Dissertations / Theses on the topic 'Deoxy'
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1
Roig, Ricard. "Synthesis of 6-deoxy-6-fluorosugars." Thesis, University of Leicester, 2006. http://hdl.handle.net/2381/29987.
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This project is based on the chemical synthesis of fluorosaccharide end-products, which could be used potentially as substrates for the combinatorial biosynthesis of novel complex structures like antibiotics. Although fluorine is the most abundant halogen in the earth's crust, the incidence of fluorinated natural products is extremely low. There are no examples of fluorosaccharide end-product molecules in nature, so novel architecture will result from their incorporation within oligosaccharides or complex antibiotics. Introducing fluorine into pharmaceutical compounds can increase the biological activity and stability to metabolism. Enantiomerically enriched and racemic 6-fluoro and racemic 6,6-difluoro analogues of amicetose and rhodinose have been synthesized successfully using different and scaleable strategies from commercially available starting materials. The equilibria between furanoses and pyranoses favoures the smaller rings, due to the inductive electron withdrawing effects of fluorine, so it was necessary to use protection to deliver pyranoses exclusively. Two very efficient new fluorinating methods have been developed, one with in situ cis/trans-isomerisation of a double bond with a mixture of TBAI and TBAF, and another one with high regioselective epoxides ring-opening with a mixture of KHF2 and TBAF. In addition to the synthesis of 6-deoxy-6-fluorosugars, a long lived difluoroenol was discovered and fully characterised, methanolysis rates and solvent isotope effect were measured.
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Park, Sung-Hae. "The biosynthesis of the deoxyhexose moieties in oleandomycin /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/8152.
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Sande, Marc van de. "Asymmetrische Synthese von 3-Oxa-15-Deoxy-16-(m-tolyl)-Tetranorisocarbacyclin und 15-Deoxy-16-(m-tolyl)-Tetranorisocarbacyclin." Aachen Mainz, 2007. http://d-nb.info/100174103X/34.
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Fazio, Fabio. "Building blocks for 2-deoxy-L-nucleosides." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963273434.
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Jiao, Hailong. "Synthetic studies on 2-amino-2-deoxy glycosides." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0002/NQ39546.pdf.
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Ellenberger, Suzanne Ray. "Total synthesis of selected deoxyamino sugars /." Full text open access at:, 1986. http://content.ohsu.edu/u?/etd,110.
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Sande, Marc van de [Verfasser]. "Asymmetrische Synthese von 3-Oxa-15-Deoxy-16-(m-tolyl)-Tetranorisocarbacyclin und 15-Deoxy-16-(m-tolyl)-Tetranorisocarbacyclin / vorgelegt von Marc van de Sande." Aachen : Mainz, 2007. http://d-nb.info/100174103X/34.
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Heß, David. "Palladium(II) complexes and phenylboronic acid esters of deoxy sugars." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-151675.
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Hardy, Simon. "Approaches towards the total synthesis of the 20-deoxy bryostatins." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496225.
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This thesis describes approaches towards the total synthesis of the 20-deoxy bryostatins. The use of CI9 acyl anion equivalents as a means of forming the C19-C20 bond was investigated, leading to the synthesis of 2-[(2'E,6'Z)-(R)-6'-(2-benzyloxymethoxy-ethyl)-1', 1' -dimethyl-4' -triethylsilyloxy-8' -triisopropylsilyloxyocta-2',6'-dienyl]-[l,3]-dithiane (276), representing the C11-CI9 fragment of the bryostatatins.
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Steer, Andrew Mark. "Studies on the prebiotic origin of 2-deoxy-D-ribose." Thesis, University of York, 2017. http://etheses.whiterose.ac.uk/19070/.
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This research attempts to provide a possible explanation to the chemical origin of 2-deoxy-D-ribose via an aldol reaction of acetaldehyde and D-glyceraldehyde. The sugar mixture is trapped with N,N-diphenylhydrazine for ease of purification and characterisation. The reaction is promoted by amino acids, amino esters and amino nitriles consistently giving selectivities in favour of 2-deoxy-D-ribose. This is the first example of an amino nitrile-promoted reaction. The research is developed further by exploring the formation of 2-deoxy-D-ribose in a "protocell" environment - a primitive cell. Here we suggest that primitive cells may have been simple hydrogel systems. A discussion of the characterisation and catalytic ability of small peptide-based structures is included.
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Rose, Graeme William. "The synthesis of some 3-deoxy-α-keto sugar acids." Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/14324.
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Zhu, Danyang. "Stereoselective Synthesis of 2-Deoxy Glycosides via Anomeric O-Alkylation." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438900175.
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Cumming, Hemi Adam. "Probing the Substrate Specificity of 3-Deoxy-D-arabino-Heptulosonate 7-Phosphate Synthase and 3-Deoxy-D-manno-Octulosonate 8-Phosphate Synthase using Analogues of Phosphoenolpyruvate." Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/2190.
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3-Deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase and 3-deoxy-D-mannooctulosonate 8-phosphate (KD08P) synthase are two bacterial enzymes that are vital for host virulence. DAH7P synthase catalyses the first commited step of the shikimate pathway that results in the biosynthesis of aromatic metabolites. KD08P synthase catalyses the formation of the sugar KDO, which is an essential component of the cell wall of Gram-negative bacteria. The enzymes that catalyse these reactions are not present in animals, and therefore they are attractive targets for anti-bacterial agents. Interestingly, these two enzymes catalyse very similar aldol-like reactions and share a common substrate, phosphoenolpyruvate (PEP). In this thesis, the synthesis of various analogues to the shared substrate, PEP, has been described. Alterations to PEP include; substitution of a vinylic proton for either a fluorine, a bromine, a chlorine, a methyl group or deuterium; substitution of the carboxylic acid group for a methylchloride or a phosphonate; reduction of the double bond, and substituting the phosphate bridging oxygen for a methylene group. These analogues were tested as competitive inhibitors, and some as substrates and irreversible inhibitors against DAH7P synthase (from E. coli) and KD08P synthase (from N. meningitidis). 3-FluoroPEP was observed to act as a substrate for both DAH7P synthase and KD08P synthase. However, following the reaction progress via ¹⁹F NMR spectroscopy showed that in the KD08P synthase reaction the (Z)-isomer was processed much slower than the (E)isomer, whereas in the DAH7P synthase reaction both isomers were processed at a similar rate. Chloro, bromo and methyl 3-substituted PEP analogues were found to be reasonable competitive inhibitors of DAH7P synthase and KD08P synthase . DAH7P synthase was shown to have better inhibition with the (E)-isomers of these 3-substituted PEP analogues, whereas in KD08P synthase this varied. l-(Chloromethyl)vinyl phosphate was shown to be a poor competitive inhibitor of both DAH7P synthase and KD08P synthase. However, this compound showed time-dependent covalent inactivation of both DAH7P synthase and KD08P synthase. DiphosphoPEP was shown to be a reasonable competitive inhibitor towards DAH7P synthase, and was a poor competitive inhibitor of KD08P synthase (at pH 6.5). Lowering the pH to 5.3 resulted in significantly greater inhibition of KD08P synthase. DiphosphoPEP was shown not to act as a substrate to both enzymes. The (R)-isomer of 2-phospholactic acid was found to be the best competitive inhibitor of DAH7P synthase, from the PEP analogues tested, and the (S)-isomer had approximately 6-fold weaker inhibition. Inhibition of KD08P synthase with 2-phospholactic acid was poor, with slightly better inhibition with the (R)-isomer. The phosphonate of PEP was shown to be a reasonable competitive inhibitor towards DAH7P synthase and close to no inhibition was observed ofKD08P synthase (at pH 6.5). Lowering the pH to 5.3 resulted in some inhibition of KD08P synthase.
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Koo, Ki Chul. "Studies towards the total synthesis of 1-deoxy-8-demethyl taxol." Tallahassee, Florida : Florida State University, 2009. http://etd.lib.fsu.edu/theses/available/etd-08222009-032151/.
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Thesis (Ph. D.)--Florida State University, 2009.Advisor: Robert A. Holton, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Title and description from dissertation home page (viewed on April 27, 2010). Document formatted into pages; contains xvii, 362 pages. Includes bibliographical references.
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Rodríguez, Gómez Miguel Angel. "Stereoselective Synthesis of 2-Deoxy-glycosides. Approach to the Synthesis of Digitoxine." Doctoral thesis, Universitat Rovira i Virgili, 2007. http://hdl.handle.net/10803/9010.
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"Stereoselective Synthesis of 2-Deoxyglycosides. Approach to the synthesis of Digitoxine"2-Deoxy and 2,6-dideoxy-glycosides are important structural units in many natural products including antitumor drugs (anthracyclines, aureolic acids, calicheamicin, esperamicin), antibiotics active against Gram-positive bacteria (erythromycins, orthosomycins), antibiotics inhibiting platelet aggregation (angucyclines), drugs used in the treatment of cardiac insufficiency (cardiac glycosides), antiparasitic agents (avermectins).
The stereocontrolled formation of the glycosidic linkage in 2-deoxy-oligosaccharides has been found to be one of the most challenging tasks in glycosylation reactions. This could be solved using C-2 substituents (I, SeR, SR) in order to aid stereocontrol in the glycosylation step. These groups can be then easily removed under mild conditions after stereocontrol has been achieved. On the other hand, one of the most important intermediates in the synthesis of 2 deoxycarbohydrates are 1,2-unsaturated glycosides, commonly called glycals.
The aim of the study reported in this thesis was to develop a new method for the stereoselective synthesis of 2-deoxyoligosaccharides and precursors such as glycals. Moreover, an approach to the synthesis of digitoxine was also reported. Thus, in a preliminary introduction, previous reported methods for the synthesis of deoxysugars were discussed. In chapter 1, we developed a new procedure for synthesizing phenyl 2-deoxy-2-iodo-1-thio-glycosides and their use as glycosyl donors for the stereocontrolled synthesis of 2-deoxy-2-iodo-oligosaccarides. The key step for the synthesis of 2-deoxy-2-iodo-1-thio-glycosides is a regio- and stereoselective 6-endo cyclization of alkenols induced by iodine electrophiles. In chapter 2, Deoxy-2-iodopyranosides were synthesized from sulfanyl alkenes using a "one pot" consecutive cyclization-glycosylation process. The "one pot" procedure was also applied to the synthesis of a 2,6-dideoxy-2-iodo-glycoside, which was successfully deiodinated to afford the 2,6-dideoxyglycoside. In chapter 3, it is showed that pyranoid glycals of all configurations can be obtained from pentoses through an olefination-cyclization-elimination sequence. This method provides access to non conventional glycals having C3-alkoxy substituent in axial configuration, such as D-allal and D gullal, which are difficult to synthesize by usual methods. Furthermore, other functionalized glycals such as 2 phenylselenenyl or 2 iodoglycals can be synthesized starting from enolthioethers by direct selenium-mediated elimination or through dehydrative reaction of 2-iodolactols, respectively. Finally, Starting from a common precursor such as D-ribonolactone, we have explored a new approach to the synthesis of digitoxine and other cardiac glycosides as application of the previous methodology developed.
Títol: "Stereoselective Synthesis of 2-Deoxyglycosides. Approach to the synthesis of Digitoxine"
Paraules Clau: Síntesi estereoselectiva, 2-desoxi i 2,6-didesoxiglicòsids, glicósids cardiacs, glicals i iodoglicals, síntesi "one-pot", ciclació (electròfila), digitoxina.
Informe Preceptiu sobre la Tesi doctoral "Estereoselective Synthesis of 2 Deoxyglycosides. Approach to the síntesis of Digitoxine" presentada per Miguel Àngel Rodríguez Gómez.
La tesi s'emmarca dins el camp de la síntesis de carbohidrats i glicoconjugats amb estructures que presenten posicions on una o més de les funcions hidroxil característiques del sacàrids no hi estan presents. El treball realitzat ha tingut com objectiu final la síntesis estereoselectiva de 2-desoxi i 2,6-didesoxiglicòsids ja que són part constituent de moltes substàncies biològicament actives i/o productes naturals com antitumorals, antibiòtics, agents antiparasitaris, cardiotònics...i a més a més són difícils d'obtenir a partir de carbohidrats naturals.
D'aquesta forma en aquesta tesi s'aborda la síntesis de 2-desoxi-2-iodo-1-tiopiranósids com a nous dadors de glicosil i la seva aplicació en la síntesis estereoselectiva d'oligosacàrids i glicòsids. Aquest dadors de glicosil es caracteritzen per la presència d'un grup fenilsulfanil com a grup sortint en la posició anomèrica (C1) i un grup iodo en el C2 que actua com element de control en la reacció de glicosilació. Aquests dos grups funcionals donen, a més a més, moltes possibilitats de derivatització i una variada reactivitat.
La memòria s'ha organitzat en una introducció general sobre la biologia i la química dels 2-desoxi i 2,6-didesoxiglicòsids, un objectius, quatre capítols on es s'exposen i discuteixen els resultats obtinguts amb les seves corresponents conclusions i un annex amb els espectres dels productes seleccionats.
La introducció tracta sobre la importància i el variat paper biològic dels 2-desoxi i 2,6-didesoxicarbohidrats a la vegada que parla de la dificultat i els especials problemes que comporta la síntesis química d'aquests tipus de compostos. D'aquesta forma es fa una revisió dels mètodes desenvolupats fins avui per la síntesis d'aquest glicòsids. Lligat amb aquests mètodes anteriors, en els objectius es posa de manifest la necessitat d'arribar a un nou mètode de síntesis de 2-desoxicarbohidrats que permeti assolir totes les configuracions de piranòsids possibles.
En el primer capítol es desenvolupa el nou mètode d'obtenció de 2-desoxi-2 iodo-1-tioglicòsids que després es faran servir com a dadors de glicosil. D'aquesta forma, partint de pentoses de totes les configuracions i diferentment protegides es van olefinar per diversos mètodes, obtenint polihidroxihexenilsulfurs. El mètode més convenient per aquesta reacció en termes de rendiment i estereoselectivitat fou la olefinació amb oxid de fosfina (Wittig-Horner-WH). Aquests alquenols es van ciclar amb electrofils de iode, conduint de forma regioselectiva als 2-desoxi-2-iodo-1 tiopiranòsids. Aquest dadors de glicosil es van fer reaccionar amb colesterol com a model d'aglicona de diferents compostos bioactius i amb un glucosid com a model de síntesi d'oligosacàrid.
En el segon capítol s'aborda la síntesis dels mateixos compostos del capítol primer aprofitant la semblança de les condicions de ciclació i de glicosilació, que permet en una sola etapa la glicosilació de diversos compostos partint de l'alquenol, un precursor acíclic molt més estable i fàcil de sintetizar que el 2-desoxi-2-iodo-tioglicòsid corresponent. Aquest procediment "one-pot" es mostra igual en diasteroselectivitat i superior en termes de rendiment i de facilitat de manipulació que la síntesi per passos del capítol 1. A més es va sintetizar un 2,6-didesoxicarbohidrat model del supressor de l'apetit P57AS3.
En el tercer capítol s'exposa la síntesi de glicals a partir del 1-tio-2-desoxi-2 iodo-piranosids. El glicals són compostos molt versàtils i útils en la síntesis de carbohidrats i amb el procediment desenvolupat en aquest capítol s'arribà a obtenir glicals de configuracions difícils d'obtenir per altres mètodes, com el D-allal i el D gullal. A més, en una segona part del capítol tercer, aplicant un procediment de glicosilació estàndar per a com el de Gin ("dehydrative glycosylation") s'obtenen a partir de 2 iodolactols diversos compostos com a 2 iodoglicals, glicals o 1,1'-disacàrids.
En el quart capítol tots els anteriors procediments s'apliquen en la aproximació a la síntesis d'un glicósid cardíac, la digitoxina, molt utilitzat en el tractament de la insuficiència cardíaca. D'aquesta forma es realitzà la síntesi dels alquenols precursors dels 2,6-dideoxiglicòsids que formen part de l'estructura d'aquest fàrmac (unitats de digitoxosa) i es va unir a la aglicona obtenint el monosacàrid de la digitoxigenina. A més a més es van obtenir altres intermedis valuosos, tals com el corresponents 2 iodolactols o els trichloroacetimidats, en el camí cap a la síntesis de la digitoxina i/o anàlegs.
Amb el treball d'aquesta tesi els objectius inicialment proposats de desenvolupament d'un nou mètode de glicosilació per la síntesi de 2-desoxiglicòsids i han estat ampliament assolits i a més a més, s'han desenvolupat vies alternatives (glicals, lactols, 2-iodoglicals,...) que amplien els procediments sintètics inicials, ampliant les vies de síntesis dels 2-desoxiglicòsids.
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Schell, Christoph. "Steuerung humaner testikulärer peritubulärer Zellen durch TNFalpha und 15-deoxy-Prostaglandin J2." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-142254.
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Ebel, Susanne. "The synthesis and study of oligo(deoxy)ribo-nucleotides and their analogues." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/13766.
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Laboratory procedures for the synthesis, workup and purification of oligoribonucleotides using RNA phosphoramidites protected with a) Fpmp- and b) TBDMS- groups on the 2'-hydroxl functions have been developed and employed in the following projects: 1. Modified minimised DNA/RNA ribozymes were synthesised and purified, which contained a) a dT4-loop, b) a hexaethylene glycol- or, c) a tetraethylene glycol-loop closing the catalytic site. Their catalytic activity was confirmed. The cleavage activity of the hexaethylene glycol minizyme was superior to that of the tetraethylene glycol minizyme, but cleaved less efficiently than the dT4-minizyme. 2. Tetra-biotinylated antisense RNA was synthesised and purified using two methods. The method using 2 successive additions of a multiple hydroxyl phosphoramidite followed by 1 addition of a single-addition biotin phosphoramidite, generated biotinylated antisense oligoribonucleotides of superior specificity in biotin/streptavidin based pre-mRNA depletion experiments. 3. The stability of tandem GA mismatches was analysed using thermal denaturation techniques. In DNA tandem GA mismatches of the kind 5' pry GA pu 3' adopted an amino-type basepairing and were very stable, tandem AG mismatches were imino-paired and significantly less stable. The amino-type base pair has a distinctly shifted phosphorus resonance in the 32P-NMR spectrum. Tandem GA mismatches in RNA did pair in the amino-form when flanked by 5' pyr..pu 3' but were highly unstable, as were tandem AG mismatches. Tandem GA mismatches in DNA/RNA hybrid sequences were also unstable. Multiple GA mismatches of the kind d(5' pyr GA pu 3') did not destabilise duplexes compared to T.A. base pairs. d(GA)n sequences formed homo-duplexes with exclusively G.A basepairing.
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Pongdee, Rongson. "New methods for 2-Deoxy-Beta-Oligosaccharide synthesis and progress towards the total synthesis of Lomaiviticinone." Texas A&M University, 2003. http://hdl.handle.net/1969.1/356.
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The oligosaccharide domain of many secondary metabolites have been demonstrated to be pivotal for the biological efficacy of the parent glycoconjugate. In most cases, the alteration or removal of these carbohydrate residues results in the greatly diminished or completely abolished biological activity of the natural product. A common structural motif found in secondary metabolites possessing carbohydrate domains is the 2-deoxy-β-glycosidic linkage which are among the most difficult to establish in a stereocontrolled fashion.
Chapter I provides background information describing the difficulties associated with the synthesis of 2-deoxy-β-glycosidic linkages in addition to a sampling of the current methodology available for their construction. Chapter II details our use of diethyl and pinacol phosphite glycosyl donors towards a direct synthesis of a designed 2-deoxy-β-oligosaccharide in a "one-pot" process which constitutes a novel approach towards the synthesis of these glycosidic linkages.
Lomaiviticin A was isolated as the major metabolite from fermentation of the halophilic strain LL-37I366 which was later assigned the name Micromonospora lomaivitiensis. Lomaiviticin A displayed potent biological activity towards numerous cancer cell lines with IC50 values ranging from 0.01 to 98 ng/ml. While postulated to induce double-stranded DNA cleavage, the mechanism of action was unique when compared to known DNA-damaging agents such as adriamycin and mitomycin C.
Chapter III details progress towards the synthesis of lomaiviticinone employing an "inside-out" strategy to take advantage of the molecule's own C2-symmetrical nature. The focus of the chapter will pertain to our efforts to construct the stereochemically-rich cyclohexenone central core highlighted by the use of organometallic C-C bond formation processes.
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McCarter, John D. "Deoxy and deoxyfluoro glycosides as mechanistic probes of Escherichia coli (lacZ) B-galactosidase." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30083.
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The mechanism of galactoside hydrolysis by Escherichia coli (lacZ) β-galactosidase was probed with a series of 2',4' dinitrophenyl deoxy and deoxyfluoro glycopyranosides. A two-step mechanism has been proposed previously for this process:
1) cleavage of the glycosidic bond and formation of a covalent galactosyl-enzyme intermediate ("galactosylation");
2) hydrolysis of the mtermediate to give free enzyme and galactose ("degalactyosylation").
A series of deoxy and deoxyfluoro analogs of 2',4'-dinitrophenyl-β,-D-
galactopyranoside was prepared for this study. The 2-deoxyfluoro derivative was found to be an effective mechanism-based inactivator of E. coli (lacZ) β-galactosidase. This
compound thus joins a class of 2-deoxy-2-fluoro glycosides which inactivate glycosidases of this type by the accumulation of a stable glycosyl-enzyme intermediate. The active site-directed nature of this inhibitor was shown by protection against inactivation by a competitive ligand and the near 1:1 stoichiometry of dinitrophenolate release with enzyme inactivation. Furthermore, when freed from excess inactivator the 2-deoxy-2-fluorogalactosyl enzyme intermediate turned over slowly in buffer (t₁⃓₂ = 69 h at 25°C) and exhibited enhanced rates of reactivation in the presence of the acceptors methanol or glucose, providing strong evidence that the intermediate is catalytically competent
The other deoxy and deoxyfluoro analogs synthesized were substrates for the enzyme although the rates of enzymic hydrolysis were two to four orders of magnitude slower than have been measured for the parent compound. These large rate reductions are thought to result primarily from the loss of important transition state binding interactions due to the substitution of a hydrogen or a fluorine for a hydroxyl at a given position on the galactopyranose ring. These results strongly suggest that much of the catalytic power of the enzyme is derived from non-covalent interactions between the enzyme active site and the galactopyranose ring of the substrate.
A linear free energy relationship (r = 0.80) was shown to exist between the logarithm of kcat/Km for the enzyme-catalyzed reaction and the logarithm of the first order rate constant for the spontaneous hydrolysis of the same series of deoxy and deoxyfluoro glycopyranosides. Since the spontaneous process has considerable oxocarbonium ion character at the transition state, these data suggest that the enzymic mechanism involves a similar electron deficient transition state.Science, Faculty of
Chemistry, Department of
Graduate
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Harrison, Aidan Nicholas. "Investigations into the Inhibition of 3-Deoxy-D-manno-Octulosonate 8-Phosphate Synthase." Thesis, University of Canterbury. Chemistry, 2010. http://hdl.handle.net/10092/5382.
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The enzyme 3-deoxy-D-manno-octulosonate 8-phosphate (KDO8P) synthase catalyses the aldol condensation of the five-carbon sugar phosphate, arabinose 5-phosphate (A5P), and phosphoenol pyruvate (PEP) to give the eight-carbon phosphorylated sugar, KDO8P. It is the second committed step in the synthesis of KDO, a necessary component of the cell wall of Gram-negative bacteria.
This thesis describes the design, synthesis and evaluation of a number of inhibitors of KDO8P synthase that utilise the functionality of one or both substrates.
The KDO8P synthase family can be divided based on the requirement of a divalent metal ion. Chapter 2 describes the growth, purification and characterisation of an example from both the metal-independent KDO8P synthases (Neisseria meningitidis, Nme) and metal-dependent KDO8P synthases (Acidithiobacillus ferrooxidans, Afe) in order to utilise these enzymes for the inhibition studies described in this thesis.
In Chapter 3, a number of small molecule PEP analogues were selected as mimics of KDO8P synthase reaction intermediates and tested as inhibitors of KDO8P synthase from N. meningitidis and A. ferrooxidans. Glyphosate, (E)-vinyl phosphonate and the fluorinated analogue of (E)-vinyl phosphonate were selected as mimics of the high-energy oxocarbenium intermediate through which the KDO8P synthase reaction is thought to occur. The two enantiomers of phospholactate were selected in order to investigate the chirality of the tetrahedral intermediate and determine the importance of this chirality for inhibition of KDO8P synthase. All five inhibitors were found to be moderate to poor inhibitors of both the KDO8P synthase from N. meningitidis and A. ferrooxidans.
Chapter 4 describes the design and synthesis of inhibitors that incorporated structural features of the second substrate, A5P, in order to improve inhibition from that observed for the PEP analogues investigated in Chapter 3. A bisphosphate inhibitor was designed that incorporated a terminal phosphate moiety, representative of the phosphate of A5P. A large increase in inhibition was found, compared to the phospholactates from which it was derived. A structure-activity-relationship study was undertaken on this compound by design of compounds that lacked one of the two phosphate moieties of the bisphosphate inhibitor, in order to determine their relative importance. The inhibition results indicate that the primary terminal phosphate, thought to bind in the A5P phosphate binding site, is more important for inhibition of KDO8P synthase than the secondary phosphate.
In Chapter 5 these investigations into the inhibition of KDO8P synthase are discussed in detail, and interpreted using the aid of computational studies. In addition several approaches are described for the completion and advancement of the studies presented here in this thesis.
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Liang, Theresa. "Silver-Mediated Trifluoromethoxylation of Aryl Nucleophiles and Synthesis of 3-Deoxy-3-Fluoromorphine." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10547.
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Fluorine incorporation has become increasingly important in pharmaceutical applications. Upon fluorination and incorporation of fluorinated moieties such as trifluoromethoxy groups, many small molecules become more bioavailable and metabolically stable and additionally can better cross the blood-brain-barrier. This thesis describes the development of a method mediated by silver salts for the synthesis of pharmaceutical-like trifluoromethoxylated compounds via \(C-OCF_3\) bond formation. Additionally the synthesis of 3-deoxy-3-fluoromorphine via late-stage fluorination of morphine is described as well as in vitro and in vivo evaluation of 3-deoxy-3-fluoromorphine as a potential analgesic.Chemistry and Chemical Biology
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Englert, Nadine Esther [Verfasser]. "NMR Strukturanalyse der 1-Deoxy-D-xylulose-5-phosphat Reduktoisomerase / Nadine Esther Englert." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1064837557/34.
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White, Justin K. "Investigations into the Non-Mevalonate Isoprenoid Biosynthesis Pathway's First Two Enzymes utilizing Hybrid QM/MM Techniques." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/7107.
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Molecular drug design begins with the identication of a problem to solve. This work identies the growing resistance among human pathogens to current treatments. Once the problem is identied and understood, solutions must be proposed. This one is straight forward, we need new antimicrobial drugs. More specically, we need to identify novel targets to inhibit. A large portion of antibiotics focus on disruption of macromolecular production while only a few target metabolic systems. Finally, you need to propose solutions based on the information gathered. In order to avoid existing resistance, it is important to avoid the macromolecular route and focus on metabolic enzymes. Preferably, the pathway would have little overlap or similarity with pathways found in the treatment organism. With this in mind, the non-mevalonate (NMA) pathway poses as a very good target for drug design. Many pathogens have been found to be strictly dependent on this pathway while it is absent in humans. Additionally, fosmidomycin has already been shown to inhibit this pathway. Initially thought to just inhibit the 1-deoxy-D-xylulose 5- phosphate (DXP) reductoisomerase (DXR), it has been shown to inhibit several enzymes along the path to a lesser extent. Ideally, this could be repeated or improve upon for future drug design.
With this in mind, the initial stages of the rst two enzymes of the NMA pathway were examined utilizing quantum mechanical/molecular mechanical (QM/MM) techniques. The rst enzyme was DXP synthase (DXS), which catalyzes a transketolase-like condensation of pyruvate and glyceraldehyde-3-phosphate to produce DXP. DXS and other transketolases are dependent on the thiamine diphosphate (TDP) cofactor, which must be deprotonated of the imidazolium C2 atom producing a highly reactive ylide. A tautomerization occurs prior to this deprotonation to prime the pyrimidinium ring N4 atom to perform the C2 abstraction. The question at hand was the identity of a general base to perform the N4 abstraction. The results favored a water-mediate mechanism with a higher than usual Ez of 22.7 kcal/mol. An observation pertaining the tautomerization pertained to the aromaticity of the pyrimidine ring. Upon further investigation, aromaticity was found to play a signicant role in the ΔE observed. Aromaticity might contribute 14.2 kcal/mol to the barrier height. This high energy would drive the reaction forward producing the ylide.
Investigation of the DXR enzyme followed this work. Initially, the work was going to focus on the 2 mechanisms proposed for activity, alpha-ketol rearrangement and retroaldol/ aldol mechanism. Subsequent publications involving secondary kinetic isotope effects (KIEs) add to the pile of evidence supporting the retro-aldol/aldol mechanism. So the project was retooled to investigate the energetic dierences between two metal binding modes. The results of this work support a metal coordination across the C3-C4 bond, which eventually extends coordination to include the C2 oxygen. This conformation was help explain the tight binding eecting observation of the putative intermediates (transition states) and aldehyde intermediate. Additionally, as the C2-C3 mode consistently transfers a proton to the phosphate group of DXP or produces an elongated C-O bond, the C2-C3 mode would not be favorable.
Further investigations of these enzymes (e.g. completing the step begin, continuing through the reaction) could provide further illumination into the mechanism of action and possibly reveal new avenues of drug design. Examining the enzymes downstream in the NMA pathway might provide details of interest. Of particular interest is the radical reaction proposed for HDR/IspH. The nal step of the pathway produces IDP and DMADP in a 4:1 proportion, which corresponds to the general system requirements for production of the long chain, branched isoprenoids. It would be interesting to compute the mechanism to see if energetics could provide further insights. Additionally, normal mode analysis coupled with vibrational subsystem analysis could identify allosteric sites for feedback sensitivity.
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Astles, David James. "Synthetic and mechanistic studies in the field of deoxy, branched-chain and amino sugars." Thesis, University of Ottawa (Canada), 1985. http://hdl.handle.net/10393/4768.
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Zhu, Jiang. "Synthesis and mechanistic studies on 2-deoxy-Ã- and ß-D-glucopyranosyl pyridinium tetrafluoroborates." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape3/PQDD_0027/NQ51942.pdf.
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Bierau, Jörgen. "The pivotal role of CTP synthetase in the metabolism of (deoxy)nucleosides in neuroblastoma." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/70985.
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Isaac, Siara. "Synthesis and gene silencing activity of ribonucleic acid duplexes containing 3'-deoxy-3'-thiothymidine." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32408.
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This thesis reports the first synthesis and biophysical characterization of oligoribonucleotides (RNA) containing 3'-deoxy-3'-thiothymidine (3'-S-dT) units. Optimized conditions for incorporating 3'-S-dT into 21-nt RNA strands is also reported. The impact of 3'-S-dT substitutions on the structure and stability of RNA:RNA duplexes was investigated by circular dichroism (CD) and UV/thermal (Tm) studies. Generally, replacement of the 3'-oxygen by a sulphur atom resulted in a significant decrease in the thermal stability of the duplex and strong positional effects were observed. No significant disruption of the A-form helical structure of the duplexes was detected by CD, although in some cases 3'-S-dT inserts led to a reduction in base-base stacking and/or local distortion of the duplex. Assays revealed that short interfering RNA (siRNA) duplexes containing 3'-S-dT on the guide strand were not efficient at down-regulating gene products, but those containing 3'-S-dT on the passenger strand OR on both strands exhibited activities that often surpassed those of unmodified siRNA duplexes. Substitutions at the scissile phosphate position of the passenger strand suggest that the non-bridging 3'-oxygen is not involved in the coordination of a metal ion during the rate determining step in RISC-induced RNA cleavage.Cette thèse présente la première synthèse et caractérisation biophysique d'oligoribonucleotides (ARN) contenant des unités de 3'-deoxy-3'-thiothymidine (3'-S-dT). Des conditions optimisées pour l'intégration de 3'-S-dT en 21-nt ARN sont aussi présentées. L'impact de la substitution de 3'-S-dT sur la structure et la stabilité des duplex ARN:ARN fut recherché systématiquement par l'entremise de dichroïsme circulaire (CD) et d'études UV/thermale (Tm). Généralement, le remplacement du 3'-oxygène par un atome de sulfure résulta en une baisse significative de la stabilité thermique du duplex, et des effets de positionnement important furent observés. Aucune disruption significative de la structure hélicoïdale A-form du duplex ne fut détectée par le CD, quoi que parfois des inserts de 3'-S-dT entraînèrent une réduction des interactions base-base et/ou une distorsion locale du duplex. Des essaies révélèrent que des duplex interférents d'ARN court (siRNA) contenant du 3'-S-dT sur le brin guide n'ont pas baissé la production de gènes, mais que celles contenant du 3'-S-dT sur le brin complémentaire OU sur les deux brins présentèrent des activités qui fréquemment surpassaient celles de duplex non-modifiés de siRNA. Les substitutions à la position phosphate de rupture du brin complémentaire suggèrent que l'étape déterminante du clivage par RISC n'implique pas le 3'-oxygène pour la coordination d'un ion de métal.
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Wilds, Christopher James. "Synthesis, physicochemical and biological properties of oligonucleotides containing 2-fluoro-2-deoxy-℗-D-arabinose." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36730.
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Oligonucleotides containing the modification 2-fluoro-2-deoxy-beta-D-arabinose (2'F-ANA) were synthesized via solid phase synthesis in order to investigate their ability to bind to nucleic acids (DNA and RNA). The ability of this modification to serve as a suitable antisense oligonucleotide construct was also evaluated.All four nucleobase monomers (thymine, cytosine, adenine and guanine) were prepared for solid phase oligonucleotide synthesis, from which homopolymeric and heteropolymeric base sequences were assembled. These molecules bound with very good affinities to both DNA and RNA targets. Structural studies via NMR experiments demonstrated that in a 2'F-ANA/RNA duplex the 2'F-ANA residues adopt an O4' -endo conformation, similar to what has been proposed for the structure of DNA in a DNA/RNA hybrid.
A 2'F-ANA oligopyrimidylate formed a triple-helical complex with duplex DNA and hybrid DNA(Pu):RNA(Py) with an affinity higher than that of a corresponding DNA strand. Also, a cytosine-rich 2' F-ANA strand was found to form a complex at acidic pH which has properties similar to that of i-motif DNA.
Finally, 2'F-ANA strands when hybridized to RNA were found to activate RNase H, an enzyme that is involved in the mechanism of action of antisense drugs. 2'F-ANA is the first example of an antisense analogue that demonstrates improved binding to RNA relative to DNA and still retains the ability to elicit RNase H activity.
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Tran, David. "Investigating the substrate specificity of 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase." Thesis, University of Canterbury. Chemistry, 2011. http://hdl.handle.net/10092/6565.
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The shikimate pathway is a biosynthetic pathway that is responsible for producing a variety of organic compounds that are necessary for life in plants and microorganisms. The pathway consists of seven enzyme catalysed reactions beginning with the condensation reaction between D-erythrose 4-phosphate (E4P) and phosphoenolpyruvate (PEP) to give the seven-carbon sugar DAH7P. This thesis describes the design, synthesis and evaluation of a range of alternative non-natural four-carbon analogues of E4P (2- and 3-deoxyE4P, 3-methylE4P, phosphonate analogues of E4P) to probe the substrate specificity of different types of DAH7P synthases [such as Mycobacterium tuberculosis (a type II DAH7PS), Escherichia coli (a type Ialpha DAH7PS) and Pyrococcus furiosus (a type Ibeta DAH7PS)].
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Blackmore, Nicola Jean. "The regulation of 3-deoxy-D-arabino-heptulosonate 7 phosphate synthase from Mycobacterium tuberculosis." Thesis, University of Canterbury. Chemistry, 2015. http://hdl.handle.net/10092/10242.
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Allosteric regulation of important enzymes is a mechanism frequently employed by organisms to exert control over their metabolism. The shikimate pathway is ultimately responsible for the biosynthesis of the aromatic amino acids in plants, microorganisms and apicomplexans. Two enzymes of the pathway, 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) and chorismate mutase (CM) are located at critical positions along the aromatic amino acid biosynthetic pathway and are often tightly feedback regulated in order to control the flux of metabolites through the pathway. This research presents studies on the allosteric function of these two enzymes. These studies emphasise the complexity of the intersecting network of allosteric response, which alters the catalytic activity of each enzyme in response to metabolic demand for the aromatic amino acids.
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Reichau, Sebastian. "Inhibition and regulation of Mycobacterium tuberculosis 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase." Thesis, University of Canterbury. Chemistry, 2013. http://hdl.handle.net/10092/7896.
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The shikimate pathway is responsible for the biosynthesis of the aromatic amino acids and other aromatic metabolites in plants, micro-organisms and apicomplexan parasites. The shikimate pathway is essential in bacteria and plants, but absent from mammals, which has led to interest in the enzymes of the pathway as targets for the design of antimicrobial and herbicidal agents. 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first commit¬ted step of the shikimate pathway, the condensation of phosphoenolpyruvate and erythrose 4-phosphate to yield 3-deoxy-D-arabino-heptulosonate 7-phosphate. The subject of this thesis is the investigation of inhibition and allosteric regulation of the DAH7PS enzyme from Myco¬bacterium tuberculosis (MtuDAH7PS), the pathogen that causes tuberculosis. Tuberculosis remains a major health threat to the global community, and the emergence of multi-drug resistant strains highlights the need for new tuberculosis treatments. Inhibitors of MtuDAH7PS have the potential to be developed into new anti-tuberculosis drugs.
Chapter 2 describes the design, synthesis and evaluation of active site inhibitors based on intermediate mimic scaffolds. The intermediate mimics synthesised represent the first reported example of inhibitors targeting the active site of MtuDAH7PS. The most active compounds tested displayed inhibition constants in the sub-micromolar range, making them the most potent inhibitors of any DAH7PS enzyme reported to date.
MtuDAH7PS displays a complex and subtle mechanism of synergistic regulation: The enzyme is inhibited by binary combinations of the aromatic amino acids tryptophan (Trp), phenylalanine (Phe) and tyrosine (Tyr). Three allosteric binding sites were identified using X-ray crystallo¬graphic analysis of MtuDAH7PS in complex with Trp and Phe. While these crystal structures led to the identification of an allosteric binding site which preferentially binds Trp, the role and selectivity of the other two sites with respect to Phe and Tyr remained unclear. The results described in Chapter 3 provide structural and biochemical evidence for the hypothesis that each of the three allosteric binding sites has a preference for binding one of the aromatic amino acids Trp, Phe and Tyr, respectively. The results furthermore show that the ternary combination of Trp, Phe and Tyr synergistically regulates MtuDAH7PS, leading to almost complete loss of enzymatic activity in the presence of all three allosteric ligands.
In Chapter 4, the interaction of MtuDAH7PS with the naturally less common D-enantiomers of the aromatic amino acids is described. It was found that the D-enantiomers of the aromatic amino acids have no effect on enzymatic activity of MtuDAH7PS, suggesting an efficient mechanism by which the enzyme can discriminate between allosteric ligands of opposite configuration. Studies of the binding affinity of the D-amino acids to MtuDAH7PS as well as structural characterisation of MtuDAH7PS-D-amino acid complexes by X-ray crystallographic analysis suggest that D-Trp and D-Phe can still bind to their respective sites. The lack of inhibition is attributed to subtle differences in the binding mode of the D-enantiomers of the ligands compared to the L-enantiomers.
Chapter 5 details the discovery of alternative ligands and inhibitors targeting the allosteric sites of MtuDAH7PS using virtual screening. Libraries of potential alternative ligands were docked into the allosteric sites of MtuDAH7PS and the predicted docking poses were used to guide the selection of compounds for physical screening. Using this approach, a number of ligands and inhibitors of MtuDAH7PS were discovered and their interaction with the enzyme structurally characterised. Comparison of the crystallographically observed binding modes of new ligands with the docking poses predicted by computational docking highlighted potential improvements to the virtual screening method. The analysis of the correlation between ligand binding modes and inhibition of enzymatic activity provided further insight into which interactions between the allosteric ligand and the binding site are crucial in order to achieve inhibition. The crystal structures of MtuDAH7PS in complex with the new alternative ligands can serve as a starting point for the design of ligands with increased affinity and potency.
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Hellmuth, Isabell [Verfasser]. "Functionally modified (Deoxy)Ribonucleotides : synthesis and study of physicochemical and biological properties / Isabell Hellmuth." Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1132364590/34.
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Mehta, Dipti J. "15-deoxy-delta-12, 14-prostaglandin J2 (15d-PGJ2) Mediated Signaling in Colon Cancer." Diss., The University of Arizona, 2006. http://hdl.handle.net/10150/194039.
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Normal tissue structure and function are maintained by a dynamic interaction between epithelial cells and the stroma consisting of fibroblasts, adipose, vasculature and resident immune cells, and a multitude of cytokines and growth factors. Stroma was usually studied in the background of the malignant lesion, only in recent years researchers have started considering its role before carcinogenic lesions appear. Recent studies have shown that stromal cells and their products can cause the transformation of adjacent cells through transient signaling during phenomena like adipogenesis and inflammation by secreting various cytokines and chemokines into the matrix which can lead to apoptosis resistance, proliferation, mutations etc. Research in the last few years has demonstrated a functional role for stroma in the initiation and progression of breast, colon and prostate carcinomas. In this study effect of adipogenesis and/or inflammation on prostaglandin biosynthesis is investigated and the effects that these prostaglandins can have on epithelial cells is highlighted. This work demonstrates that normal colonic fibroblasts CCD18Co can produce anti-tumorigenic and pro-tumorigenic prostaglandins during adipogenesis and that this signaling is mediated via COX-2 activation. Although deoxycholic acid (DCA), a secondary bile acid that is responsible for inflammation in the gastro-intestinal tract, induces COX-2 signaling in the fibroblasts the downstream signaling of prostaglandin synthases is suppressed. Adipogenesis also leads to an increased polyamine catabolism. Effects of the prostaglandins were studied on various epithelial colon cancer cell lines. It was seen that 15d-PGJ2 causes growth inhibition and apoptosis in all cell lines tested and it was demonstrated that an activated K-RAS suppressed this phenomena. It was also seen that 15d-PGJ2 treatment could induce MAPK signaling and that an activated K-RAS suppressed JNK activation via AKT and MKK4. In conclusion this work reports that colonic fibroblasts can produce anti-tumorigenic factors like 15d-PGJ2 which may then induce apoptosis in epithelial cancer cells. This would be suppressed by an activated K-RAS and at the same time 15d-PGJ2 mediated MAPK signaling could confer a growth advantage for these cells and thus aid in tumor progression.
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Zagorodna, Oksana. "Bcl-2 family members regulate the sensitivity to 2-deoxy-D-glucose in lymphomas." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2794.
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Bcl-2 family members are important regulators of apoptosis, and their tampered expression is often involved in oncogenesis. Of particular importance are the levels of Bcl-2 family members in forming lymphomas. We studied two groups of murine thymic T cell lymphomas derived from either Bcl-2 or Bax overexpression in order to predict their sensitivity and resistance to treatments. While the growth rate and histological characteristics were similar for both lymphoma groups, Bax-derived lymphomas failed to undergo cell cycle arrest following radiation treatment and had frequent p53 mutations. In contrast, Bcl-2-derived lymphomas often halted proliferation following radiation delivery and rarely had p53 mutations. Bax-derived lymphomas were uniformly sensitive to treatment with 2-deoxy-D-glucose (2DG) while all Bcl-2-derived lymphomas were resistant. This led us to hypothesize that the Bcl-2 family is involved in 2DG-induced cell death. Focusing on the mechanism of 2DG toxicity in Bax-derived lymphomas, our studies demonstrate the following: cell death involved the activation of proapoptotic Bax, was effectively blocked by anti-apoptotic Bcl-2, and was mediated, at least in part, by the BH3-only family member Bim. Based on these results, we explored whether a BH3 mimetic (ABT-737) could sensitize lymphomas to 2DG killing. Indeed, a combination of ABT-737 with 2DG enhanced killing in Bax-derived lymphomas and resensitized Bcl-2-overexpressing lymphomas to 2DG. Since both 2DG and BH3 mimetics are currently in clinical trials, understanding their killing mechanisms and optimal combinations are of potential clinical significance. The work in this dissertation demonstrates a novel role of Bcl-2 family member proteins in regulating 2DG toxicity and may predict response to 2DG treatment. The information found presents a new strategy of combining 2DG with BH3 mimetics to improve existing lymphoma therapies.
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Montel, Sonia. "La 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase, une métalloenzyme cible pour l'élaboration d'inhibiteurs chélatants." Thesis, Montpellier, Ecole nationale supérieure de chimie, 2012. http://www.theses.fr/2012ENCM0013.
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La voie non-mévalonate est fortement présente chez les plantes et les bactéries mais est absente chez les mammifères. C'est pourquoi inhiber la synthèse des isoprénoïdes et identifier un inhibiteur de cette voie enzymatique contribuera grandement à la recherche de nouveaux antibiotiques, antifongiques et herbicides. Les propriétés uniques de la 1-deoxy-D-xylulose 5-phosphate reductoisomérase (DXR), l'enzyme centrale de cette voie enzymatique, en font une cible très intéressante pour la synthèse de nouveaux composés. La Fosmidomycine agit comme un inhibiteur de la DXR et reste aujourd'hui, avec son homologue acétylé FR90098, la référence en termes d'inhibiteur même si de nombreux efforts ont été faits pour la synthèse d'analogues depuis plusieurs années comme expliqué dans le premier chapitre avec la mise en relation de la structure des composés et leur activité. L'analyse de la diffraction des rayons X de la DXR avec la Fosmidomycine où le substrat naturel montre que la fonction phosphonate ou phosphate interagit avec une poche polaire hautement spécifique dans le site actif de l'enzyme permettant peu de modifications. Par comparaison, la fonction acide hydroxamique qui chélate le cation de l'enzyme offre la possibilité de modifications par l'introduction d'autres fonctions complexantes. Dans ce contexte, de nombreuses modifications comme l'introduction de fonctions carbamoylphosphinate, amidoxime, N-hydroxyurée et dérivées d'uraciles comme unités complexantes ont été synthétisées pour trouver des nouvelles familles d'inhibiteurs de la DXR. Toutes ces fonctions possèdent des propriétés de chélation intéressantes. En effet, elles ont déjà conduit à de puissants inhibiteurs de différentes métalloenzymesThe non-mevalonate pathway is highly present in higher plants, protozoa and bacteria but as no equivalent in mammals. That is why shut down isoprenoid biosynthesis and identify a non-mevalonate pathway inhibitor would greatly contribute to the search for safer antibiotics, antimalarials and for our concern herbicides. The unique properties of the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), the central enzyme of this pathway, make it a remarkable and attractive target for drug design. Fosmidomycin acts as an inhibitor of DXR and still remains, along with its N-acetyl homologue FR90098, one of the most potent inhibitor ever known even if extensive work on the development of Fosmidomycin analogue derivatives have been developed since the last decade as demonstrated in the first chapter with the development of a structure activity relationship of all the potential inhibitors of this enzyme already reported in the literature. The X-ray diffraction analysis of the co-crystals of DXR and Fosmidomycin or substrate shows that the phosphonic/phosphate group interacts with a highly specific polar pocket in the enzyme site, allowing only few structural modifications. By contrast, the cation chelating subunit represented by the hydroxamic acid function offers fine tuning possibilities for the complexation abilities as well as potential secondary interactions with the NADPH cofactor or directly with the enzyme. In this context, several modifications such as the introduction of carbamoylphosphinate, amidoxime, N-hydroxyurea and uracil complexing subunits have been made in order to find new families of DXR inhibitors. All of these functions show promising chelation capabilities as they already led to potent inhibitors of different metalloenzymes
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Walker, Scott Raymond. "Design, Synthesis and Characterisation of Inhibitors of 3-Deoxy-D-arabino-Heptulosonate 7-Phosphate Synthase." Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/3932.
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The enzyme 3-deoxy D-arabino-heptulosonate 7-phosphate (DAH7P) synthase catalyses the first step of the shikimate pathway. This pathway lies at the heart of bacterial metabolism, and is responsible for the synthesis of a variety of compounds essential to the chemistry of life; from the aromatic amino acids phenylalanine, tyrosine and tryptophan, to a number of aromatic and non-aromatic natural products. This thesis describes the design, synthesis and evaluation of inhibitors of DAH7P synthase. These inhibitors exploit a variety of strategies to interrupt the activity of DAH7P synthase, ranging from simple substrate mimicry to inhibitors that mimic unstable reaction intermediates; inhibitors that exploit metal coordination and entropic effects, and inhibitors that gain improved potency by interacting with multiple sites. In Chapter Two, the synthesis of a mimic for a proposed unstable reaction intermediate is described, and its interaction with DAH7P synthase characterised. The compound was prepared in twelve steps from D-arabinose, and was found to be a slow-tight binding inhibitor of Escherichia coli DAH7P synthase. In Chapter Three, a number of compounds are prepared that were designed to bind to the phosphoenolpyruvate subsite of the DAH7P synthase active site. The binding of these compounds to the enzyme is investigated in order to gain an understanding of the factors involved in DAH7P synthase inhibition. The enantiomeric phospholactates were prepared, and the extent of inhibition of E. coli DAH7P synthase was shown to be dependent on compound chirality. Several other phosphoenolpyruvate-like molecules were prepared, and were also shown to be effective DAH7P synthase inhibitors. In Chapter Four extended compounds are designed that will bind the enzyme by multiple interactions at both substrate binding sites. Four compounds were prepared, and an increase in inhibitory potency was observed. In Chapter Five computational techniques are explored to aid the interpretation of the inhibition of DAH7P synthase by the compounds prepared in these studies. Several approaches for more potent inhibition of this enzyme are outlined and discussed.
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Cross, Penelope Jane. "Unravelling the Evolution of Allosteric Regulation in 3-Deoxy-D-arabino-heptulosonate 7-phosphate Synthase." Thesis, University of Canterbury. Chemistry, 2012. http://hdl.handle.net/10092/6823.
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The enzyme 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first reaction in the shikimate pathway, leading to the biosynthesis of aromatic compounds including the aromatic amino acids. The catalytic activity of DAH7PS is regulated through feedback inhibition and is the major control point for the pathway. DAH7PSs are divided into two families, type I and type II, based on molecular weight and amino acid sequence. Type I DAH7PSs can be further divided based on sequence similarity. All DAH7PS enzymes with their crystal structures solved share a basic (β/α)₈-barrel fold in which the key catalytic components are housed. Furthermore, all structurally characterised DAH7PSs, except Pyrococcus furiosus DAH7PS (PfuDAH7PS) and Aeropyrum pernix DAH7PS, have recruited extra structural motifs that are implicated in allosteric regulation. However, there are significant differences in the additional structural elements.
This thesis investigates the hypothesis that the diverse regulation strategies for controlling DAH7PS activity have evolved by domain recruitment, whereby regulatory domains have been added to the catalytic barrel.
Chapter 2 describes the functional characterisation of the type Iβ Thermotoga maritima DAH7PS (TmaDAH7PS), and the exploration of its response to inhibitors. The catalytic activity of TmaDAH7PS was found to be substantially inhibited by tyrosine (Tyr) and to a lesser extent, phenylalanine (Phe). The putative regulatory domain previously identified as a ferredoxin-like domain was recognised as an aspartate kinase-chorismate-mutase-tyrA (prephenate dehydrogenase) or ACT domain.
Chapter 3 describes the characterisation of TmaDAH7PS with the N-terminal domain removed. The truncated enzyme was found to be more catalytically active than wild-type TmaDAH7PS and insensitive to inhibition by the aromatic amino acids, Tyr, Phe and tryptophan. Apart from the truncation of the ACT domain, the crystal structure of truncTmaDAH7PS showed no major changes to the monomer structure when compared to wild-type TmaDAH7PS. However, truncTmaDAH7PS crystallises as a dimer, unlike wild-type TmaDAH7PS.
In Chapter 4, the solution of the crystal structure of TmaDAH7PS with Tyr bound is presented. Tyr binding was shown to induce a significant conformational change, and Tyr is observed to bind at the interface between the ACT domains from two diagonally located monomers of the tetramer. The major reorganisation of the regulatory domain with respect to the barrel observed in the crystal structure, was confirmed by small angle X-ray scattering. The closed conformation adopted by the protein on Tyr binding physically gates the neighbouring barrel and blocks substrate entry into the active site.
Chapter 5 explores the interactions between TmaDAH7PS and the allosteric inhibitor, Tyr. The residues His29 and Ser31, which form hydrogen bonds with the hydroxyl moiety of the Tyr ligand, were examined for their impact on the sensitivity and selectivity of the enzyme for the inhibitors Tyr and Phe. The hydroxyl side chain of Ser31 was found to be important for both the preferential inhibition by Tyr over Phe and the inhibitory mechanism. His29 (the hydrogen-bonding partner of Ser31) appears to play a secondary role in determining ligand selectivity and the relative positioning of these two residues is crucial to the inhibition of the enzyme.
Chapter 6 evaluates the transferability of allosteric control of catalytic activity. The ACT domain of TmaDAH7PS was fused onto the barrel of the unregulated PfuDAH7PS. This chimeric enzyme was found to be catalytically active, inhibited by Tyr (although less sensitive) and preliminary crystallographic results show inhibition occurs via the same conformational change observed for wild-type TmaDAH7PS.
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Othman, Mohamad. "Characterisation and Control of 3-Deoxy-D-arabino-heptulosonate 7-phosphate Synthase from Geobacillus sp." Thesis, University of Canterbury. Department of chemisty, 2014. http://hdl.handle.net/10092/10113.
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3-Deoxy-D-arabino heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first step of the shikimate pathway, responsible for the biosynthesis of aromatic amino acids. This pathway is found in microorganisms, plants and apicomplexan parasites and its absence in mammals makes it a viable target for antimicrobial drug design. DAH7PS enzymes differ in the regulatory machinery that decorates the catalytic (β/α)8 barrel. Some DAH7PS enzymes are fused to chorismate mutase (CM), another enzyme in the shikimate pathway. This fusion protein is allosterically regulated by chorismate (CA) or prephenate (PA), the precursor of tyrosine and phenylalanine. It has been suggested that DAH7PS enzymes evolved these extensions to the core barrel for the sole purpose of regulation.
Geobacillus sp DAH7PS (GspDAH7PSWT) is a thermophilic type Iβ DAH7PS enzyme with an N-terminal CM domain fused through a linker region. This thesis describes the functional characterisation work carried out on GspDAH7PSWT, in attempt to help determine how DAH7PS enzymes evolved such diverse methods of regulation.
Chapter 2 describes the functional characterisation work carried out on the catalytic and regulatory domains of GspDAH7PSWT. The enzyme demonstrated both DAH7PS and CM activities with the DAH7PS domain determined to be metal dependent and most activated by Cd2+. PA completely inhibited the catalytic activity of GspDAH7PSWT, and AUC demonstrated an equilibrium exists between the dimeric and tetrameric quaternary states of the enzyme in solution.
Chapter 3 describes the domain truncation of GspDAH7PSWT carried out at the linker region in order to obtain two separate protein domains, the catalytic domain lacking the N-terminal domain (GspDAH7PSDAH7PS) and the regulatory domain without the catalytic domain (GspDAH7PSCM). Both variants were fully characterised, and information obtained from each domain was compared to the respective catalytic and regulatory domains of the wild-type enzyme, which was also characterised. Like GspDAH7PSWT, GspDAH7PSDAH7PS showed greatest activation in the presence of Cd2+, with other metals having varying effects on activation rates and stability of the enzyme. Both truncated variants followed Michaelis-Menten kinetics where GspDAH7PSDAH7PS was found to be more active than GspDAH7PSWT and unaffected by PA, whereas GspDAH7PSCM was a less efficient catalyst than the CM domain of GspDAH7PSWT. AUC demonstrated that in solution an equilibrium occurs between the monomeric and tetrameric oligomeric states of GspDAH7PSDAH7PS.
Chapter 4 summarises the findings of the thesis along with future directions of this research, combining the results obtained and expanding upon them. It is concluded that the catalytic regulatory CM domain supports both protein structure and allosteric regulation of GspDAH7PSWT
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Chudziak, Christopher Mark. "Production, characterisation and modification of 1-deoxy-d-xylulose-5-phosphate synthase as a biocatalyst." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445214/.
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The use of biotransformations in organic synthesis is a small but growing field. Biotransformations can be used for many steps which prove difficult with traditional chemistry, particularly stereospecific syntheses and chiral resolutions. However, to enable the increasing use of biotransformations in chemical synthesis, a broader range of biocatalysts will be required than those of which we are currently aware. Bioprospecting and genome sequencing are increasing the awareness of Nature's library of biocatalysts. These enzymes need to be characterised for their use as biocatalysts, and where necessary modified to meet needs that may not be catered for in nature. One currently used biocatalyst is transketolase. Transketolase is an enzyme which is produced by most organisms. As a biocatalyst it is most often extracted from spinach, or produced by recombinant Escherichia coli. Transketolase carries out a stereospecific carbon-carbon bond formation, removing a 2-carbon ketol group from a ketose sugar, and adding it to the aldehyde group of the aldose sugar. It is a useful biocatalyst as it has a broad substrate specificity. Significantly it will use hydroxypyruvate as the ketol donor, thus liberating carbon dioxide and driving the reaction in a forward direction. In this thesis the transketolase-like enzyme, 1-Deoxy-D-xylulose 5-Phosphate Synthase (DOX-P Synthase), is identified as another possible biocatalyst. Significantly DOX-P Synthase catalyses the addition of a carbonyl unit, not from hydroxypyruvate, but from pyruvate, a reaction which cannot be catalysed by transketolase. This thesis therefore describes studies that aimed to produce recombinant DOX-P Synthase as a biocatalyst, and to optimise its production. Further studies aimed to characterise the properties of DOX-P Synthase, with the aim of optimising its use as a biocatalyst. Analysis of the substrate range of DOX-P Synthase could then be used to describe the set of reactions for which it would be a useful biocatalyst. Finally, this thesis describes modifications made to the enzyme, carried out by site-directed mutagenesis, and the effects on enzyme properties.
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Michailidou, Freideriki. "Structural and mechanistic studies on the biosynthesis of the 3'-deoxy nucleoside of the pacidamycins." Thesis, University of St Andrews, 2018. http://hdl.handle.net/10023/15668.
Full textAbstract:
Nucleic acids are ubiquitous in nature and modified nucleosides are present in a wide range of anti-viral, anti-cancer drugs and antibiotics. Although a variety of naturally occurring nucleoside analogues exist, few include modifications to the ribose or deoxyribose ring. Intriguingly, the uridyl peptide antibiotics (UPAs), such as pacidamycin, contain a biosynthetically unique 3'-deoxyuridine which resembles synthetic anti-retrovirals. Elucidation of the biosynthesis of this structuraly unique nucleoside motif suggests a degree of substrate flexibility, making it a highly attractive prospect for biosynthetic approaches to nucleoside modification. In order to fully exploit the biotransformative potential, a detailed mechanistic understanding of the individual enzymes involved in the biosynthesis of the nucleoside moiety, and especially the enzyme employed at the installation of the 3'-deoxy modification, is required. Chapter 1, the introduction the thesis, discusses the importance of nucleosides for Chemistry and Biology. The section describes the biosynthesis of the nucleoside antibiotics and reviews the recent advances relating to the synthesis and biosynthesis of 3'-deoxy-nucleosides. The Chapter proceeds to describes the biosynthesis of deoxy-sugars, deoxy-nucleosides and nucleotides, reviewing the most common dehydratase mechanisms in addition to examining unusual dehydratases involved in carbohydrate metabolism. Chapter 2, the study of Pac13, the uridine-5'-aldehyde dehydratase of the pacidamyicin nucleoside cluster, is reported. Through detailed functional, structural and kinetic analysis of the wild-type enzyme as well a series of mutants, Chapter 2 provides insight into the mechanism emplyed by this unusual enzyme. Chapter 3 describes the structural and functional analysis of Pac11, the flavin-dependent oxidoreductase of the nucleoside biosynthetic cluster, while Chapter 4 revolves around Pac5, the PLP-dependent aminotransferase. In Chapter 5, the chemical synthesis of fluorinated nucleosides, as probes for exploring the enzymes' mechanism is investigated. Chapter 7 reports the experimental procedures for the research described in this document. The work described in this thesis broadens the understanding of the biosynthesis of deoxy-nucleosides and constitutes the first structural and mechanistic study of the biosynthesis of the biosynthesis of the valuable yet, synthetically challenging 3'-deoxy nucleosides.
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Hann, Ronald Koy. "Synthesis of N, N'-bis-(3-deoxy-beta-cyclodextrin)-ethyl Endiamine and Potential Photochemical Applications." W&M ScholarWorks, 1987. https://scholarworks.wm.edu/etd/1539625389.
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Wangpaichitr, Medhi. "The Relevance of mTOR and Hypoxia Inducible Factor to 2-Deoxy-D-Glucose Toxicity in Lung Cancer Cell Lines Under Hypoxia." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/156.
Full textAbstract:
Hypoxic regions found in most solid tumors often contain cells which are resistant to various cancer therapies. However, hypoxia also forces cells to rely solely on the catabolism of glucose through glycolysis for ATP production and survival, thereby creating a therapeutic window that can be exploited by glycolytic inhibitors, such as 2-deoxy-D-glucose (2-DG). Previous studies in our lab demonstrated that activation of Hypoxia Inducible Factor (HIF-1) in hypoxic tumor cells confers resistance to glycolytic inhibition by 2-DG. In surveying a number of tumor types for differences in intrinsic levels of HIF-1 alpha under hypoxia, we found that pathways upstream of HIF -- i.e. AKT and mammalian target of rapamycin (mTOR) -- have significantly reduced activity in 2 human non-small lung cancer cell lines (NSCLC) as compared to 4 small cell lung cancer cell (SCLC) lines. This reduced activity of AKT and mTOR correlated with increased sensitivity to 2-DG under hypoxia. Since HIF-1 alpha translation is regulated by the mammalian target of rapamycin (mTOR), we examined the effects of blocking mTOR with an analog of rapamycin (CCI-779) in SCLC cells which express high levels of mTOR activity. Under hypoxia, treatment with CCI-779 resulted in HIF-1 alpha down-regulation. Furthermore, CCI-779 potentiated the cytotoxic effects of 2-DG in hypoxic SCLC cells. Conversely, CCI-779 did not increase 2-DG toxicity in NSCLC lines that do not express HIF, SCLC lines treated with siRNA against HIF-1 alpha, or HIF-deficient mutants. These latter results support the hypothesis that, although mTOR modulates numerous downstream pathways, mTOR inhibition by CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1 alpha. Overall, our findings show that CCI-779 hyper-sensitizes HIF-expressing hypoxic tumor cells to 2-DG. Additionally, our results suggest that the intrinsic expression of AKT, mTOR, and HIF in many tumor types may be important predictors of clinical responsiveness to 2-DG and could be used to guide future treatment decisions on whether to use 2-DG alone or in combination with an mTOR inhibitor.
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Galvão, Fábio Carrilho. "Caracterização de mutantes condicionais do gene da desoxi-hipusina sintase em Saccharomyces cerevisiae /." Araraquara : [s.n.], 2011. http://hdl.handle.net/11449/87674.
Full textAbstract:
Orientador: Cleslei Fernando ZanelliBanca: Nilson Ivo Tonin Zanchin
Banca: Paulo Sergio Rodrigues Coelho
Resumo: O fator de início de tradução 5A (eIF5A) é altamente conservado de arqueas a mamíferos e é essencial para a viabilidade celular. Este fator é a única proteína conhecida que sofre uma modificação pós-traducional única e necessária para a função de eIF5A, em que uma lisina específica é convertida em um resíduo de hipusina pela ação das enzimas desoxi-hipusina sintase (Dys1) e desoxi-hipusina hidroxilase (Lia1). Inicialmente, eIF5A foi relacionada à etapa do início da tradução, porém, dados recentes sugerem a sua atuação na etapa de elongação ao invés de início. No entanto, além do fato de a função específica de eIF5A na célula não ser conhecida, o papel da hipusinação para o funcionamento de eIF5A também não é conhecido. Diante disso, o objetivo deste trabalho é caracterizar mutantes condicionais para o gene da desoxi- hipusina sintase e, dessa forma, contribuir para o entendimento não só da função da hipusinação sobre eIF5A, mas também para o entendimento da função específica de eIF5A na célula. Para isso, foram iniciadas análises de caracterização fenotípica com os alelos dys1Δ1-28 e dys1W75R/T118A/A147T (dys1-1). Inicialmente, foi realizada a subclonagem do alelo dys1Δ1-28 , uma vez que, por ter sido identificado em um rastreamento de duplo-híbrido, este alelo estava em fusão com a região codificadora do domínio de ativação de Gal4. Porém, após realização da subclonagem, ou seja, quando na ausência do domínio de ativação, este alelo não apresentou o fenótipo condicional de crescimento inicialmente observado. Portanto, o mutante se tornou impróprio para a realização dos ensaios subsequentes e foi descartado. Em seguida, foram iniciadas as análises com o alelo dys1-1, nas quais foi observada diminuição nos níveis totais de Dys1 mutada, e consequentemente, diminuição nos níveis de hipusinação. Devido a isso ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The translation initiation factor 5A (eIF5A) is highly conserved from archaea to mammals and is essential for cell viability. This factor is the only known protein that undergoes an unique and essential post-translational modification, in which a specific lysine residue is converted into hypusine by the action of the enzymes deoxyhypusine synthase (Dys1) and deoxyhypusine hydroxylase (Lia1). Initially, eIF5A was related to the initiation step of translation, however, recent data suggest a role in the elongation step of translation. However, besides the fact that the specific function of eIF5A in the cell is still obscure, the role of hypusination in eIF5A function is unknown. Thus, the goal of this project is to characterize conditional mutants of the deoxyhypusine synthase gene and thereby contribute to the understanding not only the function of hypusination in eIF5A, but also of the specific role of eIF5A in the cell. We started a phenotypic characterization of two different alleles: dys1Δ1-28 and dys1W75R/T118A/A147T (dys1-1). Initially, we performed a subcloning of the allele dys1Δ1-28 , once the allele was fused with the coding region of GAL4 activation domain, due to the fact that this allele is devived of a two-hybrid screening. However, after performing the subcloning, that is, in the absence of the activation domain, this allele showed no conditional growth phenotype as originally observed. Therefore, this mutant has become improper to carry out the subsequent analysis and was discarted. Then, the analyses with dys1-1 allele were initiated, in which it was observed a decrease in total levels of Dys1 and, consequently, a decrease in the hypusination levels. Because of that, this allele shows a decrease in cell growth rate and growth arrests after 24 hours in medium lacking the osmotic regulator. However, this growth arrest is not followed by cell lysis. Furthermore, the mutant ... (Complete abstract click electronic access below)
Mestre
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Bassiri, Jackie Mehrnaz. "Synthesis of UDP-6-deoxy-6,6-difluoro-D-GlcNAc : a potential mechanism-based inhibitor of pseB." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/31825.
Full textAbstract:
Pseudaminic acid is a nine carbon sugar, similar to sialic acid, and has been found
to play an important role in the biosynthesis of flagella in pathogenic bacteria such as C.
jejuni and H. pylori. For these bacteria the flagella is crucial in motility and colonization
of the host. Because this sugar is found only in bacteria, enzymes required for its
biosynthesis serve as novel targets for antibiotic development. A UDP-GlcNAc
dehydratase, pseB, catalyses the first step of pseudaminic acid biosynthesis in C. jejuni.
This enzyme catalyzes the conversion of UDP-GlcNAc to UDP-6-deoxy-4-keto-
HexNAc. The proposed mechanism of this conversion is composed of oxidation of the
C4 hydroxyl resulting in the formation of a 4-keto group, then a dehydration across the
bond between C5 and C6 producing a UDP-4-keto-5,6-ene-hexose, and finally reduction
in which a hydride from the enzyme bound NADFt cofactor is transferred to C6, and C5
is reprotonated on the opposite face such that the stereocentre at C5 is inverted during this
dehydration reaction.
In 1998, the synthesis of CDP-6-deoxy-6,6-difluoro-D-glucose, 9, was published
by Chang et al. This compound was the first mechanism-based inactivator known for a
dehydratase enzyme, more specifically, CDP-D-glucose 4,6-dehydratase, isolated from
Yersinia pseudotuberculosis. Based on this work, a 10-step synthesis of UDP-6-deoxy-
6,6-difluoro-D-GlcNAc 11 was completed which generated a potential mechanism-based
inhibitor for pseB.
[image in original]
The preliminary enzyme kinetics performed did not support 11 as a mechanismbased
inactivator of pseB. One possible explanation for this is based on the steric aspect
of the inhibitor vs. the substrate. The two fluorine groups on the C-6 positions are
possibly too bulky for the inhibitor to bind the enzyme active site and cause inactivation.
Another reason might be that the H-bonding of the C-6 hydroxyl group of the substrate to
the enzyme is crucial in substrate binding. When it is replaced with two fluorines the lack
of this H-bonding does not allow binding of the inhibitor to the active site.Science, Faculty of
Chemistry, Department of
Graduate
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Liu, Yan. "Stereoselective synthesis of α-, β- and 1,1-disubstituted C-glycosides of 2-amino-2-deoxy sugars." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420899.
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Wong, Ursula. "Investigation into potential inhibitors of 1-deoxy-xylulose 5-phosphate reductoisomerase (DXR) and relevant mechanistic studies." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442179.
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Burnside, I. J. "Synthetic studies on macrolide antibiotics : the total synthesis of (+)-(6R)-Fluoro-6-deoxy-(9S)-dihydroerythronolide A." Thesis, University of Cambridge, 1996. https://www.repository.cam.ac.uk/handle/1810/273078.
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RESSAYRE, CATHERINE. "Modelisation du comportement cinetique du 5'-deoxy-5-fluorouridine (5'dfur) : apports methodologiques en pharmacocinetique experimentale." Aix-Marseille 2, 1990. http://www.theses.fr/1990AIX22985.
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Guardado, Puentes Julian. "Trans diequatorially fused 3',3'-Diphenyl-2'-morpholinone derivatives of 2-Amino-2-deoxy-D-glucose." Scholarly Commons, 1985. https://scholarlycommons.pacific.edu/uop_etds/2113.
Full textAbstract:
The chemistry of amino sugar compounds has been studied in the last years in connection with the study of natural products, and many of them have been isolated. 57,17,18 Amino sugars play an important role in biochemistry, forming blocks of homo- and heteropolymers and complex molecules such as microbial polysaccharides, enzymes, gangliosides, glycoproteins, and antibiotics.
This research project had the purpose of preparing a derivative of 2-amino-2-deoxy-D-glucose, with a free hydroxyl group at the anomeric carbon, with the 4,6-positions blocked with the benzylidene cyclic acetal, and the 2,3-positions being blocked by a 3,3-diphenyl-2-morpholinone ring trans diequatorially fused to the amino sugar ring. The C-1 position was initially protected with a β-benzyl aglycon, which was expected to be removable selectively by catalytic hydrogenation. It was also hoped that we could optimize conditions for the synthesis of the morpholinone derivative. Selective cleavages of the blocking groups were to be investigated.
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Baney, Tara S. "Examining the behavior of RluA and TruB towards tRNA containing 2'-deoxy-2'-fluorouridine or 2'-deoxyuridine." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 127 p, 2010. http://proquest.umi.com/pqdweb?did=1992442041&sid=6&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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