Dissertations / Theses: 'Enzyme inhibition'

1

Edge, Colin Michael. "Theoretical studies of enzyme inhibition." Thesis, University of St Andrews, 1989. http://hdl.handle.net/10023/14388.

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The glyoxalase enzyme system catalyses the conversion of methylglyoxal to D-lactic acid. The first of the two component enzymes, glyoxalase I, is responsible for the transfer of two protons in an iscmerisation reaction. This enzyme has been ascribed a role in tumorigenesis in the past and some of its inhibitors are known to be carcinostatic. This thesis describes quantum chemical calculations on the enzyme mechanism and on some enzyme inhibitors. The calculations on the mechanism of the enzyme take the form of studies of model reaction schemes, with minimal and split-valence basis sets. The calculation of the energies of various intermediates has led to the evaluation of different pathways as models of the enzyme mechanism. The comparison of different substituted compounds has led to further conclusions on the part played by the sulphur atom in the enzyme-catalysed reaction. Two main groups of inhibitor molecules are discussed; these are flavone and coumarin derivatives. The molecular electrostatic potential of these molecules has been calculated on various surfaces, using a minimal basis set, to attempt to correlate this property with the compounds' inhibitory power. A FORTRAN program is presented which depicts calculated properties on the surfaces. This program allowed the identification of various regions which seemed to be indicative of the inhibitory strength of the compounds.

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2

Kakkar, Tarundeep Singh. "Theoretical studies on enzyme inhibition kinetics." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/289017.

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Enzyme inhibition studies are conducted to characterize enzymes and to examine drug-drug interactions. To characterize the inhibitory process (competitive, non-competitive and uncompetitive) and to determine the inhibitory constant (Kᵢ), data analysis techniques (e.g., Dixon, Lineweaver-Burk, etc.) are used to linearize the inherently non-linear rate of substrate metabolism vs. substrate concentration data. These techniques were developed before the general use of computers. However, many investigators still rely on these techniques in spite of the easy availability of non-linear regression fitting programs. In Chapter 2, three methods (simultaneous nonlinear regression fit (SNLR); Dixon; non-simultaneous, nonlinear fit [K(m,app)]) were compared for estimating Ki from simulated data sets generated from a competitive inhibition model equation with 10% CV added random error to the data values. Of the three methods, the SNLR method was found to be the most robust, the fastest and easiest to implement. The K(m,app) method also gave good estimates but was more time-consuming. The Dixon method failed to give accurate and precise estimates of Kᵢ. The purpose of the study in Chapter 3 was to examine the minimal experimental design needed to obtain reliable and robust estimates of Kᵢ (as well as V(max) and K(m)). Four cases were examined. In the experimental design that relied upon the least amount of data, a control data set was fit simultaneously with one of the substrate-inhibitor pairs (25-10 or 250-100 μM). A total of 4 rate values were analyzed per fit (i.e., 3 control + 1 inhibitor value). A total of 100 data sets were fit per substrate-inhibitor pair. The preceding was repeated for a random error of 20 %CV. Thus, the total number of experiments was reduced from 108 (in Chapter 2) to 12 (in Chapter 3) (Case IV). Good estimates of the enzyme kinetic parameters were obtained. In Chapter 4, the ability of the SNLR method to identify the correct mechanism of inhibition was evaluated; competitive or noncompetitive enzyme-inhibition. Two experimental designs were examined ("conventional, non-optimal" and "semi-minimal"). The semi-minimal design was successful in discriminating between the two enzyme-inhibition mechanisms even for data with 30 %CV added random error.

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3

Bjelic, Sinisa. "Molecular Simulation of Enzyme Catalysis and Inhibition." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7468.

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4

Axamawaty, Mohammed Taleb Hassan. "Inhibition and inactivation of hydrolases." Thesis, University of Bristol, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481028.

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5

Khan, Amjad. "NMR spectroscopy studies of enzyme function and inhibition." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:698d69c7-d4f1-4bc7-bf0b-3b9e7fb3a4fe.

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The work described in this Thesis focuses on the application of NMR spectroscopy methods in understanding the function and inhibition of two protein systems; these are ?-butyrobetaine hydroxylase (BBOX) and the bacterial potassium ion efflux (Kef) system. BBOX belongs to the super family of enzymes called the 2- oxoglutarate (2OG) and FeII dependent oxygenase and is involved in the biosynthesis of L-carnitine in humans and other prokaryotes. BBOX is a current drug target for the treatment of myocardial infarction. Kef is a ligandgated system that protects bacteria from toxic electrophilic species. Kef is inhibited by the binding of cytoplasmic glutathione (GSH) to KTN (K+ transport and nucleotide) binding domains and activated by glutathione-S-conjugates (GS-X). Since bacterial Kef activation during electrophilic exposure is a critical determinant of their survival, perturbation of Kef activity is potentially a novel target for the development of antibiotic drugs. 1H NMR direct ligand-observation was employed to study the binding interaction of the natural substrate ?- butyrobetaine (GBB) and co-substrate 2OG with BBOX. A 1H NMR-based dual-reporter ligand displacement method was developed to assess the nature of inhibitor binding to BBOX i.e to determine whether an inhibitor competes with GBB or 2OG or both. The method was exemplified with a set of isoquinoline-based inhibitors; the results reveal 'cystallographically unexpected' structure-activity relationship with some inhibitors competing 2OG only and some competing both 2OG and GBB. Using 1H NMR spectroscopy, a simple and efficient BBOX inhibition assay was developed for inhibitor IC50 measurement. Similarly, 1H NMR-based assays were applied to demonstrate that the cation-p interaction between the substrates and aromatic cage residues of BBOX play a critical role in BBOX substrate recognition. 1H NMR spectroscopy was applied to show that in the absence of a 2OG oxygenase, ascorbate in the assay mixture is slowly degraded by the dissolved oxygen to yield H2O2 which simultaneously leads to 2OG breakdown into succinate. It is proposed that in the assays of 2OG oxygenases, the apparent increase in the level of "uncoupled" 2OG turnover with ascorbate over time could possibly be due to the artifacts of the ascorbate induced-2OG breakdown instead of being due to enzyme catalysis. Other reducing agents were also found to oxidise identically by the dissolved oxygen as ascorbate in the mixture and result in 2OG breakdown. In the Kef system, 1H NMR direct ligand-observation was applied to investigate the influence of each functional group of the Kef activating ligand glutathione-S-N-tertiary butylsuccinimide on its binding interaction (KD 0.4 μM) with Kef-QCTD (Q-linker carboxy terminal domain; a KTN domain) from Shewanella denitrificans (sd) with the aim of developing novel non-peptidic ligands (antibacterial agents) of Kef. In addition, 19F NMR was employed to develop an efficient ligand-observed binding assay for Kef that was used for ligand screening as well as measuring their binding dissociation constant value from a single NMR spectrum. Finally, a 1H NMR technique was applied to confirm that the electron density found in the nucleotide binding pocket in the crystal structure of apo-sdKef-QCTD is unambiguously an AMP molecule that is naturally bound to the protein and has a role in stabilising the dimeric form of KTN domains (Kef proteins).

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6

Ghous, T. "Flow injection determination of drugs by enzyme inhibition." Thesis, University of Hull, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296138.

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7

Apperley, Kim Yang-Ping. "Reversible and Photolabile Inhibitors for Human Tissue Transglutaminase." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36593.

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Tissue transglutaminase (TG2) is a calcium-dependent enzyme that natively catalyses the formation of isopeptidic bonds between protein- or peptide-bound glutamine and lysine residues. Physiologically, it is ubiquitously expressed in tissues, with roles in cellular differentiation, extracellular matrix stabilisation, and apoptosis, among others. However, its unregulated activity has been associated with various pathologies including fibrosis, cancer and celiac disease. Since most pathologies are associated with an increased transamidation activity, efforts have been directed towards the development of TG2 inhibitors. In this context, the work described in this thesis is centred on reversible inhibitors, building on recent work done within the Keillor group in two directions, namely localisation and potency. In a localisation-driven approach, we developed a photolabile derivative of a known reversible inhibitor, in order to form a covalent bond with the enzyme and determine the inhibitor’s binding site. In tandem, we optimised a protocol for the expression of TG2 incorporating ArgΔ10 and LysΔ8, amino acids that are 13C- and 15N-labelled to provide a mass shift of 10 and 8 Da, respectively, compared to the corresponding unlabelled amino acids. This “heavy” TG2 was developed as a tool for reference in the analysis of the tryptic digest of labelled protein. In a potency-driven approach, based on the observation that previous trans cinnamoyl inhibitor scaffolds were susceptible to nucleophilic attack by glutathione, we developed a bis(triazole) scaffold with reduced electrophilicity. The preparation of a small library of compounds showed that this scaffold demonstrates a preference for electron-withdrawing substituents, such as nitro groups. Continuing in a potency-driven approach, and inspired by work done in the identification of glutathione-resistant scaffolds, we studied a new alkynyl scaffold. While still susceptible to glutathione addition, these compounds showed a marked improvement in potency, with the lead compound having an IC50 of 930 nM and being established as a competitive inhibitor with a Ki of 420 nM, our most potent reversible inhibitor to date. Furthermore, this scaffold also produced an inhibitor lacking nitro groups (to limit eventual cellular toxicity), but maintaining good potency, with an IC50 value of 3.03 μM.

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8

Kownarumit, Supaporn. "Multiplex screening using enzyme inhibition, fluorescence detection and chemometrics." Thesis, Loughborough University, 2006. https://dspace.lboro.ac.uk/2134/12308.

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Fluorescence enzyme inhibition assays have been established for a number of years as valuable methods of analysis in clinical chemistry and other fields. Those in common use are normally single analyte assays. However, in many cases (e.g. drug screening) dual or multiplex assays would be much more valuable, with the advantages of increased information content, saving in time and costs, and the elimination of some sources of sampling variance. This project has investigated single and dual screening assays of enzyme inhibitors, namely 3-nitrophenylboronic acid (3-NPBA), phenylethyl /3-0- thiogalactopyranoside (PETG) and sodium vanadate (VI), using flow injection fluorescence spectroscopy and chemometric methods to resolve strongly overlapping fluorescence spectra. The single and dual screening assays have been based on flow injection analysis methodology, with immobilised enzymes on solid phase reactors to investigate the enzyme inhibitors. The assays were rapid, allowing around 15-25 measurements to be made per hour. The inhibitions of alkaline protease, alkaline phosphatase and /3-galactosidase with their inhibitors at flg/ml levels were achieved. An alternative approach to these dual assays has been investigated by the use of multivariate techniques. Such techniques allow accurate and reliable results to be obtained even from spectra that contain extremely overlapping signals. Moreover, preliminary investigation of three fluorophores which gave strongly overlapping spectra, using flow injection fluorescence spectroscopy and partial least squares (PLS-1) model has been successful. By combination of this flow injection fluorescence spectroscopy with the use of chemometrics, many applications can be envisaged in biochemical, clinical, and pharmaceutical industries. With the findings of this research the system described here can be developed for use in high throughput screening of candidate drug molecules and many screening processes throughout the different industries.

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9

Page, Simon Matthew. "Ruthenium anticancer complexes : a targeted approach to enzyme inhibition." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608027.

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10

Al-Timari, A. A. A. K. "Binding determinants for some glutathione-dependent enzymes." Thesis, University of Essex, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.354003.

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11

Marakalala, Mohlopheni Jackson. "Inhibition of a Mycothiol biosynthetic enzyme and a detoxification enzyme as anti-tubercular drug targets." Doctoral thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/2694.

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12

Rapolu, Chaitanya. "Inhibition of Cysteine Protease by Platinum (II) Diamine Complexes." TopSCHOLAR®, 2011. http://digitalcommons.wku.edu/theses/1137.

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Chemotherapy is the first line of treatment used in cancer. Chemotherapy drugs such as cisplatin, carboplatin and oxaliplatin are used in treatment. Cisplatin enters the cell through copper transporter CTR1 by passive diffusion and bind to DNA and proteins. Cisplatin is found to inhibit several enzymes targeting cysteine, histidine and methionine residues, which are expected to be responsible for its anticancer activity. A better understanding of how the size and shape and leaving ligands of platinum complexes affect cysteine protease, papain enzyme are studied. This could give new ways to optimize anticancer activity. The activity of papain enzyme was measured on UV-Visible spectroscopy. The inhibition profile of papain with different platinum (II) complexes, and with different combinations was studied.

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13

Debord, Jean. "Relation structure chimique-activité biologique pour quelques phosphoramides et benzamides." Poitiers, 1988. http://www.theses.fr/1988POIT2331.

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Les constantes d'inhibition reversible de la butylcholinesterase par une serie de 16 phosphoramides aliphatiques ont ete determinees par spectrophotometrie et par microcalorimetrie. L'activite des substituants amines augmente avec la lipophilie. L'inhibition irreversible de la butylcholinesterase par le thio-tepa et le methyl-parathion a ete etudiee en suivant l'hydrolyse d'une faible concentration de substrat en presence de l'inhibiteur

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14

Dogaru, Daniela. "Hydrogenase inhibition by O2 density functional theory/molecular mechanics investigation /." Cleveland, Ohio : Cleveland State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=csu1231721611.

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Thesis (Ph.D.)--Cleveland State University, 2008.
Abstract. Title from PDF t.p. (viewed on Apr. 13, 2009). Includes bibliographical references (p. 102-109). Available online via the OhioLINK ETD Center. Also available in print.

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15

Zhang, Yixin. "Rational design of cyclosporin A derivatives for selective enzyme inhibition." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=964279401.

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16

Gutiérrez, Arenas Omar. "Sensitivity, Noise and Detection of Enzyme Inhibition in Progress Curves." Doctoral thesis, Uppsala University, Department of Biochemistry, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6886.

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Starting with the development of an enzymatic assay, where an enzyme in solution hydrolysed a solid-phase bound peptide, a model for the kinetics of enzyme action was introduced. This model allowed the estimation of kinetic parameters and enzyme activity for a system that has the peculiarity of not being saturable with the substrate, but with the enzyme. In a derivation of the model, it was found that the sensitivity of the signal to variations in the enzyme concentration had a transient increase along the reaction progress with a maximum at high substrate conversion levels.

The same behaviour was derived for the sensitivity in classical homogeneous enzymatic assays and experimental evidence of this was obtained. The impact of the transient increase of the sensitivity on the error structure, and on the ability of homogeneous end-point enzymatic assays to detect competitive inhibition, came into focus. First, a non-monotonous shape in the standard deviation of progress curve data was found and it was attributed to the random dispersion in the enzyme concentration operating through the transient increase in the sensitivity. Second, a model for the detection limit of the quantity Ki/[I] (the IDL-factor) as a function of the substrate conversion level was developed for homogeneous end-point enzymatic assays.

It was found that the substrate conversion level where the IDL-factor reached an optimum was beyond the initial velocity range. Moreover, at this optimal point not only the ability to detect inhibitors but also the robustness of the assays was maximized. These results may prove to be relevant in drug discovery for optimising end point homogeneous enzymatic assays that are used to find inhibitors against a target enzyme in compound libraries, which are usually big (>10000) and crowded with irrelevant compounds.

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17

Gutiérrez, Arenas Omar. "Sensitivity, noise and detection of enzyme inhibition in progress curves /." Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6886.

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18

Al-Malki, Fatima Khamis S. "Model studies of reductase enzyme inhibition using hindered phenoxyl radicals." Thesis, University of Sussex, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550838.

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The reactions of a number of unsaturated compounds with tri-t-butylphenoxyl, pentabromophenoxyl and pentachlorophenoxyl radicals (models for the tyrosyl phenoxyl centreso f reductasee nzymes)h ave been investigatedt o assessth e suitability of different unsaturated groups as potential inhibitors for the enzyme. To do this, we studied kinetically (by ESR and UVNIS) the reactions of the phenoxyl radicals with a number of unsaturated compounds to obtain rates of reaction for loss of the phenoxyl radicals. Compounds which have conjugated or cumulated unsaturation are more reactive than simple alkenes or ketones. These include azidotrimethylsilane, cyclopentadiene, styrene and methyl methacrylate. Product studies were carried out for reactions with azidotrimethylsilane and cyclopentadiene, which react relatively rapidly with the phenoxyl radicals. Cyclopentadiene gives adducts, azidotrimethylsilane gives the trimethylsilyl ether of the phenol. Molecules of these types thus have the potential to act as ribonucleotide reductase inhibitors, since the products will not readily be reoxidised to the phenoxyl radical in vivo

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19

Hatz, Sonja. "Towards an enzyme inhibition assay in a flow-through format." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614665.

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20

Lubbe, Lizelle. "Investigating domain-selective angiotensin converting enzyme inhibition and oxidative inactivation." Doctoral thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29324.

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Angiotensin converting enzyme (ACE) is a zinc metalloprotease comprised of two highly homologous, catalytically active domains (90% active site identity and 60% sequence similarity). The C-domain is responsible for blood pressure regulation via angiotensin I cleavage while the N-domain inactivates an antifibrotic peptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP). Since selective N-domain inhibition will result in AcSDKP accumulation, it shows promise for the treatment of fibrosis without affecting blood pressure. Low bioavailability, however, precludes the use of currently available N-selective ACE inhibitors in a clinical setting. Inhibition of ACE by a phosphinic, peptidomimetic compound, 33RE, was characterized using a continuous assay with quenched fluorogenic substrate. The N-domain displayed nanomolar (Ki = 11.21±0.74nM) and the C-domain micromolar (Ki = 11 278±410nM) inhibition, thus 1000-fold selectivity. Residues predicted to contribute to selectivity based on the N-domain-33RE co-crystal structure were subsequently mutated to their C-domain counterparts. S2 subsite mutation with resulting loss of a hydrogen bond drastically decreased 33RE affinity (Ki = 2794±156nM), yet did not entirely account for the selectivity. Additional substitution of all unique S2’ residues, however, completely abolished N-selectivity (Ki = 10 009±157nM). Interestingly, these residues do not directly bind 33RE. All mutants were therefore subjected to molecular dynamics (MD) simulations in the presence and absence of 33RE in addition to co-crystallization of 33RE with the N-domain mutant having all S2 and S2’ residues mutated. Trajectory analyses highlighted the S2’ residues’ importance in formation of a favourable interface between the ACE subdomains and thus a closed, ligand-bound complex. This was supported by X-ray crystallography and provides a molecular basis for the inter-subsite synergism governing 33RE’s 1000-fold N-domain selectivity. Enzyme kinetics were also used to study the concentration-dependent competitive inhibition and time-dependent irreversible oxidative inactivation of ACE catalysed by the Cu-Gly-GlyHis-lisinopril (CuGGHLis) metallodrug. Although both domains displayed nanomolar affinity for metallodrug binding (N-domain Ki = 44.94±1.84nM and C-domain Ki = 15.57±1.30nM), rapid and complete CuGGHLis-mediated inactivation occurred exclusively in the N-domain upon incubation with ascorbate and H2O2 redox co-reactants (k2 = 59 710 M-1 min-1 ). Michaelis-Menten characterization of the residual activity after partial N-domain inactivation revealed a decreased rate for hydrolysis of a non-domain selective substrate. This suggests that although CuGGHLis binds with similar affinity to both domains, the metal-chelate is optimally orientated in the N- but not the C-domain to catalyze oxidation of residues involved in substrate hydrolysis. The C-domain, in contrast, showed increased susceptibility to oxidative inactivation by diffuse radicals. This is of physiological significance as C-domain inactivation in normotensive individuals could result in accumulation of pro-inflammatory peptides. Since the N-domain is more heavily glycosylated, the potential role of unique glycans in diffuse radical shielding was studied using glycoprotein MD simulations. Unique C-domain solvent tunnels were identified that could increase diffuse radical access and, additionally, the mechanism whereby glycosylation contributes to ACE thermal stability was described for each site. This has implications for future ACE crystallography studies and the design of ACE-modulating agents with potential anti-inflammatory activity. This study demonstrated the utility of combining in vitro and in silico approaches to reveal how subtle amino acid or glycosylation site differences between the highly homologous domains control dynamic behaviour. It furthermore elucidated how two inhibitors with different mechanisms of action selectively target the N-domain active site by exploiting these differences and provided valuable insight for future anti-fibrotic ACE inhibitor design.

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21

Brice, Edmund Andrew William. "Rat angiotensin-converting enzyme : tissue specific expression during pharmacological inhibition." Doctoral thesis, University of Cape Town, 1995. http://hdl.handle.net/11427/27042.

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The renin-angiotensin system plays a central role in the maintenance of blood pressure. Angiotensin II, the main effector of this system, results from the action of angiotensin-converting enzyme (ACE) on angiotensin I. Angiotensin II, maintains vasomotor tone via its vasoconstrictor action, and also increases salt and water retention by stimulating the release of aldosterone. ACE inhibitors, such as captopril, enalapril and lisinopril, are highly effective in the treatment of hypertension and congestive cardiac failure. Previous studies have suggested that angiotensin converting enzyme (ACE) production may be enhanced during pharmacological inhibition of the enzyme. Little is known, however about the mechanism of this induction. After demonstrating increases in circulating ACE protein in cardiac failure patients receiving the ACE inhibitor captopril, a rat model was used to study this effect. A sensitive enzyme linked immunosorbent assay for rat ACE was developed and a partial cDNA for rat ACE cloned to enable examination of ACE mRNA and protein expression during enzyme inhibition with enalapril. Rat lung ACE mRNA increased by 156% (p<0.05) and ACE protein doubled within 3 hours of administering a single dose of enalapril. Testicular ACE mRNA also increased by 300% (p<0.05) within 2 hours and returned to pretreatment levels by 6 hours. The angiotensin II antagonist saralasin similarly caused a significant (p<0.0001) 800% enhancement of mRNA expression. Aldosterone pretreatment of rats prior to enalapril administration was found to abolish this mRNA induction. These findings indicate that increased ACE expression during inhibition results from reduced levels of angiotensin II with consequent reduced stimulation of the angiotensin 11 receptor and its effects, such as aldosterone release. This suggests that ACE levels are regulated by a negative feedback loop involving the distal components of the renin-angiotensin system, namely angiotensin II and aldosterone. In situ hybridisation and immunohistochemical techniques were employed to localise the site of this inductive response in rat tissue sections. It was found that lung macrophages were markedly induced to produce ACE, as was ACE in seminiferous tubules. ACE induction was also noted in the expected sites of renal tubular epithelium and glomerular tissue. Interestingly, ACE expression was also enhanced in cardiac valves. In these studies it has been conclusively demonstrated that new ACE expression is induced by enzyme inhibitor therapy. A variety of techniques have been developed that will allow futher study of ACE in rat tissues.

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22

Gutierrez, Arenas Omar. "Sensitivity, Noise and Detection of Enzyme Inhibition in Progress Curves." Doctoral thesis, Uppsala universitet, Institutionen för naturvetenskaplig biokemi, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6886.

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Starting with the development of an enzymatic assay, where an enzyme in solution hydrolysed a solid-phase bound peptide, a model for the kinetics of enzyme action was introduced. This model allowed the estimation of kinetic parameters and enzyme activity for a system that has the peculiarity of not being saturable with the substrate, but with the enzyme. In a derivation of the model, it was found that the sensitivity of the signal to variations in the enzyme concentration had a transient increase along the reaction progress with a maximum at high substrate conversion levels. The same behaviour was derived for the sensitivity in classical homogeneous enzymatic assays and experimental evidence of this was obtained. The impact of the transient increase of the sensitivity on the error structure, and on the ability of homogeneous end-point enzymatic assays to detect competitive inhibition, came into focus. First, a non-monotonous shape in the standard deviation of progress curve data was found and it was attributed to the random dispersion in the enzyme concentration operating through the transient increase in the sensitivity. Second, a model for the detection limit of the quantity Ki/[I] (the IDL-factor) as a function of the substrate conversion level was developed for homogeneous end-point enzymatic assays. It was found that the substrate conversion level where the IDL-factor reached an optimum was beyond the initial velocity range. Moreover, at this optimal point not only the ability to detect inhibitors but also the robustness of the assays was maximized. These results may prove to be relevant in drug discovery for optimising end point homogeneous enzymatic assays that are used to find inhibitors against a target enzyme in compound libraries, which are usually big (>10000) and crowded with irrelevant compounds.

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23

Shoemark, Deborah Karen. "The kinetic characterization of the lactate dehydrogenase enzyme from Plasmodium falciparum." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326677.

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24

Varley, Denise Joyce. "Novel inhibitors of glutamine synthase." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308650.

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25

Lanthier, Christopher Michael. "The inhibition of carboxypeptidase A and angiotensin-converting enzyme by target enzyme-activated inhibitors and N-acylhydrazones." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq21362.pdf.

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26

Wilmouth, Rupert C. "Structural studies on the mechanism and inhibition of elastase." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389072.

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27

Burbank, Susan Elizabeth. "Development of rapid toxicity tests using enzyme inhibition as sulethal biomarker." Thesis, Georgia Institute of Technology, 1994. http://hdl.handle.net/1853/25401.

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28

Hathroubi, Chokri. "Systems for the inhibition of the vacuolar (Hâº)-ATPase enzyme." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436405.

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29

Walz, Ingrid. "Enzyme inhibition assays for the determination of insecticidal organophosphates and carbamates." Aachen Shaker, 2008. http://d-nb.info/989929930/04.

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30

Bareich, David C. Wright Gerard D. "Fungal aspartate kinase mechanism and inhibition /." *McMaster only, 2003.

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31

Yu, Yue. "UNDERSTANDING INHIBITION OF A BIODESULFURIZATION ENZYME TO IMPROVE SULFUR REMOVAL FROM PETROLEUM." UKnowledge, 2018. https://uknowledge.uky.edu/cme_etds/81.

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The biodesulfurization 4S-pathway is a promising complementary enzymatic approach to remove sulfur from recalcitrant thiophenic derivatives in petroleum products that remain from conventional hydrodesulfurization method without diminishing the calorific value of oil. The final step of this pathway involves the carbon-sulfur bond cleavage from HBPS, and the production of the final products 2-hydroxybiphenyl (HBP) and sulfite, has been recognized as the rate-limiting step, partially as a result of product inhibition. However, the mechanisms and factors responsible for product inhibition in the last step have not been fully understood. In this work, we proposed a computational investigation using molecular dynamic simulations and free energy calculations on 2’-hydroxybiphenyl-2-sulfinate (HBPS) desulfinase (DszB) with different bound ligands as well as different solvent conditions to develop a fundamental understanding of the molecular-level mechanism responsible for product inhibition. Based on available crystal structures of DszB and biochemical characterization, we proposed a “gate” area close to substrate binding site of DszB is responsible for ligand egress and plays a role in product inhibition. We have conducted biphasic molecular dynamic simulations to evaluate the proposed gate area functionality. Non-bonded interaction energy analysis shows that hydrophobic residues around the gate area produce van der Waals interactions inhibiting translocation through the gate channel, and therefore, the molecules are easily trapped inside the binding site. Umbrella sampling molecular dynamics was performed to obtain the energy penalty associated with gate conformational change from open to close, which was 2.4 kcal/mol independent of solvent conditions as well as bound ligands. Free energy perturbation calculations were conducted for a group of six selected molecules bound to DszB. The selections were based on functional group representation and to calculate binding free energies that were directly comparable to experimental inhibition constants, KI. Our work provides a fundamental molecular-level analysis on product inhibition for the biodesulfurization 4S-pathway.

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32

Pavlova, Alona. "Mechanism of action of mammalian cystatins : studies of inhibition of cysteine endo- and exopeptidases by cystatins A and C /." Uppsala : Dept. of Molecular Biosciences, Swedish Univ. of Agricultural Sciences, 2003. http://epsilon.slu.se/v154.pdf.

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33

Guha, Susmita. "Properties of liposomes containing aminoanthraquinones and their biochemical evaluation." Thesis, Edinburgh Napier University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340692.

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34

Alexander, Nathan Austin. "Molecular Switches: The Design, Synthesis and Biological Applications of Photoactive Enzyme Inhibitors." Thesis, University of Canterbury. Chemistry, 2006. http://hdl.handle.net/10092/1314.

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This thesis examines the design, synthesis and biological applications of a series of inhibitors which incorporate an azobenzene photoswitch, a peptidyl backbone and a trifluoromethyl ketone warhead. The photoswitch can be isomerised by irradiation with UV or visible light and has been employed to modulate the reactivity of the enzyme. Chapter one gives a brief outline of some of the important areas related to this work. Examples of previously utilised photoswitches as well as some background on serine protease and the uses of fluorine in medicine has been covered. Chapter two outlines the synthesis of the key trifluoromethyl carbinol 2.6 by two different methods. The condensation of a fluorinated aldehyde with a nitroalkane affords an α-nitro trifluoromethyl carbinol which can be reduced to give the desired amine 2.6. Treatment of oxazolones with trifluoroacetic anhydride via a modified Dakin-West reaction gives trifluoromethyl ketones which can be reduced to give trifluoromethyl carbinols. Chapter three investigate the synthesis of substituted stilbenes and phenanthrenes as alternative molecular switches to azobenzenes. Molecular modelling of phenanthrenes suggests they may be suitable mimics of E-azobenzenes. Chapter four outlines the synthesis of a series of mono and disubstituted azobenzenes by direct sulfonation of azobenzene or by condensation of nitroso arenes with aryl amines. The switches incorporate one or two peptidyl residues designed to improve specificity towards the enzyme. Chapter five examines the photoisomerisation of eight potential inhibitors by irradiating with UV or visible light. Irradiation with UV light enriches the sample to give 78-93 % of the Z-isomer. Irradiation with visible light gave photostationary states with 14-21 % Z-isomer. Ambient photostationary states are ca. 22 % Z-isomer. Chapter six looks at the testing of five trifluoromethyl ketones as potential inhibitors ofα-chymotrypsin. The inhibitors vary in substituents, substitution patterns and chain length. The inhibitors were tested at both ambient and Z-enriched photostationary states and were found to exhibit slow binding kinetics. In all cases the Z-enriched inhibitor solution was at least 3-fold more potent than the ambient solution. Chapter seven is an experimental chapter and outlines the synthesis of the compounds prepared in this thesis.

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Beaton, Nigel Alexander. "Inhibition of collagenase by the angiotensin-converting enzyme inhibitors captopril & enalapril." Thesis, University of Strathclyde, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502348.

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Collagen scaffolds provide a biocompatible matrix within tissue engineering and have already found many clinical uses. Two key requirements are that they are biologically Stable and mechanically strong. However, once seeded with cells or implanted in vivo collagen scaffolds are constantly being degraded and rebuilt. The balance of these two processes determines the matrix integrity. Studies have found that excessive degradation leads to mechanically weak matrices. The collagenases, members of the matrix metalloproteinase (MMP) family, play a vital role in matrix degradation. Collagenase inhibition should allow collagen scaffolds to retain their desirable qualities of mechanical strength and biological compatibility. Previous research has discovered that angiotensin converting enzyme (ACE) inhibitors, common hypertension drugs, inhibit MMP activity, MMP-9 specifically. The collagenases (MMP-1, MMP-8 and MMP-13) are members of the same family and are structurally similar to MMP-9 so these drugs may also inhibit collagenases.

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36

Harding, Pamela. "Glomerular prostanoid production in rats : the influence of angiotensin converting enzyme inhibition." Thesis, Keele University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385190.

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37

Taton, Maryse. "Mecanisme et inhibition rationnelle d'enzymes de la biosynthese des phytosterols." Université Louis Pasteur (Strasbourg) (1971-2008), 1986. http://www.theses.fr/1986STR13224.

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38

Frase, Hilary. "TOWARDS DEVELOPING SPECIFIC INHIBITORS OF THE ATP-DEPENDENT LON PROTEASE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1175637588.

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39

Livingstone, Emma Kathrine. "Allosteric Regulation of the First Enzyme in Histidine Biosynthesis." Thesis, University of Canterbury. Chemistry, 2015. http://hdl.handle.net/10092/10470.

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The ATP-PRTase enzyme catalyses the first committed step of histidine biosynthesis in archaea, bacteria, fungi and plants.1 As the catalyst of an energetically expensive pathway, ATP-PRTase is subject to a sophisticated, multilevel regulatory system.2 There are two families of this enzyme, the long form (HisGL) and the short form (HisGS) that differ in their molecular architecture. A single HisGL chain comprises three domains. Domains I and II house the active site of HisGL while domain III, a regulatory domain, forms the binding site for histidine as an allosteric inhibitor. The long form ATP-PRTase adopts a homo-hexameric quaternary structure.3,4 HisGS comprises a similar catalytic core to HisGL but is devoid of the regulatory domain and associates with a second protein, HisZ, to form a hetero-octameric assembly.5 This thesis explores the allosteric regulation of the short form ATP-PRTase, as well as the functional and evolutionary relationship between the two families. New insight into the mode allosteric inhibition of the short form ATP-PRTase from Lactococcus lactis is reported in chapter two. A conformational change upon histidine binding was revealed by small angle X-ray scattering, illuminating a potential mechanism for the allosteric inhibition of the enzyme. Additionally, characterisation of histidine binding to HisZ by isothermal titration calorimetry, in the presence and absence of HisGS, provided evidence toward the location of the functional allosteric binding site within the HisZ subunit. Chapter three details the extensive effort towards the purification of the short form ATP-PRTase from Neisseria menigitidis, the causative agent of bacterial meningitis. This enzyme is of particular interest as a potential target for novel, potent inhibitors to combat this disease. The attempts to purify the long form ATP-PRTase from E. coli, in order to clarify earlier research on the functional multimeric state of the enzyme, are also discussed. Chapter four reports the investigation of a third ATP-PRTase sequence architecture, in which hisZ and hisGS comprise a single open reading frame, forming a putative fusion enzyme. The engineering of two covalent linkers between HisZ and HisGS from L. lactis and the transfer of the regulatory domain from HisGL to HisGS, is also discussed, in an attempt to delineate the evolutionary pathway of the ATP-PRTase enzymes. Finally, the in vivo activity of each functional and putative ATP-PRTase was assessed by E. coli BW25113∆hisG complementation assays.

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Jeffreys, Robert K. "Leader peptidase as an antibacterial target." Thesis, Bangor University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341216.

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41

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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42

Walz, Ingrid [Verfasser]. "Enzyme Inhibition Assays for the Determination of Insecticidal Organophosphates and Carbamates / Ingrid Walz." Aachen : Shaker, 2008. http://d-nb.info/1162793430/34.

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43

Eveson, David Jonathan. "The haemodynamic and vascular effects of angiotensin-converting enzyme inhibition following acute stroke." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29494.

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Stroke is the third commonest cause of adult death and the commonest cause of adult disability in the UK. Arterial stiffness is a recognised independent risk factor for cerebrovascular disease. Phase I of the thesis examines arterial stiffness in the context of stroke, evaluating its role as a risk factor and relevance to other abnormalities of cardiovascular regulation during the acute stroke phase. Central, but not peripheral, arterial stiffness was increased in acute ischaemic stroke, particularly in lacunar and atherothrombotic but not cardioembolic subtypes compared to matched controls. Prognostically-important haemodynamic parameters following stroke, for example impaired cardiac baroreceptor sensitivity and increased beat-to-beat blood pressure (BP) variability, were related to central arterial stiffness.;There is uncertainty over the treatment of elevated BP levels following acute stroke. Angiotensin-converting enzyme inhibitors (ACEI) have not been tested in the immediate post-stroke phase, but studies suggest beneficial effects in secondary stroke prevention. Phase II of the thesis presents pilot work evaluating the oral ACEI, Lisinopril, for hypertension treatment immediately following acute stroke. A single 5mg dose resulted in prompt BP reduction within the first 4 hours of administration and a once-daily regimen over the subsequent 14 days lead to sustained BP reduction. Measures of patient outcome in the short and medium-term showed a neutral effect of treatment. However, no drug-related improvement was shown in other cardiovascular variables such as arterial stiffness, BP variability and cardiac baroreceptor sensitivity despite the hypotensive effect.;Reduction of arterial stiffness might be a valid therapeutic target in the primary prevention of stroke and in the acute phase of stroke. Lisinopril administered early in the acute stroke phase appears to be an effective hypotensive agent and is well-tolerated. On the basis of these findings, larger multicentre studies are now ongoing evaluating the effects of ACEI and other drugs on outcome immediately following acute stroke.

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44

Humble, Robert William. "The purification and characterisation of the enzymes phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase and synthesis and enzyme inhibition of imidazole nucleotides." Thesis, University of Lincoln, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304791.

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45

Zhai, Rui. "Can we enhance cellulose hydrolysis by minimizing enzyme inhibition resulting from pretreatment-derived inhibitors?" Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61769.

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Any pretreatment process used to enhance the enzymatic deconstruction of lignocellulosic substrates, although opening up and enhancing access to the cellulose, will typically generate inhibitory compounds (i.e. soluble mono/oligomeric sugars, phenolics, furans, extractives, etc.) that will limit or restrict the efficiency of cellulose hydrolysis. To develop more effective inhibition mitigation strategies, it would be beneficial if we had a better understanding of the inhibitory mechanisms of these soluble compounds on the enzyme components of cellulase cocktails. Most of the previous studies which have tried to assess the effects of inhibitors on cellulase enzymes, have used “synthetic mixtures of inhibitors” and “traditional” cellulase preparations such as Celluclast. The work presented in this thesis assessed the major inhibitory compounds derived from a range of “real-life” lignocellulosic biomass substrates that were steam pretreated at various severities. The major inhibitory mechanisms, such as reversible/irreversible inhibition of the major enzyme activities (e.g. exo/endo-glucanase, β-glucosidase, xylanase activities, etc.), were investigated and potential inhibitor mitigation strategies were evaluated. Initial work showed that, although the more recent cellulase mixture CTec3 was more inhibitor tolerant than the older Celluclast enzyme preparation, they were still strongly inhibited by pretreatment derived inhibitors. Of the various inhibitors, sugars and phenolics were shown to be the major groups that significantly contributed to the observed decrease in cellulose hydrolysis. This was mostly because of the strong inhibition and deactivation of β-glucosidase and cellobiohydrolase activities present within the cellulase mixture. Surprisingly, although hemicellulose derived sugars did not appear to inhibit individual enzyme activities, they did inhibit overall cellulose hydrolysis. Subsequent work suggested that hemicellulose-derived sugars inhibited the processive movement of cellobiohydrolase Cel7A and thus restricted cellulose hydrolysis. In addition to sugars, pretreatment derived phenolics were shown to be more influential, with the molecular size and carbonyl content of the phenols playing major roles in influencing the extent of phenolic inhibition. However, the phenolics could be modified to minimize enzyme inhibition and allow the use of lower enzyme loadings.
Forestry, Faculty of
Graduate

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46

Mackin, Paul. "The effects of angiotensin-converting enzyme inhibition on glomerular morphology in acute experimental diabetes." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262885.

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Parker, J. C. "Investigations into the effects of angiotensin converting enzyme inhibition and anaesthesia on renin release." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376172.

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Ryan, Caroline Mary. "Anti-Diabetic and Anti-Obesity Activities of Cocoa (Theobroma cacao) via Physiological Enzyme Inhibition." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/75003.

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Fermentation and roasting of cocoa (Theobroma cacao) decrease levels of polyphenolic flavanol compounds. However, it is largely unknown how these changes in polyphenol levels caused by processing affect cocoa's anti-diabetic and anti-obesity bioactivities, such as inhibition of certain enzymes in the body. Polyphenol profiles, protein-binding abilities, presence of compounds termed oxidative polymers, and abilities to inhibit α-glucosidase, pancreatic α-amylase, lipase, and dipeptidyl peptidase-IV (DPP4) in vitro were compared between unfermented bean (UB), fermented bean (FB), unfermented liquor (UL), and fermented liquor (FL) cocoa extracts. Overall, there were significant decreases (p<0.05) in total polyphenols, flavanols, and anthocyanins between the two sets of unfermented and fermented cocoa extracts (CEs). All CEs effectively inhibited α-glucosidase (lowest IC50 = 90.0 ug/mL for UL) and moderately inhibited α-amylase (lowest IC50=183 ug/mL for FL), lipase (lowest IC25=65.5 ug/mL for FB), and DPP4 (lowest IC25=1585 ug/mL for FB) in dose-dependent manners. Fermentation and roasting of the samples affected inhibition of each enzyme differently (both processes enhanced α-amylase inhibition). Improved α-glucosidase and α-amylase inhibitions were correlated with presence of different classifications of oxidative polymers, suggesting that these compounds could be contributing to the bioactivities observed. Some α-glucosidase inhibition might be due to non-specific protein-binding. Improved DPP4 inhibition was strongly correlated to increased CE degree of polymerization. In conclusion, potential enzyme inhibition activities of cocoa were not necessarily negatively affected by the large polyphenol losses that occur during fermentation and roasting. Additionally, it is possible that more complex compounds could be present in cocoa that contribute to its potential anti-diabetic and anti-obesity bioactivities.
Master of Science in Life Sciences

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Mendes, Nuno Eduardo dos Anjos Serra. "Evaluation of different natural ingredients as satiety inductors." Master's thesis, Faculdade de Ciências e Tecnologia, 2012. http://hdl.handle.net/10362/8056.

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Dissertation to obtain a Master’s Degree in Chemical and Biochemical Engineering
Using natural ingredients to combat obesity has emerged as a promising alternative to conventional therapies which present many side effects. Satiety induction by the ingestion of certain natural compounds has been proven to be an interesting strategy. In this context, the present study had the following objectives: - Isolation of rucola, watercress and spinach, plum and tomato waste and cladodes of Opuntia ficus-indica extracts, rich in compounds with the potential to induce a prolonged feeling of satiety - Assess the satiety inducing potential of isolated extracts using two enzymatic methods: - Inhibition of pancreatic lipase, an enzyme responsible for the conversion of complex lipids into simple and easily absorbable fat, which when inhibited is associated with a prolongation of satiety and a reduction in fat absorption, being the therapeutic target of Orlistat (the most common anti-obesity drug) - Inhibition of trypsin’s proteolytic activity, which is associated with a prolongation of satiety as it promotes the secretion of cholecystokinin (CCK), a polypeptide which regulates pancreatic enzyme release, which not only promotes satiety but also slows gastric emptying. In this work a method for extracting thylakoids, which are potent inhibitors of pancreatic lipase,was optimized. In addition to spinach, this method was applied for the first time to rucola and watercress. The extracts from these three matrixes exhibited lipase inhibitory activity, with spinach being the most efficient one. Hydroalcoholic extracts were prepared from plum residue, rich in polyphenols and saponins, which also showed efficient inhibitory capacity of pancreatic lipase. A protocol was optimized for the extraction of proteins which applied to the plum residue,tomatoes and cladodes of Opuntia ficus-indica. Only the opuntia and tomato extracts presented effective inhibition of trypsin’s proteolytic activity.

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Cockrell, Gregory Mercer. "New Insights into Catalysis and Regulation of the Allosteric Enzyme Aspartate Transcarbamoylase." Thesis, Boston College, 2013. http://hdl.handle.net/2345/3156.

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Thesis advisor: Evan R. Kantrowitz
The enzyme aspartate transcarbamoylase (ATCase) is an enzyme in the pyrimidine nucleotide biosynthetic pathway. It was once an attractive target for anti-proliferation drugs but has since become a teaching model due to kinetic properties such as cooperativity and allostery exhibited by the Escherichia coli form of the enzyme. ATCase from E. coli has been extensively studied over that last 60 years and is the textbook example of allosteric enzymes. Through this past research it is understood that ATCase is allosterically inhibited by CTP, the end product of pyrimidine biosynthesis, and allosterically activated by ATP, the end product of the parallel purine biosynthetic pathway. Part of the work discussed in this dissertation involves further understanding the catalytic properties of ATCase by examining an unregulated trimeric form from Bacillus subtilis, a bacterial ATCase that more closely resembles the mammalian form than E. coli ATCase. Through X-ray crystallography and molecular modeling, the complete catalytic cycle of B. subtilis ATCase was visualized, which provided new insights into the manifestation of properties such as cooperativity and allostery in forms of ATCase that are regulated. Most of the work described in the following chapters involves understanding allostery in E. coli ATCase. The work here progressively builds a new model of allostery through new X-ray structures of ATCase*NTP complexes. Throughout these studies it has been determined that the allosteric site is bigger than previously thought and that metal ions play a significant role in the kinetic response of the enzyme to nucleotide effectors. This work proves that what is known about ATCase regulation is inaccurate and that currently accepted, and taught, models of allostery are wrong. This new model of allostery for E. coli ATCase unifies all old and current data for ATCase regulation, and has clarified many previously unexplainable results
Thesis (PhD) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

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Dissertations / Theses on the topic 'Enzyme inhibition'

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