeptides doublement chargés TIK(H+)2 et TLK(H+)2 et l'anion L-cystéine-sulfate. Pour l'étude de ce dernier système en particulier, nous avons utilisé les résultats de nos simulations pour interpréter des expériences faites avec différents montages expérimentaux. / In the present thesis, we focus on the study of the collision induced dissociation (CID) of biomolecules. CID is a well known mass spectrometry (MS) fragmentation technique which aim is the dissociation of ions through the impact with an inert buffer gas. The collisional translational energy is converted in internal energy of the ion that can thus dissociate. CID is thus widely used in MS in order to identify or quantify one or more species through detection of the mass over charge ratio of the fragments products.Reactivity and kinetics of chemical reactions are generally studied theoretically through the research of the stationary points along the reaction coordinate. It is thus, possible, to identify the reaction minimum energy path or potential energy surface (PES). Another possibility is to perform chemical dynamics simulations, which allow to explore the reactivity of one specie without the knowledge of the products, that is a crucial point for larger molecules. Moreover, to interpret MS it is important to have a fundamental understanding of the ion’s fragmentation dynamics and important information can be recovered with simulations. In the present work, we have studied and developed physical models to address the study of complex and flexible biomolecules, like amino-acids and peptides.Once the ion is excited by single-collision, the translation-to-vibration energy transfer can be followed by a statistical internal vibrational energy redistribution (IVR) of the ion and typical statistical products are obtained. On the other hand, the collision can cause localization of the energy and a fast excitation, giving different products than those observed after an IVR. In particular a limit situation is when the ion fragments right after the collision with the gas. In order to recover these (less or fully) non-statistical fragmentations it is important to model the collision, which can be done performing explicit collision chemical dynamics. However, this activation way in simulations is limited in the time-scale (~ 10-15 ps). Statistical internal energy (or thermal) activation chemical dynamics can be used to obtain longer time scale and statistical reactivity. Moreover, observing the population decay versus the time it is possible to obtain the global and single pathways rate constants. Both activation modes have been applied to study the reactivity of the di-proline anion, the two doubly charged tri-peptides TIK(H+)2 and TLK(H+)2 and the L-Cysteine sulphate anion. In particular for the study of this last system we used our understanding of simulations to interpret experiments done with different set-ups.

Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2004. / "A dissertation in pharmaceutical sciences and chemistry." Advisor: Thomas P. Johnston. Typescript. Vita. Description based on contents viewed Feb. 28, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 135-148). Online version of the print edition.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 131-148).

Ribosomal synthesized and post translational modified peptide natural products have attracted a lot of interest in the past decade. Backbone cyclization of the translated linear peptides is generally catalysed by specific enzymes giving them peptidase resistance, thermodynamic stability and various other physiological activities. These features have made backbone cyclic peptide to become an attractive resource for drug discovery. Here, we described the synthesis of linear peptides containing natural and unnatural residues and its biosynthetic mechanism to generate man-made cyclic peptides. In this thesis we used SPPS to make short and medium linear peptide chains, we purified them using HPLC, and analysed them using MS. We incorporated unnatural residues such as homocysteine, homoserine, aminoalanine, propargyl glycine and the substrates were subjected to different enzymatic reaction such as prenylation, heterocyclization and macrocyclization modification reactions to generate small macrocycles (4-6 residues), prenylated linear peptides, and patellamime analogues. The final products were analysed using LC-MS. In our results, we verified that kawaguchipeptin (kgp) gene cluster is responsible for the production of kawaguchipeptins through heterologous expression of the kgp gene cluster in Escherichia coli. The KgpF prenyltransferase was overexpressed and was shown to prenylate C-3 of Trp residues in both linear and cyclic peptides in vitro. We also found out that PatGmac can macrocyclise short peptides (4-6 residues) to generate small macrocyclic peptides. We also tested the flexibility of OscGmac using unnatural amino acid residues such as pseudoprolines and pipecolic acid that can mimic the heterocyle incorporated as the final residue in the natural product. Our results show that OscGmac recognises pseudoprolines before AYD(G) to process a linear peptide.

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Thesis (Ph. D.)--University of Stellenbosch, 2006. / Includes bibliographical references. Also available via the Internet.

Thesis (Ph.D.)--University of Adelaide, School of Chemistry and Physics, Discipline of Chemistry, 2006. / "February, 2006" Includes copy of author's previously published article. Bibliography: leaves 145-156. Also available in print form.