Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06

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Ludwig-Maximilians-Universität München

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Latest episodes from Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06

Low Sensitivity Energetic Materials

Play Episode Listen Later Apr 25, 2008


Fri, 25 Apr 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8495/ https://edoc.ub.uni-muenchen.de/8495/1/Welch_Jan.pdf Welch, Jan ddc:500, ddc:540, Fakultät für Chemie und Pharmazie

Reactions of Carbanions with Michael Acceptors and Electron-deficient Arenes

Play Episode Listen Later Apr 24, 2008


Thu, 24 Apr 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8415/ https://edoc.ub.uni-muenchen.de/8415/1/Seeliger_Florian.pdf Seeliger, Florian ddc:500, ddc:540, Fakultät für Chemie und Phar

The roles of integrin Alpha4Beta1, Alpha4Beta7 and the small GTPase RhoH during hematopoiesis and autoimmunity

Play Episode Listen Later Apr 24, 2008


Thu, 24 Apr 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9971/ https://edoc.ub.uni-muenchen.de/9971/1/Bauer_Martina.pdf Bauer, Martina ddc:540, ddc:5

The Effect of Lethal Toxin on the Respiratory Epithelium.

Play Episode Listen Later Apr 17, 2008


Inhalational anthrax is an acute infectious disease caused by exposure of the lungs to B. anthracis spores. Alveolar macrophages engulf spores causing them to germinate to the vegetative form of B. anthracis, which secretes edema toxin (ET)and lethal toxin (LT). The pathogenesis of inhalational anthrax is characterized by flu-like symptoms, respiratory distress, meningitis and shock, which is fatal in almost all cases. The mechanism behind the respiratory distress is not well understood. Therefore, our goal was to determine the effects of lethal toxin in the human lung epithelium. To study alterations in a more physiological setting, we developed a differentiated, polarized lung epithelial system. Lethal toxin exposure disrupted the lung barrier function and wound healing. Assembly defects of junction proteins and additional multicellular junction sites resulted in a higher permeability. Pretreatment with keratinocyte growth factor (KGF) and dexamethasone increased the viability, resulting in the rescue of the permeability changes. Upon LT treatment, a more rigid cytoskeleton was observed, evidenced by enhanced actin stress fiber formations and tubulin stabilization. Cytoskeleton and adhesion alterations prevented the epithelial cells from polarization, directed migration, and wound healing. The MAPK pathway and Cdc42 activity might be partially responsible for these motility defects. Lethal toxin is known to induce rapid cell death in murine macrophages. In contrast, human epithelial cells are more resistant to the cytotoxic effect of LT. By following the growth of epithelial cells after LT treatment, we observed inhibited cell proliferation due to a cell cycle arrest in the G1 phase. Surprisingly, biotinylated lethal factor did not induce cytotoxicity in murine macrophages. This is not due to an internalization or proteolytic activity defect; instead changes in the mitochondrial potential and proteasome activity were observed. Biotinylated LT did not reduce proteasome activity as seen in LT treated cells and caused hypopolarization of the mitochondria. However, it is possible that biotinylation of lethal toxin could prevent interaction of LT with proteins that induce cell death. The major challenge for anthrax treatment is to find a treatment, which can act faster, is easy to use and can bring patient out of the dangerous physiological state in late pathogenesis. Our study has implications in saving the viability and barrier function of lung epithelial cells. One can devise better dosage and delivery of KGF and dexamethasone as treatment modality for post anthrax exposure to reduce respiratory distress. Furthermore, overcoming the cell cycle arrest by the development of a drug would reduce the damage of lung epithelial cells and induce proliferation. The discovery that biotinylated LT is non-toxic to murine macrophages could revolutionize treatment of anthrax infection. Exploring the types of posttranslational modifications of LT that decrease toxicity and finding the mechanism behind it might, lead to therapies that directly counteract the effects of the lethal toxin in vivo.

NMR-spektroskopische und röntgenkristallographische Untersuchungen von ein- und zweikernigen Palladium(II)-Kohlenhydratkomplexen

Play Episode Listen Later Apr 3, 2008


Kohlenhydrate gehören zu den Biomolekülen mit dem mengenmäßig größten Anteil in der Natur, jedoch wurden sie lange Zeit fast ausschließlich als Energiespeicher, Stütz- und Gerüstsubstanzen betrachtet. Die in den letzten Jahren stetig wachsenden Erkenntnisse ihrer essentiellen Bedeutung in wichtigen biologischen Prozessen und die damit verbundenen vielversprechenden Anwendungsmöglichkeiten als Impfstoffe und Medikamente gegen eine Reihe von Krankheiten wie zum Beispiel Krebs, Aids, Diabetes oder Alzheimer führen jedoch zu einem immer größer werdenden Interesse dieser Stoffklasse. Die vorliegende Dissertation gibt einen umfassenden und systematischen Einblick in die Koordinationsmöglichkeiten von Kohlenhydraten an Palladium(II). Dabei erweist sich Palladium(II) in besonderem Maße als ein Zentralatom, das in der Lage ist, die Isomeren- und Konformerenverteilung von Monosacchariden drastisch zu verschieben und so Formen zugänglich zu machen, die ohne Komplexierung nur schwer oder gar nicht nachweisbar sind. Palladium(II) ermöglicht nicht nur stabile Komplexe sowohl mit Pyranosen als auch mit Furanosen in den verschiedensten Bindungsmodi aufzubauen, sondern dient darüber hinaus, durch die in Abhängigkeit des jeweiligen Bindungsmodus auftretenden charakteristischen CIS-Werte der 13C-NMR-Signale, als „Sonde“ für die Koordination an ein bestimmtes Kohlenhydratisomer. Die erhaltenen Ergebnisse erweitern grundlegend die Kenntnisse der Koordinationschemie auf diesem Gebiet und können auch aus pharmazeutischer und katalytischer Sicht von Bedeutung sein.

Investigations on Flagellar Biogenesis, Motility and Signal Transduction of Halobacterium salinarum

Play Episode Listen Later Mar 17, 2008


Mon, 17 Mar 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9276/ https://edoc.ub.uni-muenchen.de/9276/1/Staudinger_Wilfried.pdf Staudinger, Wilfried ddc:500, ddc:540, Fakult

Persistente Radikalanionen mit ungewöhnlichen Eigenschaften auf der Basis von Carbonsäureimiden

Play Episode Listen Later Feb 28, 2008


Thu, 28 Feb 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/11625/ https://edoc.ub.uni-muenchen.de/11625/1/Ritter_Ulrike.pdf Ritter, Ulrike ddc:540, ddc:500, Fakultät

Functional Architecture of RNA polymerase I

Play Episode Listen Later Feb 27, 2008


Synthesis of ribosomal RNA by RNA polymerase (Pol) I is the first step in ribosome biogenesis and a regulatory switch in eukaryotic cell growth. In this thesis a reproducible large-scale purification protocol for Pol I from S. cerevisiae could be developed. Crystals were obtained, diffraction to < 4 Å could be recorded, however, the enormously complex non-crystallographic symmetry impeded structure solution. Switching to cryo-electron microscopy, the structure of the complete 14-subunit enzyme could be solved to 12 Å resolution, a homology model for the core enzyme could be generated, and the crystal structure of the subcomplex A14/43 could be solved. In the resulting hybrid structure of Pol I, A14/43, the clamp, and the dock domain contribute to a unique surface interacting with promoter-specific initiation factors. The Pol I-specific subunits A49 and A34.5 form a heterodimer near the enzyme funnel that acts as a built-in elongation factor, and is related to the Pol II-associated factor TFIIF. In contrast to Pol II, Pol I has a strong intrinsic 3’-RNA cleavage activity, which requires the C-terminal domain of subunit A12.2, and apparently enables rRNA proofreading and 3’-end trimming.

Molecular analyses of resistance and sensitivity mechanisms to anti-EGFR directed tumor therapy

Play Episode Listen Later Feb 25, 2008


This study characterized a panel of NSCLC cell lines as well as a stably transfected cell model expressing wild-type and mutated EGFR variants in terms of response to the EGFR-targeting drugs, gefitinib and cetuximab. The examinations support the notion that response to gefitinib is neither exclusive nor strictly determined by the presence of EGFR kinase mutations. Yet, cells expressing EGFR kinase domain mutations tended to generally respond better to treatments with gefitinib compared to those with wild-type EGFR. On the other hand, preliminary studies suggesting that cellular sensitivity to cetuximab is determined by factors other than EGFR kinase domain mutations could be substantiated through a robust set of data. Moreover, several promising candidate genes differentially expressed in gefitinib sensitive and resistant NSCLC cell lines were revealed by a global mRNA expression analyses. In addition, though statistically questionable, several biologically interesting genes that are possibly involved in determining in vitro response of NSCLC cells to cetuximab have been postulated. In this work, four cancer cell models, which are long-term exposed to gefitinib or cetuximab were established and characterized in terms of gain-of-resistance towards EGFR-targeting compounds, as well as in regard to biological and molecular alterations caused by long-term treatments. It was found that gefitinib long-term treatment of primary sensitive A431 cells confered growth-resistance to this TKI, but not to cetuximab. This observation may have clinical implications for patients that relapsed on gefitinib as it suggests that they might still profit from cetuximab therapy. On the other hand long-term exposure of A431 cells to cetuximab did not render cells resistant to neither the antibody nor gefitinib in regard to in vitro growth-inhibition. Furthermore, it appeared that long-term gefitinib-treated A431 cells downregulate overall EGFR levels, while long-term cetuximab exposed cells displayed decreased EGFR surface levels but constant overall expression. In addition, a candidate-based approach identified genes that are differentially expressed in cancer cells with primary or secondary resistance to gefitinib or cetuximab. Finally, this study for the first time provided evidence that cetuximab may block metastasis-facilitating epithelial-mesenchymal-transition (EMT) in an epithelial cell line. Moreover, it was suggested that activation of the HGFR may compensate for cetuximab-mediated blockage of EGFR. This was also reflected by an increased response of this population towards treatment with HGFR inhibitors.

Klonierung, rekombinante Expression und erste Charakterisierung des humanen hodenspezifischen Serinprotease-ähnlichen Proteins T-GPI-SP1

Play Episode Listen Later Feb 20, 2008


Wed, 20 Feb 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9087/ https://edoc.ub.uni-muenchen.de/9087/1/Profanter_Birgit.pdf Profanter, Birgit

Neue Wege zur Synthese der marinen Naturstoffe Oroidin, Cyclooroidin und verwandter Moleküle

Play Episode Listen Later Feb 19, 2008


Tue, 19 Feb 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8636/ https://edoc.ub.uni-muenchen.de/8636/1/Poeverlein_Christoph.pdf Pöverlein, Christoph ddc:500, ddc:540, Fakultät fü

Structural Characterization of the DNA Repair Protein Complex SbcC-SbcD of Thermotoga maritima

Play Episode Listen Later Feb 14, 2008


DNA damage poses a considerable threat to genomic integrity and cell survival. One of the most harmful forms of DNA damage are double-strand breaks that arise spontaneously during regular DNA processing like replication or meiosis. In addition, they can also be induced by a variety of DNA damaging agents like UV light, cell toxins or anti-cancer drugs. Failure of the rapid repair of these breaks can lead to chromosomal rearrangements and ultimately tumorigenesis in humans. In response to these genomic threats, a highly developed DNA repair network of protein factors has evolved, where the Mre11/Rad50/Nbs1 (MRN) complex is sought to play a key role in sensing, processing and repair of DNA double-strand breaks. Orthologs of Mre11 and Rad50, but not Nbs1, are found in all taxonomic kingdoms of life, suggesting that Mre11 and Rad50 form the core of this complex. In this work structural studies were performed to decipher the overall architecture and the interaction of SbcC and SbcD, the bacterial orthologs of Rad50 and Mre11. Using X-ray crystallographic and small angle X-ray scattering techniques the crystal as well as the in solution structures of the Thermotoga maritima SbcC ATPase domain in complex with full-length SbcD were solved. The crystal and in solution structure match well fortifying the calculated models that reveal an open, elongated complex with dimensions of approximately 210 Å * 75 Å * 65 Å. The heterotetrameric protein assembly consists of two SbcD molecules that homodimerize at domains I to form the central portion of the complex. Located at the outer areas of this homodimer domains II are arranged close to lobe II of SbcC building a small protein-protein interface. The C-terminal domains III of SbcD are connected to domains II via a flexible linker and associate through hydrophobic interactions with the coiled-coils of SbcC. These arrangements in combination with earlier findings lead to a model where upon ATP-binding the complex performs a conformational switch resulting in a ring-shaped structure. This conformation would bear a central cavity to harbor DNA strands that can be processed by the inwards oriented nuclease active sites of SbcD.

Structural characterisation of transcription and replication through cisplatin lesioned DNA

Play Episode Listen Later Feb 7, 2008


Replication of the genome is strongly inhibited when high fidelity DNA polymerases encounter unrepaired DNA lesions, which can not be processed. The highly stringent active sites of these polymerases are unable to accommodate damaged bases and therefore DNA lesions block the replication fork progression. In order to overcome this problem, cells have evolved mechanisms for either repairing the damage, or synthesising past it with specially adapted polymerasases. Eukaryotic DNA polymerase eta (Pol eta), belonging to the Y-family of DNA polymerases, is outstanding in its ability to replicate through a variety of highly distorting DNA lesions such as cyclobutane pyrimidine dimers (CPDs), which are the main UV-induced lesions. Also cisplatin induced 1,2-d(GpG) adducts (Pt-GGs), which are formed in a typical cancer therapy with cisplatin can be processed by Pol eta. The bypass of such intrastrand crosslinks by high fidelity DNA polymerases is particularly difficult because two adjacent coding bases are simultaneously damaged. Thus, replication by Pol eta allows organisms to survive exposure to sunlight or, in the case of cisplatin, gives rise to resistances against cisplatin treatment. Mutations in the human POLH gene, encoding Pol eta, causes the variant form of xeroderma pigmentosum (XP V), characterized by the failure to copy through CPDs. This leads to strongly increased UV sensitivity and skin cancer predisposition. This thesis describes mechanistic investigations of the translesion synthesis (TLS) process by S. cerevisiae DNA Pol eta at atomic resolution, which were undertaken in collaboration with the Hopfner group. To study this process, cisplatin lesioned DNA had to be prepared first. Once this technique was established, the catalytic fragment of Pol eta was crystallized as ternary complex with incoming 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) and an primer - template DNA containing a site specific Pt-GG adduct. The first obtained structure shows the ddCTP positioned in a loosely bound conformation in the active site, hydrogen bonded to the templating base. Realizing the importance of the 3’ hydroxy group for positioning the NTP and the DNA correctly inside the polymerase, the complex was crystallized again with a 2’-deoxynucleoside 5’-triphosphate (dNTP). To prevent nucleotidyl transfer, primer strands which terminate at the 3’-end with a 2’,3’ dideoxy ribose were prepared by reverse DNA synthesis and used for cocrystallization. The resulting crystals diffracted typically to 3.1-3.3Å resolution at a synchrotron light source. A Pol eta specific arginine (Arg73 in yeast Pol eta) was identified for its importance to position the dNTP correctly in the active site and was shown to be necessary for lesion bypass. In contrast to the fixed preorientation of the dNTP in the active site, the damaged DNA is bound flexibly in a rather open DNA binding cleft. Nucleotidyl transfer requires a revolving of the DNA, energetically driven by hydrogen bonding of the templating base to the dNTP. For the 3’dG of the Pt-GG, this step is accomplished by bona fide Watson-Crick base pairs to dCTP and is biochemically efficient and accurate. In contrast, bypass of the 5’dG of the Pt-GG is less efficient and promiscuous for dCTP and dATP. Structurally, this can be attributed to misalignment of the templating 5’dG due to the rigid Pt crosslink. In cooperation with the Cramer group the structural reasons for the blockage of RNA Polymerase II (RNAP II) by the cisplatin lesion were elucidated. Using structural as well as biochemical methods it could be shown that stalling results from a translocation barrier that prevents delivery of the lesion to the active site. AMP misincorporation occurs at the barrier and also at an abasic site, suggesting that it arises from nontemplated synthesis according to an 'A-rule' known for DNA polymerases. RNAP II can bypass a cisplatin lesion that is artificially placed beyond the translocation barrier, even in the presence of a G A mismatch. Thus, the barrier prevents transcriptional mutagenesis.

The Structure of RseB, a Sensor for Periplasmic Stress in Escherichia coli

Play Episode Listen Later Feb 7, 2008


RseB from Escherichia coli has been crystallized and crystal structures were determined at 2.4 Å and at 2.8 Å resolution. The structure of cytoplasmic expressed RseB revealed that it consists of two domains; an N-terminal large and a C-terminal small domain. The large domain resembles an unclosed β-barrel that is structurally remarkably similar to a protein family (LolA, LolB) capable of binding the lipid anchor of lipoproteins. Detailed structural comparison of RseB and LolA led to the hypothesis that RseB might be a sensor for mislocalized lipoproteins. The small C-terminal domain, connected to the large domain by a partially unstructured loop, was identified to mediate interaction with RseA. A peptide comprised of a putative helix of RseA was shown to constitute the binding site for RseB. Structure based results presented in this thesis indicate a new role of RseB in acting as a sensor for periplasmic stress: it detects mislocalized lipoproteins in the periplasm and propagates the signal to induce σE-response.

Hochfunktionalisierte Magnesiumorganyle zur Synthese von funktionalisierten Benzyl-, Ferrocen- und Indolderivaten

Play Episode Listen Later Jan 30, 2008


Wed, 30 Jan 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8009/ https://edoc.ub.uni-muenchen.de/8009/1/Stoll_Armin.pdf Stoll, Armin ddc:500, dd

Influence of Ginkgo biloba extract EGb 761 on signaling pathways in endothelial cells

Play Episode Listen Later Jan 25, 2008


Fri, 25 Jan 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8079/ https://edoc.ub.uni-muenchen.de/8079/1/Koltermann_Anja.pdf Koltermann, Anja ddc:500, ddc:540, Fakultät für Chemie

Polyfunctionalizations of N-Heterocycles via Chemo- and Regioselective Metalations

Play Episode Listen Later Jan 10, 2008


Thu, 10 Jan 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8031/ https://edoc.ub.uni-muenchen.de/8031/1/Boudet_Nadege.pdf Boudet, Nadège ddc:500, ddc:540, Fakultät für Chemie un

Untersuchung von Interaktionen intrazellulärer Signalkaskaden

Play Episode Listen Later Dec 21, 2007


Fri, 21 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7960/ https://edoc.ub.uni-muenchen.de/7960/1/Hennecke_Katharina.pdf Hennecke, Katharina ddc:500, ddc:540, Fakultät für Chemie und Pharmazie

Analyse der Regulation des Cav1.2-L-Typ-Kalziumkanals durch Proteinkinasen in vitro und in transgenen Mäusen

Play Episode Listen Later Dec 20, 2007


Thu, 20 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7848/ https://edoc.ub.uni-muenchen.de/7848/1/Lemke_Toni.pdf Lemke, Toni Franziska ddc:500, ddc:54

Entwicklung robuster Quantengatter auf infrarot-aktiven Qubits in MnBr(CO)5

Play Episode Listen Later Dec 20, 2007


Die vorliegende Arbeit behandelt die experimentell umsetzbare Implementierung von Molekularem Quantencomputing, wie es in der Arbeitsgruppe um R. de Vivie-Riedle entwickelt wurde. Dieses Konzept beruht auf Laser-vermittelter Kontrolle intramolekularer Schwingungsdynamik. So fungieren ausgewählte Normalmoden eines polyatomaren Moleküls als Quanteninformationseinheiten (Qubits), wobei die Information in den Schwingungseigenzuständen kodiert wird. Diese lässt sich durch kurze geformte infrarote Lichtpulse, die als logische Gatter operieren, kontrolliert manipulieren. Für die Prozessoreinheit wird Mangan-pentacarbonyl-bromid (MnBr(CO)5) gewählt und ein Zwei-Qubit-System mit den beiden stärksten IR-aktiven CO-Streckschwingungen (2000 cm^{-1} bzw. 2050 cm^{-1}) definiert. In den quantenmechanischen Untersuchungen wird das System durch seine Schwingungseigenfunktionen repräsentiert. Das zugrunde liegende Modell ergibt sich durch sorgfältige Anpassung an neueste spektroskopische Daten des MnBr(CO)5. Ein dafür im Rahmen dieser Arbeit entwickeltes komplexes Optimierungsverfahren ermöglicht die effiziente Konstruktion des Modells. Einen Schwerpunkt bildet die Berechnung und Untersuchung eines universellen Satzes globaler Quantengatter bestehend aus den Operationen NOT, CNOT, Π und Hadamard. Diese werden mit einem "multi-target-Optimal-Control"-Algorithmus optimiert, der die simultane Optimierung der relevanten Übergänge des jeweiligen Gatters unter Berücksichtigung aller berechneten Eigenfunktionen erlaubt. Schalteffizienz und Struktur des resultierenden Laserfelds hängen dabei maßgeblich von der gewählten Pulsdauer ab. Durch die individuelle Wahl einer günstigen Dauer (5 ps - 11 ps), die sich nach den spektroskopischen Anforderungen der logischen Operationen richtet, ergeben sich erstmals für alle Gatter hocheffiziente und einfach strukturierte Pulse. Besondere Beachtung findet in dieser Arbeit die Gewährleistung experimenteller Umsetzbarkeit des Molekularen Quantencomputings. Untersuchungen zur Erzeugung der optimierten Pulse sind dabei von primärer Bedeutung. Pulszerlegung und die Berechnung von Maskenfunktionen zeigen, dass sich sowohl indirektes als auch direktes Pulsformen für die Generierung der Laserfelder eignen. Gegen dabei entstehende Abweichungen von der optimalen Pulsstruktur sind die Gatter robust. Um die Laser-Molekül-Wechselwirkung im Experiment zusätzlich zu steigern, können die Prozessoreinheiten fixiert und ausgerichtet werden. Dies lässt sich durch Immobilisierung in der Kristallstruktur eines Zeoliths erreichen, wie erste Rechnungen ergeben. Darüber hinaus wird die Relevanz potentieller Störungen des Qubitsystems wie Dissipation und interner Schwingungsumverteilung überprüft. Die Ergebnisse zeigen, dass das Qubitsystem einen nahezu dekohärenzfreien Raum für die Informationsverarbeitung bietet. Durch die sorgfältige Wahl einer geeigneten molekularen Spezies und die auf das Qubitsystem individuell abgestimmten Pulsdauern ist es gelungen, Molekulares Quantencomputing experimentell zugänglich mit hocheffizienten robusten Quantengattern zu implementieren.

Application of Many-Body Perturbation Theory to the Description of Correlated Metals

Play Episode Listen Later Dec 20, 2007


An efficient computational LSDA+DMFT toolbox for the description of correlated materials has been established. The method developed in this work provides an appropriate description of 3d-transition metal correlated bulk systems, concerning their ground-state properties (magnetic moments, total energies) as well as the high- and low-energy spectroscopies (valence-band angular-resolved photoemission, Fano-effect, optical and magneto-optical properties). The incorporation of the perturbational impurity solvers within the spin-polarized relativistic Korringa-Kohn-Rostoker (SPR-KKR) Green’s function method gives rise to a fully self-consistent procedure with respect both to the DFT (charge) and the DMFT (localized dynamical self-energy) self-consistency requirements. Thus, the solution of the many-electron problem can be achieved with a high precision. In turn this opens a possibility to investigate very delicate properties, as the orbital magnetic moments of 3d-transition metals. To develop a relatively fast and accurate approach for the low-energy spectroscopies, the DMFT was implemented within the wave function formalism in the framework of the Linearized Muffin-Tin Orbitals method (LMTO). Calculations are performed in a one-shot run, that does not allow to get the charge-self-consistent solution. In such a way all effects of the localized correlations are encapsulated in the Green’s function constructed as a resolvent to the LMTO one-particle Hamiltonian and accounting for the corresponding self-energy via the Dyson equation. The LMTO+DMFT scheme gives in comparison to a plain LSDA a significantly improved description of the magneto-optics in the 3d-transition metals, half-metallic Heusler ferromagnet NiMnSb, as well as for the heavy-fermion US compound.

Struktur-basiertes Wirkstoffdisign neuer Aldose-Reduktase-Inhibitoren

Play Episode Listen Later Dec 18, 2007


Tue, 18 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8998/ https://edoc.ub.uni-muenchen.de/8998/1/Eisenmann_Michael.pdf Eisenmann, Michael ddc:500, ddc:540, Fakultät für Chemie und Pharmazie

Molekularbiologische Analysen zur Regulation des T-Zell-Rezeptor-beta-Lokus

Play Episode Listen Later Dec 17, 2007


Mon, 17 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7924/ https://edoc.ub.uni-muenchen.de/7924/2/Herbst_Andreas.pdf Herbst, Andreas ddc:500, ddc:540, Fakultät für Chemie und Pharm

Assembly, oriented growth and sorption behavior of microporous films

Play Episode Listen Later Dec 17, 2007


Mon, 17 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7983/ https://edoc.ub.uni-muenchen.de/7983/2/Biemmi_Enrica.pdf Biemmi, Enrica ddc:500, ddc:540, Fakultät für Chemie und Pharmazie

Preparation and Reactions of Allylic Zinc Reagents and Transition Metal-Catalyzed Cross-Coupling Reactions

Play Episode Listen Later Dec 14, 2007


Fri, 14 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7824/ https://edoc.ub.uni-muenchen.de/7824/1/Dunet_Guillaume.pdf Dunet, Guillaume ddc:500, ddc:540,

Herstellung partikulärer Formulierungen für rekombinante Proteine mittels Wirbelschicht

Play Episode Listen Later Dec 6, 2007


Thu, 6 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8100/ https://edoc.ub.uni-muenchen.de/8100/1/Matthias_Ganz.pdf Ganz, Matthias ddc:500, ddc:540, Fakultät für Ch

Die Funktion des cGMP-Kinase Substrates IRAG und der Isoformen der cGMP-abhängigen Proteinkinase Typ I im vaskulären System

Play Episode Listen Later Dec 4, 2007


Tue, 4 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7772/ https://edoc.ub.uni-muenchen.de/7772/1/Bernhard_Dominik.pdf Bernhard, Dominik

Fluoreszenzfarbstoffe für Solarenergie-Anwendungen

Play Episode Listen Later Nov 29, 2007


Thu, 29 Nov 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/11139/ https://edoc.ub.uni-muenchen.de/11139/1/Poxleitner_Simon.pdf Poxleitner, Simon ddc:540, ddc:500, Fakultät für Chemie und Pharmazie

Allgemeine und spezielle Beiträge zur nucleophilen Acyl-Transfer-Katalyse

Play Episode Listen Later Nov 28, 2007


One of the important transformations of alcohols to esters is the reaction with acetic anhydride catalysed by 4-(dimethylamino)pyridine (DMAP) in the presence of an auxiliary base like triethyl amine. Although this is a widely used reaction, several questions left unaddressed until now: the reaction mechanism of the latter transformation was not completely conceived. Since Steglich and Litvenencko found DMAP in 1969 independently as nucleophilic catalyst, there was hardly any effort to search for new nucleophilic catalysts of higher catalytic efficiency than DMAP or 4-(pyrrolidinyl)pyridine (PPY). All chiral nucleophilic catalysts are based on these structural motifs and due to their lack of catalytic efficiency, there are hitherto no examples for kinetic resolution experiments of tertiary alcohols described. In this dissertation, the following goals were achieved: With computational methods, the reaction pathway of tert-butanol with acetic anhydride in the presence of DMAP was explored. Based on these results a fast computational tool was developed to screen for more efficient nucleophilic catalysts. The best candidates were synthesised, the catalytic efficiency quantified and the best catalysts applied in the synthesis of esters. The reaction mechanism of the acetylation of tert-alcohols was explored by calculating the nucleophilic and base catalysed reaction pathway of tert-butanol with acetic anhydride in the presence of DMAP at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory. In the course of this study, a nucleophilic and base catalysed reaction pathway with DMAP as catalyst was found. The energetically lowest transition state of the base catalysed reaction pathway is 37.9 kJ mol-1 higher in energy then the energetically lowest transition state in the rate-determining step of the nucleophilic reaction path. The combination of kinetic measurements with the calculation of the nucleophilic reaction path reveals that no triethyl amine is involved in the rate-determining step of nucleophilic reaction pathway. This shows clearly that nucleophilic catalysis is the preferred and that the acetate anion is deprotonating the alcohol in the rate-determining step. Furthermore, the results of the recalculation of the nucleophilic reaction path with a different catalyst show that a higher stabilisation of the transient acylpyridinium cation has a pivotal influence on the overall reaction rate of the ester formation. Therefore, relative acetylation enthalpies (ΔH298) were calculated at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory by using an isodesmic reaction approach. In this way a large number of new nucleophilic catalysts were screened and numerous promising candidates were synthesised which have a larger negative ΔH298 value then DMAP (-82.1 kJ mol 1). The catalytic effiency of the new nucleophilic catalysts was quantified by a test reaction using 1 equiv. of 1-ethynylcyclohexanol, 2 equiv. of acetic or isobutyric anhydride and 3 equiv. triethyl amine. The conversion of 1-ethynylcyclohexyl acetate or -isobutyrate was monitored by 1H NMR spectroscopy. Pyrido[3,4-b]pyrazine- and pyrido[3,4 b]quinoxaline-derivatives show the best catalytic effiency. Especially (rac) 5,10-diethyl-5,5a,6,7,8,9a,10-octahydropyrido[3,4 b]-quinoxaline (DOPQ) shows equal to better catalytic efficiency then 6,6-tricyloaminopyridine (TCAP), which was hitherto the best nucleophilic catalyst. DOPQ can be synthesised very efficiently in a four step protocol starting from commercially available 3,4-diaminopyridine and cyclohexane-1,2-dione with an overall yield of 45 % while TCAP is only available in a five step synthesis with an overall yield of 8-13 %. The synthesis of DOPQ starts with the Schiff-base formation of 3,4-diaminopyridine and cyclohexane-1,2-dione. Reduction with LiAlH4 yields the cis-configured octahydro[3,4-b]quinoxaline, which can be alkylated without the use of any protecting group in the presence of acetic anhydride in pyridine and subsequent reduction with LiAlH4/AlCl3 to yield DOPQ. The structure of the latter compound was confirmed by X ray single crystal structure. The new catalysts were applied to an enhanced Gooßen esterification to transform sterically hindered acids to their tert-butyl esters. The reaction mechanism was explored by monitoring the substrate, intermediate and product conversions with 1H NMR spectroscopy. With this enhanced reaction protocol, it was possible to transform 1-phenylcyclohexane carboxylic acid into the tert-butyl ester under high concentration conditions at room temperature in the presence of 5 mol% DOPQ within 270 min while with the standard DCC/DMAP protocol only the anhydride of the carboxylic acid is formed. With this very mild method, it was possible to convert a variety of substrates into their tert-butyl- and benzyl esters, which are not accessible with any other method starting from the free carboxylic acid. In the case of chiral substrates no lose of stereochemical information was detected. Combination of high concentration conditions and new catalysts provide attractive reaction times of a few minutes instead of several hours with the Gooßen protocol.

In vivo und in vitro-Untersuchungen zur Calmodulin-abhängigen Regulation des spannungsabhängigen Calcium-Kanals CaV1.2

Play Episode Listen Later Nov 27, 2007


Tue, 27 Nov 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7741/ https://edoc.ub.uni-muenchen.de/7741/1/Peter_Lenhardt.pdf Lenhardt, Peter ddc:

Electrophilic Substitutions of Indoles and Pyrroles:

Play Episode Listen Later Nov 19, 2007


The kinetics of the electrophilic substitutions of indoles and pyrroles have been investigated and new sythetic applications (i.e. electrophilic allylations and benzylations of indoles and regio- and stereoselective ring opening reactions of epoxides with indoles and pyrroles) have been found.

Die Vermittlung der Transkriptionsregulation des viralen Aktivators VP16 durch Cofaktoren

Play Episode Listen Later Nov 19, 2007


Mon, 19 Nov 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7905/ https://edoc.ub.uni-muenchen.de/7905/1/Stuehler_Thomas.pdf Stuehler, Thomas ddc:500, ddc:540, Fakultät für Ch

Strukturen, Magnetismus und Phasenumwandlungen der Mott-Isolatoren Ga(M4-xM’x)Q8 und (M4 xM’x)Q4I4 (M, M’ = Mo, Nb, Ta; Q = S, Se; x = 0 – 4)

Play Episode Listen Later Nov 15, 2007


Thu, 15 Nov 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7765/ https://edoc.ub.uni-muenchen.de/7765/1/Jakob_Stefanie.pdf Jakob, Stefanie

Charakterisierung des humanen HCN3-Kanals und seiner cAMP-Modulierbarkeit im Vergleich zu den anderen humanen HCN-Kanälen

Play Episode Listen Later Nov 13, 2007


Tue, 13 Nov 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7700/ https://edoc.ub.uni-muenchen.de/7700/1/Stoeckl_Georg.pdf Stöckl, Georg dd

Die Funktion der ABC-ATPase Rli1p in der Translation

Play Episode Listen Later Oct 30, 2007


Zusammenfassung: Das Ziel dieser Arbeit war es, die Funktion der hochkonservierten, essentiellen ABC-ATPase Rli1p in Saccharomyces cerevisiae aufzuklären. Es konnte gezeigt werden, dass beide Nukleotid-Bindungsdomänen und eine Scharnierregion, welche die beiden ABC-Domänen miteinander verbindet, wichtig für die Funktion von Rli1p sind. Des Weiteren konnte auch das N-terminale Eisen-Schwefel Cluster Bindemotiv als essentielle Domäne identifiziert werden. Durch Überexpression von inaktiven rli1p-Proteinvarianten wurde ein dominant-negativer Phänotyp erzeugt. Es konnte nachgewiesen werden, dass Rli1p im Zytoplasma lokalisiert ist und mit den Polyribosomen, den 80S Ribosomen und hauptsächlich mit der 40S Untereinheit co-fraktioniert. Des Weiteren konnte gezeigt werden, dass Rli1p mit einem Subkomplex des Translationsinitiationsfaktors eIF3 und ribosomalen Proteinen interagiert. Diese Interaktion ist abhängig von RNA und funktionalen ABC-Domänen, sowie von eIF3j/Hcr1p, einer Untereinheit des Translationsinitiationsfaktors eIF3. Um die zelluläre Funktion von Rli1p näher charakterisieren zu können, wurde versucht eine konditional temperatursensitive Mutante herzustellen und Rli1p durch Repression der Transkription in vivo zu depletieren. Beide Ansätze waren nicht erfolgreich. Aus diesem Grund wurden in vitro Depletionssysteme etabliert. Immundepletion oder Inaktivierung eines mit TEV-Protease spaltbarem Rli1p führte zu einer Reduktion der Translationsaktivität und demonstrierte damit einen direkten Einfluss von Rli1p auf die Translation. Eine vollständige Inhibition der Translation einer Reporter-mRNA konnte durch Zugabe eines a-RLI1-Antikörper erreicht werden, wobei die Translationsextrakte einen Zerfall von den Polyribosomen und der 80S Komplexe in 60S und 40S Untereinheiten aufwiesen. Die Immunoinhibition konnte durch die Zugabe von gereinigtem Rli1p rückgängig gemacht werden. Neben einer biochemischen konnte auch eine genetische Interaktion von RLI1 mit HCR1 nachgewiesen werden. Durch Kombination eines Dhcr1 Knockout mit einem C-terminal markierten Rli1p entstand ein synthetisch-temperatursensitiver Phänotyp. Nähere Untersuchungen dieses Stammes zeigten eine Reduktion von Polyribosomen und einen Defekt bei der 60S Bindung an den Prä-Initiationskomplex, während die Ribosomenbiogenese nicht beeinflusst wurde. Für die zelluläre Funktion von Rli1p konnte ein Modell erarbeitet werden, in dem Rli1p den Translationsinitiationsfaktor eIF3 auf dem 40S Ribosom assembliert oder richtig positioniert. Diese Funktion des Rli1p könnte auch in der Anti-Assoziation von 80S durch eIF1, eIF1A und eIF3 von Bedeutung sein. Dieses Modell soll in Folgeexperimenten geprüft werden und die Bindungsstelle von Rli1p im 43S Prä-Initiationskomplex durch Cryo-EM näher analysiert werden.

Scanning Tunneling Microscopy and Spectroscopy investigations of Graphene on Ru(0001) and (CO+O) on Rh(111)

Play Episode Listen Later Oct 23, 2007


Tue, 23 Oct 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7975/ https://edoc.ub.uni-muenchen.de/7975/1/Marchini_Stefano.pdf Marchini, Stefano ddc:500, ddc:540,

Folding and assembly of RuBisCO

Play Episode Listen Later Oct 22, 2007


To become biologically active, proteins have to acquire their correct three-dimensional structure by folding, which is frequently followed by assembly into oligomeric complexes. Although all structure relevant information is contained in the amino acid sequence of a polypeptide, numerous proteins require the assistance of molecular chaperones which prevent the aggregation and promote the efficient folding and/or assembly of newly-synthesized proteins. The enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), which catalyzes carbon fixation in the Calvin-Benson-Bassham cycle, requires chaperones in order to acquire its active structure. In plants and cyanobacteria, RuBisCO (type I) is a complex of approximately 550 kDa composed of eight large (RbcL) and eight small (RbcS) subunits. Remarkably, despite the high abundance and importance of this enzyme, the characteristics and requirements for its folding and assembly pathway are only partly understood. It is known that folding of RbcL is accomplished by chaperonin and most likely supported by the Hsp70 system, whereas recent findings indicate the additional need of specific chaperones for assembly. Nevertheless, this knowledge is incomplete, reflected by the fact that in vitro reconstitution of hexadecameric RuBisCO or synthesis of functional plant RuBisCO in E. coli has not been accomplished thus far. In this thesis, attempts to reconstitute type I RuBisCO in vitro did not result in production of active enzyme although a variety of reaction conditions and additives as well as chaperones of different kind, origin and combination were applied. The major obstacle for reconstitution was found to be the incapability to produce RbcL8 cores competent to form RbcL8S8 holoenzyme. It could be shown that the RbcL subunits interact properly with the chaperonin GroEL in terms of binding, encapsulation and cycling. However, they are not released from GroEL in an assembly-competent state, leading to the conclusion that a yet undefined condition or (assembly) factor is required to shift the reaction equilibrium from GroEL-bound RbcL to properly folded and released RbcL assembling to RbcL8 and RbcL8S8, respectively. Cyanobacterial RbcX was found to promote the production of cynanobacterial RbcL8 core complexes downstream of chaperonin-assisted RbcL folding, both in E. coli and in an in vitro translation system. Structural and functional analysis defined RbcX as a homodimeric, arc-shaped complex of approximately 30 kDa, which interacts with RbcL via two distinct but cooperating binding regions. A central hydrophobic groove recognizes and binds a specific motif in the exposed C-terminus of unassembled RbcL, thereby preventing the latter from uncontrolled misassembly and establishing further contacts with the polar peripheral surface of RbcX. These interactions allow optimal positioning and interconnection of the RbcL subunits, resulting in efficient assembly of RbcL8 core complexes. As a result of the highly dynamic RbcL-RbcX interaction, RbcS can displace RbcX from the core-complexes to produce active RbcL8S8 holoenzyme. Species-specific co-evolution of RbcX with RbcL and RbcS accounts for limited interspecies exchangeability of RbcX and for RbcX-supported or -dependent assembly modes, respectively. In summary, this study helped to specify the problem causing prevention of proper in vitro reconstitution of type I RuBisCO. Moreover, the structural and mechanistic properties of RbcX were analyzed, demonstrating its function as specific assembly chaperone for cyanobacterial RuBisCO. Since the latter is very similar to RuBisCO of higher plants, this work may not only augment the general understanding of type I RuBisCO synthesis, but it might also contribute to advancing the engineering of catalytically more efficient crop plant RuBisCO both in heterologous systems and in planta.

Overexpression and purification of membrane proteins in yeast

Play Episode Listen Later Oct 19, 2007


Fri, 19 Oct 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9088/ https://edoc.ub.uni-muenchen.de/9088/1/Le_Bris_Anna.pdf Le Bris, Anna ddc:500, ddc:540, Fakultät für Chemie und Pharmazie

Selektive Bindung synthetischer Kollagenmodellpeptide mit Adhäsionsmotiv und Integrin an funktionalisierten Oberflächen und artifiziellen Membransystemen

Play Episode Listen Later Oct 16, 2007


Zelladhäsion wird durch definierte Erkennungsepitope der extrazellulären Matrixproteine vermittelt. Diese werden durch Plasmamembranproteine erkannt und gebunden. Unter den Zelladhäsionsrezeptoren dominieren Integrine. Im Mittelpunkt dieser Arbeit stand die Entwicklung eines Modellsystems, das eine detaillierte Untersuchung von Zell-Oberflächen-Interaktionensprozessen ermöglicht.

Single Molecule Traffic in Mesoporous Materials and New Photostable Water-Soluble Terrylenediimide Derivatives

Play Episode Listen Later Oct 16, 2007


Tue, 16 Oct 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7840/ https://edoc.ub.uni-muenchen.de/7840/1/Jung_Christophe.pdf Jung, Christophe ddc:500, ddc:5

Unfolding and compaction in chaperonin-assisted protein folding followed by single molecule and ensemble FRET

Play Episode Listen Later Oct 9, 2007


To become biologically active, most proteins need to fold into precise three dimensional structures. It has been well established that all the folding information is contained within the primary structure of a protein. However, the mechanisms utilized by proteins to avoid sampling the extraordinarily large amount of possible conformations during their folding process are just beginning to be understood. Molecular chaperones assist the folding of newly synthesized and denatured proteins in acquiring their native state in the crowded intracellular environment. As a nascent chain leaves the ribosome, it is captured first by the upstream chaperones and then possibly transferred to the downstream chaperonins. GroEL-GroES, the Hsp-60 of E.coli, is one of the best studied chaperone systems. An appreciable amount of data is available providing information regarding its structure and function. GroEL encapsulates the substrate into the central cavity where folding occurs unimpaired by aggregation and unwanted inter-molecular interactions. Nevertheless, many important aspects of the GroEL mechanism remain to be addressed. Some of the open questions we have addressed in this study include: In what conformation does a substrate protein bind to the apical domains of GroEL; how is it that GroEL is able to accelerate the rate of folding of certain proteins, and how do the conformational properties of the substrate change as it undergoes repeated cycling. By using ensemble FRET and Sp-FRET (Single Pair-Fluorescence Resonance Energy Transfer), we have probed the conformation of the model substrate DM-MBP (Double Mutant Maltose Binding Protein) during different stages of the functional cycle of GroEL. With Sp-FRET coupled to PIE (Pulsed Interleaved Excitation), we have been able to explore the heterogeneity of the GroEL bound substrate protein and observed a bimodal conformational distribution. One of the two populations is as compact as the native state, whereas the other is as extended as the unfolded protein in denaturant. This unfolding is a local phenomena and can also be observed when the substrate is transferred from DnaK/J system (bacterial Hsp70) to GroEL, indicating the possibility of the existence of this conformational heterogeneity in vivo as the protein follows the cellular chaperone pathway. Subsequent to GroEL binding, there is a transient expansion of the protein upon binding of ATP to GroEL, followed by compaction when GroES triggers the encapsulation of the protein inside the chaperonin cage. This transient expansion is however found not to be a necessary event for the rate acceleration of DM-MBP folding, since ADP-AlFx (transition state analogue of ATP hydrolysis) results in a much slower rate of expansion, which does not cause a change in the folding rate. Anisotropy measurements, probing the freedom of motion of different regions of the GroEL bound protein, revealed that there is a segmental release of the substrate protein from the GroEL surface upon binding of ATP and GroES. As a consequence, the hydrophobic collapse of the protein upon encapsulation by GroES follows a step-wise mechanism. In this process, less hydrophobic regions are released upon binding of ATP, prior to more hydrophobic ones which are released only by GroES binding. Thus, the order of Hydrophobic collapse is reversed as compared to spontaneous folding possibly resulting in conformationally different folding intermediates. Evidence that the folding pathway inside the cage differs from that of spontaneous folding was obtained by observing the effect of external perturbations (e.g. mutations in substrate protein and use of different solvent conditions) on the rate of spontaneous and GroEL assisted folding reactions. These two folding reactions respond differently to the introduced perturbations. Kinetic data obtained from ensemble FRET measurements suggest that the conformation of refolding intermediate is altered by the GroEL cavity, which leads to a folding pathway that is different from the spontaneous refolding pathway. In summary, this study revealed significant novel aspects of the GroEL folding mechanism and provided insights into the basis of rate acceleration of the substrate protein by the chaperonin. This work may thus contribute to advance our fundamental knowledge of the chaperonin system and the basic mechanism of protein folding.

Synthese und Untersuchungen eines alpha-konfigurierten, oxidativen DNA-Schadens (alpha-cFaPydG) sowie Entwicklung einer PNA-Templat dirigierten Ligationsstrategie

Play Episode Listen Later Oct 2, 2007


Following oxidative stress often two kinds of DNA-lesions can be found: 8-OxodG and the 2,6-Diamino-4-hydroxy-5-formamidopyrimidine (FaPydG). Both derive from the DNA-Nucleobase guanine. The FaPydG-lesion can exist both in the beta-configuration and the alpha configuration. To clarify biological questions concerning the basepairing and the encoding features of both forms it was necessary to synthesise of the alpha-anomer of the carbocyclic FaPydG-DNA-lesion. The synthesis of the beta-cFaPydG-lesion was already finished in 2005 in the Carell group. In a sixteen-step synthesis the alpha-lesion could be prepared in the form of its phosphoramidite component. Oligonucleotides could be prepared on solid support using automated DNA-synthesis. Some of the synthesised DNA-Nucleotides contained the inserted FaPydG-lesion. Others showed an oxidation to alpha-c8-OxodG. This reaction is not known for natural lesion. Just a de-hydration to guanosine under harsh conditions is described. The observations can be ex-plained by formulation of a cyclic intermediate, which is possibly oxidized by the oxidation di-lution during the DNA-synthesis. If the sequence-dependent equilibrium between alpha cFaPydG and alpha c8-Hydro,hydroxydG is at the side of the closed form, an oxidation from this interme-diate directly to 8-OxodG is imaginable. This assumption is proven by the fact that at the same time synthesised and completely identically treated DNA-strands of different sequence didn´t show oxidation products. This could be ascertained by high resolution ESI-FTICR-mesurement. With this analytical method even smallest variations are detectable in a reliable way, whereas the often used MALDI-TOF-mesurements not always show these variations. Thermodynamic studies showed that alpha-cFaPydG doesn´t form a preferred DNA-basepair. All possible basepairs showed a strong destabilisation in comparison to the undamaged, cor-rect basepair. In vitro elongation experiments with S. cerevisiae polymerase Pol eta, G. stearothermophilus DNA-polymerase I and DinB from G. stearothermophilus showed that the alpha-lesion is a definitive block for all mentioned polymerases. Only by applying rigorous re-action conditions an elongation of the primer with BstPol I could be detected. This elongation showed a favored incorporation of dCTP, followed by an incorporation of dATP. In the time to come experiments to avoid the unwanted oxidation of alpha-cFaPydG will be es-sential to promote the cocristallisation of the alpha-cFaPydG-oligomere with the Fpg-protein from Lactococcus lactis and the BstPol I. In the second part of the thesis attempts were taken to prepare tetrafunctional amino acid derivatives, which were planned to be used in a PNA-template directed ligation reaction. Liga-tion takes place between two amino acids, so that for a ligation attempt with this method there is always needed a matching pair of amino acids. This pair requires a connection of the aminoacid to the PNA over the side chain of the amino acid. The N- and C-terminus of the amino acid had to be unprotected for the ultimate ligation reaction. These termini must not react during the solid support PNA-synthesis. After ligation the template should be separated selectively. Thus, the following requirements for the pair of amino acids result: The amino acids have to possess functional side chains, which exist naturally after cleavage of the PNA-template. For the selective cleavage of the template a con-nection orthogonal to acid and base unstable protecting groups is necessary, because these are already needed for the solid support synthesis on the residual three termini of the compound. Imaginable orthogonal cleavable links are allylic compounds, which are cleavable with Pd(0), but also silicon based compounds, which are cleavable with fluoridions, would be appropriate. In the area of the Pd(0)-cleavable link a retrosynthetic cut at this funtionality should be adequate. Here, e.g. a Horner-Wadsworth-Emmons-reaction is imaginable. The aldehydes and phosphorylides needed for this key step could be prepared with good yields, however only one of the two amino acid derivatives was obtained. The synthesis of the other compound didn´t succeed under diverse reaction conditions. Also efforts to prepare analogue Pd(0)-cleavable link molecules through classic Wittig or metathese reactions with Grubbs catalysts of the first and second generation were unsuccessful. The most successful efforts to make a target molecule synthetically accessible for a first liga-tion attempt involved the preparing of a fluorid-cleavable silyl link. Here all requirements stay the same, just instead of allylic compounds silyl ethers are needed. The acid stability of the silyl protecting group depends on the size of the alkyl groups (tert-butyl>isopropyl>ethyl). Firstly, substitution experiments with the compounds Di-tert-butylchlorosilane, Di-tert-butyl-dichlorosilane and Di-tert-butylsilylbis(trifluoromethanesulfonate) were undertaken to estab-lish a connection between PNA and the amino acid through a Di-tert-butyldisilylether. How-ever, the substitutions produced just monosubstituted silanoles, irrespective of the choice of reaction conditions and substitution order. The experiments with the commercially available (3-Cyanopropyl)-diisopropyl-chlorosilane were more successfull. Here the synthesis of one of the target molecules could be achieved.

Koordinations- und Kupplungs-Reaktionen von Aziridinen mit Übergangsmetallen

Play Episode Listen Later Sep 27, 2007


Übergangsmetall-Komplexe bzw. -Salze von Mangan, Rhodium, Iridium, Palladium und Kupfer wurden mit verschiedenen Aziridinderivaten umgesetzt. Dabei gelang es neutrale und kationische Mono-, Bis-, Tris- und Tetrakis-Aziridin-Komplexe darzustellen. Auch eine übergangsmetallvermittelte Aziridin-Dimerisierung konnte desöfteren beobachtet werden. Dabei entstanden N-(2-Aminoalkyl)aziridin-Komplexe. Durch die gelungene Freisetzung des formal dimerisierten Aziridinliganden, konnte eine übergangsmetallvermittelte Synthese von N-(2-Aminoalkyl)aziridinen beschrieben werden.

Ölige Suspensionen als parenterale Depotsysteme für rekombinante Proteine

Play Episode Listen Later Sep 25, 2007


Untersuchung öliger Suspensionen als parenterale Depotsysteme für rekombinante Proteine

Characterization of Novel Reference Electrophiles and Nucleophiles for the Construction of Comprehensive Reactivity Scales

Play Episode Listen Later Sep 24, 2007


Mon, 24 Sep 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7869/ https://edoc.ub.uni-muenchen.de/7869/1/Berger_Stefan.pdf Berger, Stefan dd

Diffusion of single molecules in nanoporous mesostructured materials

Play Episode Listen Later Sep 20, 2007


Single-molecule methods play a growing role in materials science because they can reveal structural and dynamic features which are obscured by ensemble averaging in conventional spectroscopic techniques. In this work, such methods were used to study the dynamics of single dye molecules (guests) within different surrounding porous matrices (hosts) using wide-field microscopy and single-molecule tracking. A significant amount of tracking data was collected and sophisticated methods to analyse the data according to diffusion theory were developed. A method was established to directly correlate the diffusion information that is provided by single-molecule trajectories with the images of the porous host systems obtained by transmission electron microscopy (TEM). Furthermore, the results from single-molecule tracking experiments were compared with diffusion measurements using pulsed-field gradient NMR in the same samples. The data presented in this thesis thus provide for the first time a detailed picture of the real mesoporous structure and its effects on the dynamic behavior of dye molecules at the nanometre to micron scale, e.g.~information about pore connectivity and accessibility. The methodology established here is expected to provide detailed insights into the dynamics of other important host-guest systems, such as bioactive molecules in porous materials for drug delivery or reactants in porous catalysts.

Role of nuclear RNP assembly in cytoplasmic mRNA localization

Play Episode Listen Later Sep 6, 2007


Messenger RNA localization occurs in the cytoplasm and allows temporal and spatial regulation of gene expression. In yeast, the localization of ASH1 mRNA to the tip of budding cells allows the asymmetric sorting of Ash1 protein, which has a key function in the regulation of mating-type switching. After cell division, asymmetric distribution of Ash1p restricts mating type switching to only the mother cell. The cytoplasmic transport of ASH1 mRNA to the bud tip depends on the myosin Myo4p, its adaptor She3p, and the specific RNA binding protein She2p. Three additional trans-acting factors Khd1p, Puf6p and Loc1p are involved in this process. All known RNA-binding proteins of ASH1 mRNA have revealed a nuclear connection, when following their cellular distribution by indirect immunofluorescence. Thus, an early step in the localization pathway might be the early recruitment of specific trans-acting factors to the mRNA already in the nucleus. The aim of this thesis was to investigate how nuclear key events such as early binding to localized transcripts and the subsequent assembly into a nuclear RNP can account for effective RNA localization. Following the route of She2p, it was possible to show nucleo-cytoplasmic shuttling of this RNA binding protein. Moreover, ASH1 mRNA and She2p were found accumulated within the nucleolus upon arrest of mRNA export. Interestingly, two additional trans-acting factors, Loc1 and Puf6p, both involved in ASH1 mRNA localization are also nucleolar proteins. Moreover, She2’s nuclear history seems to be important for an effective sorting of Ash1p. When restricting ASH1-She2p association to the cytoplasmic compartment artificially, the ASH1 mRNA was still localized but was prematurely translated during its transport. This suggests that nuclear RNP assembly has an influence on the later stages of cytoplasmic translational control. The nucleolus might represent the appropriate cellular compartment to provide the spatial framework for the assembly of localization competent RNPs since many RNPs are assembled in this region.

Hydroaminierungsreaktionen für neue Synthesen biologisch aktiver Heterocyclen

Play Episode Listen Later Aug 13, 2007


In dieser Dissertation wurden titankatalysierte Hydroaminierungsreaktionen von Alkinen und Alkenen durchgeführt. Außerdem wurde eine Methode für eine indirekte Hydratation von Alkinen mit anti-Markownikow-Regioselektivität entwickelt. Abschließend gelang es Hydroaminierungsreaktionen in der Synthese von biologisch aktiven Heterocyclen, wie Cumaronen, Indolen, Pyrrolen und Pyrrolidinen einzusetzen.

Structural Features of the GroEL-GroES Nano-Cage Required for Rapid Folding of Encapsulated Protein

Play Episode Listen Later Aug 2, 2007


Thu, 2 Aug 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7304/ https://edoc.ub.uni-muenchen.de/7304/1/Tang_YunChi.pdf Tang, Yun-Chi ddc:540, ddc:500, Fakult

Scale-Up of Liposome Manufacturing

Play Episode Listen Later Jul 30, 2007


The study provides a comprehensive overview on different stabilization techniques for liposomal formulations. The selection of the appropriate technology for a particular formulation can thereby be based on several considerations. If free flowable particulate bulk material is desired the spraying-technologies are preferred over lyophilization. Another advantage of spraying-based technologies is the possibility to combine the liposome formation step and the drying step within the same process. It is a prerequisite for the selection of the stabilization technique that the integrity of the liposomes is preserved with the incorporated drug after the process. Spray-drying is related to a thermal stress for the formulation but only for a short time. For heat labile drugs processes with low process temperatures, e.g. freeze-drying, spray freeze-drying, inert-spray drying or supercritical drying are most adequate. However, for technologies with a freezing step a sufficient stabilization against freezing induced stress e.g. by the selection of appropriate cryoprotectors is needed.

Untersuchung der Funktion und Dynamik von DNA-Transkriptionsfaktoren mittels Einzelmolekül-Fluoreszenzmikroskopie

Play Episode Listen Later Jul 27, 2007


Fri, 27 Jul 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7659/ https://edoc.ub.uni-muenchen.de/7659/1/Schluesche_Peter.pdf Schlüsche, Peter ddc:500, d

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