La proline est un acide aminé unique qui se caractérise par un cycle pyrrolidine qui lui confère des propriétés physiques et chimiques spécifiques comparé aux autres 20 acides aminés acycliques retrouvés de façon majoritaire dans le protéome humain. Cette différence se retrouve également dans les motifs polyproline et est utilisée par la Nature en de nombreuses façons comme le repliement des protéines, les mécanismes régulatoires liés à l’activité de certaines protéases, la formation de structures secondaires, le biomarquage de peptides substrats des oligopeptidases, et le clivage des motifs diproline par les proline-proline endopeptidases. La proline a par conséquent été un centre d’intérêt pour les chimistes médicinaux lors du développement d'agents thérapeutiques. Cette thèse se propose d’étudier plusieurs composés biologiquement actifs dérivés de la proline. La première étude relate les avancements liés au composé SH-BC-893, un azacycle contraint dérivé de FTY720 développé au sein du groupe Hanessian. SH-BC-893 est un agent anticancéreux qui permet l’affamement des cellules cancéreuses au travers de la disruption de l’apport des nutriments cellulaires externes et internes. Par son activation de la protéine phosphatase 2A, il permet d’internaliser les récepteurs transmembranaires d’acides aminés et de glucose et de réguler à la baisse les récepteurs de lipides à faible densité. Son action permet également la perturbation de la dégradation de nutriments internes provenant de la macropinocytose et de l’autophagie en prévenant la fusion entre le lysosome et les endosomes respectifs. Afin d’augmenter l’activité de SH-BC-893, deux séries de composés ont été synthétisés et testés en vue d’une activité double. La première série a eu pour but de cibler HDAC2 suite à une étude de Spiegel au sein de laquelle son inhibition a été rapportée pour FTY720. La seconde a visé à obtenir des composés activant d’autres portions ou d’autres homologues de PP2A via l’insertion de fragments tricycliques suite aux études rapportant l’activation de PP2A par des dérivés de composés neuroleptiques tricycliques du type de la perphénazine. La synthèse et les tests biologiques de ces composés sont également décrits. Le deuxième chapitre décrit la synthèse d’une série de morpholines pontées comportant le motif de l’acide gamma-aminobutyrique (GABA) contraint. GABA est un composant prépondérant de la régulation du système nerveux central au travers de son action inhibitrice sur les neurorécepteurs GABA-A, GABA-B, GABA-C. De nombreux agents thérapeutiques inspirés de GABA ont été développés avec les années, notamment baclofen. Les morpholines pontées rapportées ici possèdent un centre quaternaire stéréocontrôlé pour lequel un ensemble de substituants a été varié, incluant le groupement phényle para-chloré du baclofen ainsi que l’iso-butyle de la Pregabalin, autre composé actif dans le système nerveux central dérivé de GABA. La modélisation du dérivé du baclofen a été réalisée au sein du site actif de GABA-B. L’ensemble des composés ont également été modélisés sous forme d’acides aminés au sein de la base de données LLAMA afin de déterminer leur capacité à occuper l’espace de Lead-likeness et confirmer qu’ils satisfont les conditions de Lipinski. La troisième partie décrit la synthèse d’un nouveau mime de diproline, nommé ProCyp. Le dimère est composé d’un noyau pyrrolidine attaché à une unité cyclopentane à l’aide d’un pont méthylène hydroxylé. Les quatre isomères cyclopentanes trans dérivés de la (L)-proline ont été synthétisés et leur stéréochimie absolue a été déterminée par étude RMN et de cristallographie. Ces composés représentent la première forme de mimes de diproline de type ProCyp et peuvent être intégrés au sein de peptidomimétiques afin de mimer l’aspect structurel des diprolines ainsi que l’intermédiaire tétrahédral des ProPro endopeptidases. L’ensemble des isomères disponibles permet de choisir le plus opportun à l’appuis d’études de modélisation. Le dernier chapitre rapporte le développement de deux séries de composés incluant le dimère ProCyp. Les motifs polyproline sont de prime importance pour de nombreux mécanismes de reconnaissance par la Nature, en particulier dans les voies de signalisation dont le dérèglement peut entrainer une myriade de troubles de santé notamment inflammatoires, immunitaires et cancéreux. La première application est centrée sur la synthèse et les tests biologiques de peptidomimétiques du motif riche en proline du peptide p22phox, sous-unité de la NADPH oxidase 2 (NOX2) dont la reconnaissance par le domaine riche en proline de p47phox permet l’assemblage de NOX2 nécessaire à son activité. Lors de stress cellulaire externe, cet assemblage peut devenir excessif et engendrer un excès de production d’espèces réactives d’oxygènes, entrainant un ensemble de biomécanismes délétaires pour l’hôte. Les peptidomimétiques comportent un cœur triproline, dont deux des trois prolines ont été remplacées par le module ProCyp. Le meilleur isomère a été sélectionné sur la base de la modélisation moléculaire afin de mimer les angles de torsion de la triproline correspondant à une hélice de type polyproline II. La deuxième application concerne le développement de peptidomimétiques inhibiteurs de la ProPro endopeptidase (PPEP-1) de Clostridium difficile (C. diff). C. diff a été identifiée comme une des menaces nosocomiales majeures en raison de son caractère opportuniste lorsque la flore intestinale des patients est détruite suite à un traitement impliquant la prise soutenue d’antibiotiques. C. diff possède un arsenal de mécanismes d’évasion et de prolifération au sein de l’hôte incluant la formation de colonies recouvertes d’un biofilm protecteur sur la paroi epithéliale de l’hôte lors de la réponse immunitaire. Ces mécanismes sont complétés à l’aide de peptidases qui leurs permettent de couper les flagelles d’ancrages, dont PPEP-1. Le site de scission P1-P1’ de PPEP-1 implique deux prolines, flanquées par une séquence peptidique clairement identifiée. Une série de peptides basés sur cette séquence dont la diproline centrale a été remplacée par le dimère ProCyp a été synthétisée. L’isomère ProCyp a été choisi sur la base de son recouvrement avec l’heptapeptide cristallisé au sein d’un mutant de PPEP-1 par le Pr. Baumann. / Proline is a unique amino acid characterized by a cyclic side chain that gives it specific physical and chemical properties compared to the other 20 acyclic amino acids found in the human proteome. This difference is also found in polyproline motifs and is used by Nature in many ways such as protein folding, regulatory mechanisms related to the activity of certain proteases, formation of secondary structures, biomarking of peptide substrates of oligopeptidases, and cleavage of diproline motifs by proline-proline endopeptidases. Proline has therefore been a focus of interest for medicinal chemists in the development of therapeutic agents. This thesis proposes to study several biologically active compounds derived from proline. The first study reports on the advances related to the compound SH-BC-893, a constrained azacycle derived from FTY720 developed within the Hanessian group. SH-BC-893 is an anti-cancer agent that allows the starvation of cancer cells through the disruption of external and internal cellular nutrient supply. Through its activation of protein phosphatase 2A, it internalizes transmembrane amino acid and glucose receptors and downregulates low-density lipid receptors. Its action also allows the disruption of internal nutrient degradation from macropinocytosis and autophagy by preventing fusion between the lysosome and the respective endosomes. To enhance the activity of SH-BC-893, two series of compounds were synthesized and tested for dual activity. The first set aimed at targeting HDAC2 following a study by Spiegel in which its inhibition was reported for FTY720. The second set aimed at obtaining compounds activating other portions or homologs of PP2A via the insertion of tricyclic fragments following studies reporting PP2A activation by derivatives of tricyclic neuroleptic compounds of the perphenazine type. The synthesis and biological tests of these compounds are also described. The second chapter describes the synthesis of a series of bridged morpholines with a constrained gamma butyric amino acid (GABA) motif. GABA is a major component of central nervous system regulation through its inhibitory action on GABA-A, GABA-B, GABA-C neuroreceptors. Many therapeutic agents inspired by GABA have been developed over the years, notably baclofen. The bridged morpholines reported here have a stereocontrolled quaternary center for which a variety of substituents have been used, including the para-chlorophenyl of baclofen and the iso-butyl of Pregabalin, another GABA-derived compound active in the central nervous system. The baclofen derivative was modeled within the GABA-B active site. All compounds were also modeled as amino acids within the LLAMA database to determine their ability to occupy the lead-likeness space and confirm that they satisfy the Lipinski conditions. The third part describes the synthesis of a new diproline mime, named ProCyp. The dimer is composed of a pyrrolidine ring attached to a cyclopentane unit by means of a hydroxylated methylene bridge. The four trans cyclopentane isomers derived from (L)-proline were synthesized and their absolute stereochemistry was determined by NMR and crystallographic studies. These compounds represent the first form of ProCyp-type diproline mimes and can be incorporated into peptidomimetics to mimic the structural aspect of diprolines as well as the tetrahedral intermediate of ProPro endopeptidases. The set of available isomers allows to choose the most appropriate one to support modeling studies. The final chapter reports the development of two series of compounds including the ProCyp dimer. Polyproline motifs are of prime importance for many of Nature's recognition mechanisms, particularly in signaling pathways whose dysregulation can lead to a myriad of health disorders including inflammatory, immune and cancerous. The first application is focused on the synthesis and biological testing of peptidomimetics of the proline-rich motif of the peptide p22phox, a subunit of NADPH oxidase 2 (NOX2) whose recognition by the proline-rich domain of p47phox allows the assembly of NOX2 necessary for its activity. During external cellular stress, this assembly can become excessive and lead to an excess of reactive oxygen species production, resulting in a series of deleterious biomechanisms for the host. The peptidomimetics comprise a triproline core, of which two of the three prolines have been replaced by the ProCyp module. The best isomer was selected on the basis of molecular modeling to mimic the torsion angles of the triproline corresponding to a polyproline II helix. The second application concerns the development of peptidomimetics that inhibit the ProPro endopeptidase (PPEP-1) of Clostridium difficile (C. diff). C. diff has been identified as one of the major nosocomial threats due to its opportunistic nature when the intestinal flora of patients is destroyed following treatment with sustained antibiotics. C. diff has an arsenal of mechanisms of escape and proliferation within the host including the formation of colonies covered by a protective biofilm on the host epithelial wall during the immune response. These mechanisms are complemented by peptidases that allow them to cleave anchoring flagella, including PPEP-1. The P1-P1' cleavage site of PPEP-1 involves two prolines, flanked by a clearly identified peptide sequence. A series of peptides based on this sequence with the central diproline replaced by the ProCyp dimer was synthesized. The ProCyp isomer was chosen on the basis of its overlap with the heptapeptide crystallized in a PPEP-1 mutant by Prof. Baumann.

No description available.

The Glycine and Proline Reduction systems are two of the best characterized selenoenzymes in bacteria and have been found to occur in a wide variety of clostridia [1-5]. These enzymes are utilized to reduce glycine or D-proline to obtain energy via substrate level phosporylation or membrane gradients, respectively [6, 7]. This includes the pathogens C. difficile and C. botulinum [5, 8]. Strains of C. difficile are activate toxigenic pathways whenever either of these pathways is active within the cell [5, 8]. Though evolutionary studies have been conducted on ammonia producing bacteria [9] none has been done to directly characterize these two system by themselves. This includes an understanding of whether or not this system is transferred between organisms, as many of the clostridia that are to be studied are known to have an “open genome.” [8, 10] With this information we were able to generate a phylogenic model of the proline and glycine reduction systems. Through this analysis, we were able to account for many clostridial organisms that contain the system, but also many other organisms as well. These included enterobacteriaceae including a strain of the model organism, Escherichia coli. It was further concluded that Glycine Reductase was a much less centralized system and included a wide range of taxa while Proline Reductase was much more centralized to being within the phyla of firmicutes. It was also concluded that the strain of E. coli has a fully functional operon for Glycine Reductase.

No description available.

No description available.

The N-terminal tails of histone proteins protrude from the nucleosome core and are extensively post-translationally modified. These modifications are proposed to affect many DNA-based processes such as transcription, DNA replication and repair. Post-translational modifications on histone tails do not act independently but are subject to crosstalk. One example of crosstalk is on histone H3 between lysine 14 (H3K14) and trimethylated lysine 4 (H3K4me3), a modification found at the 5’ end of most active or poised genes. In this work, Western blots and chromatin immunoprecipitation (ChIP) experiments show that different amino acid substitutions at histone H3 position 14 cause varying degrees of H3K4me3 loss, indicating that H3K14 is not essential for H3K4me3 but acts as a modulator of H3K4me3 levels. A neighbouring residue, H3P16 is also important for H3K4me3 and may operate in concert with H3K14 to control H3K4me3. These crosstalk pathways have gene-specific effects and the levels of H3K4me3 are influenced to different extents on genes that fall into functionally distinct classes. A model is proposed to explain how H3K14/H3P16 may exert these varying effects on H3K4me3 at individual genes. In addition to its ability to regulate H3K4me3, H3K14 also influences the levels of two modifications on H3K18, acetylation and monomethylation. A ChIP-sequencing experiment has shown that H3K18me1, a previously uncharacterised modification in S. cerevisiae, is widely distributed throughout the genome and correlates strongly with histone H3 levels. The potential for a functional acetyl/methyl switch at H3K18 is explored. Together, these data indicate that, with gene-specific effects, crosstalk between histone modifications may be even more complex than originally thought.

In der vorliegenden Dissertation geht es um die Synthese und Charakterisierung chiraler, redoxaktiver (Raumtemperatur-)Ionischer Flüssigkeiten basierend auf Ferrocen und der natürlich vorkommenden Aminosäure S-Prolin. Diese Baueinheiten sind entweder über eine Ether- oder über eine Esterverbrückung verknüpft. Auch der Anionenaustausch vom I– - zum CF3SO3– - sowie (CF3SO2)2N– -Salz (kurz NTf2–) wird dargelegt und der Einfluss des Anions auf den Schmelzpunkt der Verbindungen untersucht und diskutiert. Die Redoxaktivität wird durch das im Ferrocen enthaltene Fe II eingebracht, das reversibel zu Fe III oxidiert werden kann. Aufgrund des Pyrrolidin-Rings sind die dargestellten Verbindungen stets chiral und bilden nach der Quaternisierung mit Halogenalkanen Diastereomere, soweit die Alkylkette größer als Methyl ist. Das Diastereomerenverhältnis wurde mittels 1H-NMR-Spektroskopie und in einem Fall anhand von Röntgenpulverdiffraktogrammen durch Rietveld-Verfeinerung analysiert. Die Verbindungen wurden thermisch anhand simultaner thermischer Analysenund Tieftemperaturversuchen untersucht, die belegen, dass die Synthese von insgesamt sechs neuen Raumtemperatur-Ionischen Flüssigkeiten gelang. Davon basiert eine Verbindung, (1S2S)- und (1R2S)-2-[(Ferrocenylcarbonyl)oxy]methylen-N-methyl-N-pentylpyrrolidin-1-iumiodid, auf I– und fünf Verbindungen enthalten NTf2– als Gegenion. Das Diastereomerengemisch der Verbindungen (1S2S)- und (1R2S)-N-Butyl-2-[(ferrocenylcarbonyl)oxy]methylen-N-methylpyrrolidin-1-ium NTf2– besitzt den größten Flüssigkeitsbereich von -25 bis +263 °C und auch die höchste Zersetzungstemperatur aller hier dargestellten Verbindungen. Insgesamt werden in dieser Arbeit elf Einkristallstrukturanalysen vorgestellt, wobei es sich um drei Verbindungen des Typs FcCH2N(CH3)2(CnH2n+1)I (Fc = Ferrocenyl, n = 1,2,3), Ferrocenmonocarbonsäurechlorid, zwei ether- sowie fünf esterverbrückte Verbindungen handelt. Mikrokristalline Proben wurden mittels Röntgenpulverdiffraktometrie charakterisiert. Ergänzende Analysen wurden mittels UV-Vis- und IR-Spektroskopie sowie Massenspektrometrie und Elementaranalyse durchgeführt. Ein wichtiger Aspekt bei Ferrocenverbindungen ist das Redoxpotential, welches mittels Cyclovoltammetrie bestimmt wurde. Hierbei liegt das Formalpotential des Fe II /Fe III -Redoxpaars der etherverbrückten Verbindungen bei +0,05 V und bei den esterverbrückten Verbindungen unabhängig vom Anion bei +0,28 V vs. Ferrocen/Ferrocenium in Acetonitril. Bei den iodidhaltigen Verbindungen zeigt das I– -Ion ebenfalls eine Redoxaktivität bei E(0,f,Fc) = -0,18 V und 0,22V. Die Diffusionskoeffizienten der esterverbrückten Triflat- und NTf2– -Verbindungen liegen in der Größenordnung von 7·10−6 cm2/s und die heterogenen Geschwindigkeitskonstanten bei 0,01 cm/s. / The present dissertation deals with the synthesis and characterization of chiral, redoxactive room temperature ionic liquids (RTILs) based on ferrocene and the naturally occurring amino acid S-proline. These building blocks are coupled either via an ether- or an ester-bridge. The anion exchange from I– to CF3SO3– and (CF3SO2)2N– salts (abbreviated as NTf2–) is presented. The influence of the anion on the melting point of the compound is investigated and discussed. The redox activity is introduced into the molecule via the Fe II -containing ferrocenyl groups, which can be oxidized reversibly to Fe III . The synthesized compounds based on the pyrrolidine ring are chiral. After quaternization with alkyl halides, they form diastereomers in case of alkyl chains longer than methyl. The ratio of the different diastereomers was analyzed by 1H NMR spectroscopy and, in one case, by Rietveld refinement of the X-ray powder diffraction pattern. The thermal behavior of the compounds was studied by simultaneous thermal analysis and low temperature experiments. The results show the successful synthesis of six new RTILs. One of them is based on iodide ((1S2S)- and (1R2S)-2-[(ferrocenylcarbonyl)oxy]methylene-N-methyl- N-pentylpyrrolidine-1-ium iodide) and six RTILs contain NTf2– as counter ion. The diastereomeric mixture of compounds (1S2S)- and (1R2S)-N-butyl-2-[(ferrocenylcarbonyl)oxy]methylene-N-methylpyrrolidine-1-ium NTf2– exhibits the widest liquid range from -25 to +263 °C and the highest decomposition temperature of all compounds presented herein. Eleven single crystal structure analyses are presented. Three of them belong to compounds FcCH2N(CH3)2(CnH2n+1)I (with Fc = ferrocenyl and n = 1,2,3), then ferrocene monocarboxylic acid chloride, two of ether- as well as five ester-bridged compounds. Microcrystalline samples were characterized by X-ray powder diffractometry. Supplementary analyses by UV/Vis and IR spectroscopy as well as mass spectrometry and elemental analyses have been carried out. An important feature of ferrocene containing compounds is their redox potential which is determined with cyclic voltammetry. The formal potential of the Fe II /Fe III redox couple in the ether-bridged compounds is at +0.05 V and in the ester-bridged compounds independent from the type of anion at +0.28 V vs. ferro- cene/ferrocenium in acetonitrile. The I– anion shows as well redox activity with formal potentials at E(0,f,Fc) = -0.18 V and 0.22 V. The diffusion coefficients of the ester-bridged triflate and NTf2– compounds are in the order of 7·10−6 cm2/s, the heterogeneous rate constants in the order of 0.01 cm/s.

O capim tanzânia (Panicum maximum cv. Tanzânia) é promissor para uso em fitorremediação, devido ao seu sistema radicular extenso, boa adaptação a variados ambientes e alto rendimento de biomassa quando bem nutrido. O enxofre faz parte de compostos essenciais ao sistema antioxidante das plantas. A toxicidade causada por alta disponibilidade de metais, como o zinco, no meio de cultivo é um problema ambiental crescente. Objetivou-se avaliar o efeito do enxofre em amenizar o estresse causado pelo excesso de zinco no capim tanzânia. O experimento foi conduzido em casa de vegetação em Piracicaba - SP, durante o verão, em delineamento de blocos casualizados em esquema fatorial fracionado, com as combinações de doses de enxofre (mmol L-1) e zinco (μmol L-1): 0,1/0,7; 0,1/500; 0,1/3000; 1,0/250; 1,0/1000; 1,9/0,7; 1,9/500; 1,9/3000; 2,8/250; 2,8/1000; 3,7/0,7; 3,7/500 e 3,7/3000. Foram avaliadas as seguintes variáveis: componentes de produção (perfilhos, folhas, área foliar, massa de parte aérea e de raízes), concentrações dos nutrientes (N, S, Ca, Mg, Cu, Fe, Mn e Zn), valor SPAD, atividades de enzimas do sistema antioxidante (GR, GPOX, APX, CAT e SOD) e concentração de prolina. A toxicidade de zinco no primeiro crescimento do capim limitou a produção de massa seca e o número total de folhas, enquanto no segundo crescimento também ocorreu limitação na área foliar e no número total de perfilhos. A concentração de enxofre na planta aumentou em função do fornecimento de enxofre e do excesso de zinco no meio de cultivo. O excesso de zinco na planta provocou desequilíbrio na nutrição da planta com os micronutrientes cobre, ferro e manganês. Os indicadores do estresse oxidativo foram sensíveis para detectar a toxicidade do zinco no capim. As reduções na concentração de prolina e nas atividades de enzimas do sistema antioxidante demonstraram o efeito do enxofre em aliviar o estresse por toxicidade de zinco no capim tanzânia. / Tanzania guinea grass (Panicum maximum cv. Tanzania) is promising for use in phytoremediation due to its extensive root system, good adaptation to diverse environments, and high biomass production when well nourished. Sulfur is part of essential compounds to the plant\'s antioxidant system. Toxicity caused by high availability of metals, such as zinc, in the growth medium is a growing environmental problem. The objective was to evaluate the effect of sulfur in mitigating the stress caused by zinc excess in tanzania guinea grass. The experiment was carried out in a greenhouse at Piracicaba, SP, during the summer, in a randomized block design with rates of sulfur (mmol L-1) and zinc (μmol L-1) of 1/0.7; 0.1/500; 0.1/3000; 1.0/250; 1.0/1000; 1.9/0.7; 1.9/500; 1.9/3000; 2.8/250; 2.8/1000; 3.7/0.7; 3.7/500 and 3.7/3000. The response variables evaluated were plant production components (number of tillers, number of leaves, leaf area, and shoots and roots dry matter), nutrient concentrations (N, S, Ca, Mg, Cu, Fe, Mn and Zn), SPAD value, activities of the antioxidant enzymes (GR, GPOX, APX, CAT and SOD) and proline concentration. Zinc toxicity in the first growth of the grass limited the dry mass production and the total number of leaves, while in the second growth also there was limitation in the leaf area and the total number of tillers. The concentration of sulfur in the plant increased as a function of sulfur supply and excess zinc in the growth medium. Excess zinc in the plant caused imbalance in plant nutrition for the micronutrients copper, iron and manganese. The indicators of oxidative stress were sensitive to detect grass toxicity by zinc. Reductions in proline concentration and enzyme activities of the antioxidant system demonstrated the effect of sulfur in alleviating the stress of zinc toxicity in tanzania guinea grass.

Die vorliegende Arbeit untersucht mit bioinformatischen Methoden die biologische Bedeutung von Ähnlichkeiten in Kleinstrukturen und peptidischen Sequenzmotiven sowie lokaler und globaler Sequenzähnlichkeit. Der erste Teil der Arbeit behandelt chemische Ähnlichkeiten. Ausgehend von bekannten Inhibitoren der Fehlfaltung des Prionproteins wurde eine Datenbank pharmakologischer Wirkstoffe nach chemisch und strukturell ähnlichen Substanzen durchsucht und 16 Substanzen als neue potentielle Inhibitoren der Fehlfaltung vorgeschlagen. Der nächste Teil untersucht Ähnlichkeiten in Sequenzmotiven, die eine Interaktion mit Pex19, dem Importrezeptor für peroxisomale Membranproteine, vermitteln. In Zusammenarbeit mit einer experimentellen Arbeitsgruppe konnte die Bindestelle charakterisiert und Präferenzen für bestimmte Aminosäuren herausgearbeitet werden. Das Bindemotiv ist eine vermutlich helikale Region mit verzweigtkettigen aliphatischen und basischen Aminosäuren. Aus experimentellen Daten konnte eine positionsabhängige Vorhersagematrix erstellt und validiert werden. Die Beziehung zwischen lokalen Sequenzähnlichkeiten und der Konformation von Prolylbindungen in Proteinen ist Thema des dritten Teils. Die Aminosäurepräferenzen in der Nachbarschaft von cis- und trans-Prolylresten unterscheiden sich, und beide zeigen unterschiedliche Austauschpräferenzen bei Mutationen. Im Gegensatz zu lokaler Sequenzähnlichkeit ist eine globale Sequenzähnlichkeit von nur 20% ein wesentlich besserer Indikator für das Auftreten von cis-Prolylbindungen. Der letzte Teil befaßt sich mit inverser Sequenzähnlichkeit zwischen Proteinen, die wesentlich öfter auftritt als erwartet. Proteine aus einem nichtredundanten Datensatz wurden gleich- und gegenläufig aligniert und strukturelle Ähnlichkeiten zwischen den aufgefundenen Proteinpaaren untersucht. Es konnte gezeigt werden, daß bis auf kurze Sekundärstruktur-Einheiten eine inverse Sequenzähnlichkeit zwischen Proteinen keine strukturelle Ähnlichkeit impliziert. / This work is dealing with the biological impact of similarities between chemical structures, protein sequence motifs and local sequence surrounding as well as global sequence similarity. All four aspects are analyzed by computational methods. The first part is dealing with chemical similarities. Based on a recently published set of prion protein misfolding inhibitors, a data base of approved drugs has been screened for compounds with chemical and structural similarities to these substances. 16 drugs are proposed as new potential inhibitors of prion protein aggregation. The next part addresses similarities of sequence motifs which mediate the interaction with the peroxisomal membrane protein import receptor Pex19. In cooperation with an experimental group, the binding site could be characterized, and amino acid preferences of the different positions of the motif have been determined. The binding motif is a probably helical region of target proteins bearing branched aliphatic and basic residues. A position specific scoring matrix for the prediction of Pex19 binding sites could be generated and validated. The relation between local sequence similarity and prolyl bond conformation is examined in the third part. Amino acid preferences of neighboring residues differ between cis and trans prolyl residues, and both species show different amino acid exchange patterns upon mutation. In contrast to local sequence similarity, overall sequence similarity between proteins as low as 20% is a much better indicator for the occurrence of cis prolyl bonds. The last part focuses on inverse sequence similarity between proteins which occurs far more often than expected by chance. Proteins from a nonredundant data set have been aligned in parallel and antiparallel, and structural similarities between the detected protein pairs have been examined. It could be shown that, with the exception of short secondary structural elements, inverse sequence similarity does not imply structural similarity.

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No. of bitstreams: 1 Tese-Gerlandio Suassuna Gonçalves.pdf: 1253081 bytes, checksum: bb8f078c3065d7b328b0bbf489d24eba (MD5) Previous issue date: 2015-02-10 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The determination of the critical period of weed interference is very important because it indicates the phase of the culture in which the management of weed shall be performed, furthermore, it limits the number of weeding and other management practices to the minimum, allowing the plant express its maximum yield potential at lower cost to the producer. The aim of this study was to identify the critical period of weed interference in the culture of orange ‘Pera’ tree by parameters valuated: falling immature fruits, productivity, juice yield, juice chemical characteristics, production of photosynthetic pigments and proline in leaves of orange tree, identify the weed species and their accumulation of biomass and nutrients. The experiment was installed in october 2012 and conducted until september 2014, in Rio Preto da Eva - AM. To define the treatments with and without interference of weeds in orange tree, was taken as reference the water balance in the region. The interference periods were defined considering the degree of water availability or absence in the soil: from october to january; february to may; june to september; october to may; october to January, june to september and february to september; period without weed interference (control treatment), and without producer management practices interference. The control of weed was obtained using the herbicide glyphosate (1.720 g ha-1 e.a.). The characteristics evaluated were: Falling immature fruits, productivity, juice yield, total soluble solids (SS), titratable acidity (TA), technological index (TI), chlorophyll production and carotenoids, proline content, biomass accumulation and nutrients by weeds. The treatment with weed interference in the period from october to may increase the fruit drop, reduced the number of fruits per plant and productivity, promoted an increase in soluble solids (SS), total acidity (TA) and reduced values of SS/TA ratio. The different periods of weed interference did not promote significant changes in the contents of chlorophyll a, b, total and of carotenoids in orange tree leaves, but viii promoted significant changes in the free proline content in the leaves. The weed species differ from each other in the accumulation of biomass and nutrients. The critical period of weed interference to the culture of orange ‘Pera’ was from october to may. / A determinação do período crítico de interferência de plantas infestantes é muito importante, pois seu conhecimento indica a fase da cultura em que o manejo das infestantes deve ser realizado, limita o número de capinas e de outras práticas de manejo ao mínimo necessário, possibilitando que a planta expresse o seu máximo potencial produtivo com menor custo para o produtor. O objetivo deste trabalho foi identificar o período crítico de interferência de plantas infestantes na cultura da laranja ‘Pera’ pela avaliação dos parâmetros: queda de frutos imaturos, produtividade, rendimento em suco e suas características químicas, produção de pigmentos fotossintéticos e de prolina nas folhas de laranjeira e identificar as espécies infestantes assim como a acumulação de biomassa e de nutrientes por elas. O experimento foi instalado em outubro de 2012 e conduzido até setembro de 2014, no município de Rio Preto da Eva – AM. Para definição dos tratamentos de interferência ou não de plantas infestantes em laranjeira, tomou-se como referência o balanço hídrico da região. Os períodos de interferência estabelecidos levaram em consideração o grau de disponibilidade ou não de água no solo: de outubro a janeiro; fevereiro a maio; junho a setembro; de outubro a maio; outubro a janeiro e de junho a setembro; fevereiro a setembro; sem interferência das plantas infestantes – tratamento controle; e sem interferência com práticas de manejo do produtor. O controle das plantas infestantes foi obtido com uso do herbicida glyphosate (1.720 g ha-1 e.a.). As características avaliadas foram: queda de frutos imaturos, produtividade, rendimento em suco, sólidos solúveis totais (SS), acidez titulável (AT), índice tecnológico (IT), produção de clorofila e de carotenoides, teor de prolina, acumulação de biomassa e nutrientes pelas infestantes. O tratamento com interferência das plantas infestantes no período de outubro a maio aumentou a queda de frutos prematuros, reduziu o número de frutos por planta e a produtividade, promoveu incremento dos sólidos solúveis (SS), da acidez total (AT) e reduziu vi os valores da relação SS/AT. Os diferentes períodos de interferência de plantas infestantes não promoveram alterações significativas nos teores de clorofila a, b, total e de carotenoides em folhas de laranjeira, mas promoveram mudanças significativas no conteúdo de prolina livre nas folhas. As espécies infestantes diferiram entre si na acumulação de biomassa e de nutrientes. O período crítico de interferência de plantas infestantes para a cultura da laranjeira foi de outubro a maio.