Academic literature on the topic 'Enzyme Inhibition Potency'
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Journal articles on the topic "Enzyme Inhibition Potency"
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Yamali, Cem, Halise Inci Gul, Tahir Cakir, Yeliz Demir, and Ilhami Gulcin. "Aminoalkylated Phenolic Chalcones: Investigation of Biological Effects on Acetylcholinesterase and Carbonic Anhydrase I and II as Potential Lead Enzyme Inhibitors." Letters in Drug Design & Discovery 17, no. 10 (October 12, 2020): 1283–92. http://dx.doi.org/10.2174/1570180817999200520123510.
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Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors. Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4- substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors. Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes. Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44±3.17 nM to 43.25±6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76±1.29-31.09±2.7 nM (hCA I) and 6.08 ± 1.18-23.12±4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted. Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.
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Giresha, Aladahalli S., Deepadarshan Urs, Sophiya Pundalik, Rajkumar S. Meti, Siddanakoppalu N. Pramod, Ballenahalli H. Supreetha, Madhusudana Somegowda, et al. "Sinapicacid Inhibits Group IIA Secretory Phospholipase A2 and Its Inflammatory Response in Mice." Antioxidants 11, no. 7 (June 25, 2022): 1251. http://dx.doi.org/10.3390/antiox11071251.
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Human Group IIA secreted phospholipase A2 (sPLA2-IIA) enzyme plays a crucial role in several chronic inflammatory diseases such asasthma, atherosclerosis, gout, bronchitis, etc. Several studies showed that the antioxidants exert an anti-inflammatory function by inhibiting the sPLA2-IIA enzyme. Hence, the present study evaluated an antioxidant molecule, sinapic acid, for sPLA2-IIA inhibition as an anti-inflammatory function. Initially, the antioxidant efficacy of sinapic acid was evaluated, and it showed greater antioxidant potency. Further, sinapic acid inhibited 94.4 ± 4.83% of sPLA2-IIA activity with an IC50 value of 4.16 ± 0.13 µM. The mode of sPLA2-IIA inhibition was examined by increasing the substrate concentration from 30 to 120nM and the calcium concentration from 2.5 to 15 mM, which did not change the level of inhibition. Further, sinapic acid altered the intrinsic fluorescence and distorted the far UltraViolet Circular Dichroism (UV-CD) spectra of the sPLA2-IIA, indicating the direct enzyme-inhibitor interaction. Sinapic acid reduced the sPLA2-IIA mediated hemolytic activity from 94 ± 2.19% to 12.35 ± 2.57% and mouse paw edema from 171.75 ± 2.2% to 114.8 ± 1.98%, demonstrating the anti-inflammatory efficiency of sinapic acid by in situ and in vivo methods, respectively. Finally, sinapic acid reduced the hemorrhagic effect of Vipera russelli venom hemorrhagic complex-I (VR-HC-I) as an anti-hemorrhagic function. Thus, the above experimental results revealed the sinapic acid potency to be an antioxidant, anti-inflammatory and anti-hemorrhagic molecule, and therefore, it appears to be a promising therapeutic agent.
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Martyn, Derek C., Michael J. B. Moore, and Andrew D. Abell. "Succinimide and Saccharin-based Enzyme-activated Inhibitors of Serine Proteases." Current Pharmaceutical Design 5, no. 6 (June 1999): 405–15. http://dx.doi.org/10.2174/138161280505230110110545.
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Abstract: The inhibition of human leukocyte elastase (HLE). and other serine proteases, by succinimide and saccharin-based compounds is reviewed. The succinimide compounds are unique in that the inactivating species is generated within the enzyme active site via a molecular rearrangement. The related saccharin derivatives also inactivate serine proteases by an enzyme-activated mechanism. Those factors effecting the potency, selectivity and stability of these important classes of inhibitor are discussed.
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Liu, Liqin, Violeta Yu, Jeanne Pistillo, Josie Lee, Laurie B. Schenkel, Stephanie Geuns-Meyer, Ivonne Archibeque, Angus Sinclair, Renee Emkey, and Graham Molineux. "New Insights on Assessing Intra-Family Selectivity for Jak2 Inhibitors." Blood 118, no. 21 (November 18, 2011): 5150. http://dx.doi.org/10.1182/blood.v118.21.5150.5150.
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Abstract Abstract 5150 Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are myeloproliferative disorders (MPDs) characterized by a chronic over-production of cells of one or more blood cell lineages and/or bone marrow fibrosis which may, on occasion, progress to acute myeloid leukemia. The V617F gain of function mutation in the pseudokinase domain of Jak2, which results in constitutive activation of Jak2, is the most frequent mutation associated with MPD. Constitutively activated Jak2 can lead to dysregulated downstream signaling pathways (STAT, MAP kinase, and PI3 kinase) which in turn trigger abnormal growth, survival and differentiation of hematopoietic progenitors. Therefore, inhibition of constitutively activated Jak2 may offer therapeutic potential. Designing a Jak2V617F specific inhibitor encounters challenges due to the lack of enzymatic activity of the pseudokinase domain of Jak2. In lieu of a Jak2V617F mutant selective inhibitor, a highly selective inhibitor of Jak2 is likely an attainable goal. Jak2 is a member of the Jak family of kinases including Jak1, Jak3, and Tyk2. Highly selective Jak2 inhibitors may provide a better safety margin in chronic dosing settings in ET and PV patients since inhibiting other Jak family members could cause side-effects such as immunosuppression. Attaining the desired selectivity of Jak2 inhibition versus the other family members has been challenging and few compounds have been reported to date that have the desired Jak2 selectivity. This can be attributed to the high homology of the ATP binding pocket among Jak family members, but is also hampered by a lack of assays capable of distinguishing the Jak-selectivity profile in a physiologically relevant setting. We compared the potency and selectivity of compounds tested in a pSTAT5 AlphaScreen® assay panel consisting of isogenic Ba/F3 cell lines individually expressing translocated ETS leukemia (TEL) fusions of each Jak-family member (Ba/F3-TEL-Jak) with data from corresponding Jak enzyme assays. Here we report that the selectivity of inhibitor compounds illustrated in enzyme assays did not correlate with the selectivity profile in cell lines due to different shifts in potency for each family member between enzyme and cells (Figure 1). As a consequence the selectivity of compounds for Jak2 against Jak1 observed in enzyme assays may be reduced or reversed in cellular assays. On the other hand, Jak2 selectivity over Jak3 seen in the enzyme assays was conserved in the cellular assay. Thus, we propose that compounds that exhibit greater potency on Jak2 compared to Jak1 in the enzyme assays are needed and should be the main focus of medicinal chemistry efforts in order to attain Jak2 selectivity over Jak1 in a cellular context. We also compared the potency and selectivity of compounds in the isogenic Ba/F3-TEL-Jak cell lines with data obtained with cytokine stimulated peripheral blood mononuclear cells (PBMCs). The potency and selectivity of compounds in PBMCs are determined by measuring the inhibition of phosphorylation of STAT5 in TPO or GM-CSF stimulated platelets or monocytes (mediated by Jak2) and in IL-2 stimulated lymphocytes (mediated by Jak1 and Jak3). We found that potency correlated well between PBMCs and Ba/F3-TEL-Jak2 cells, and the rank order of compounds based on IC50 values obtained with Ba/F3-TEL-Jak cell lines were conserved well in PBMCs; the compound selectivity profiles derived from the Ba/F3-TEL-Jak cell assays were predictive of Jak2 selectivity profiles obtained in the PBMC assays. Therefore, inclusion of Ba/F3-TEL-Jak pSTAT5 cellular assays may be useful for Jak family inhibitor development. Our results also suggest that relying solely on enzyme potency and selectivity data can be misleading, and that evaluating cellular selectivity in a biologically relevant context may provide a more meaningful understanding of selectivity and lead to the development of more selective Jak2 compounds. Disclosures: Liu: Amgen, Inc: Employment. Yu:Amgen: Employment. Pistillo:Amgen: Employment. Lee:Amgen: Employment. Schenkel:Amgen: Employment. Geuns-Meyer:Amgen: Employment. Archibeque:Amgen: Employment. Sinclair:Amgen: Employment. Emkey:Amgen: Employment. Molineux:Amgen: Employment.
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Pratasik, Veronika, Revolson Mege, and Mokosuli Semuel Yermia. "In Vitro Antidiabetic Activity Of Apis dorsata Binghami Nest Extract." JURNAL PEMBELAJARAN DAN BIOLOGI NUKLEUS 8, no. 3 (November 25, 2022): 733–43. http://dx.doi.org/10.36987/jpbn.v8i3.3196.
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Indonesia is ranked 7th out of 10 countries with the highest number of people with diabetes mellitus, which is estimated to increase every year.α -amylase is an enzyme that catalyzes the hydrolysis of α-1,4 glycosidic bonds of polysaccharides to produce dextrins, oligosaccharides, maltose and D-glucose. Apis dorsata Binghami honeycomb contains secondary metabolites that have antidiabetic potential, including inhibiting the action of the α-amylase enzyme. The purpose of this study was to determine the in vitro antidiabetic potential of Apis dorsata binghami nest extract. This study uses a descriptive research method where the research data are obtained through laboratory experiments. Honeycomb extraction using maceration method. Analysis of total flavonoid content using UV-Vis spectrophotometric method. Antidiabetic potency test using -amylase enzyme inhibition method. The results of the extraction study showed that the % yield of the extract was 11.82% with a brownish yellow color. Analysis of the total flavonoid content showed the results of 3.33 mgQE/g. The inhibitory activity of the -amylase enzyme, the IC50 value of the extract obtained was 158.48±7.42 g/mL, the acarbose value was 165.96±7.08 g/mL. These results indicate that the extract of A.dorsata Binghami nest has hyperglycemic activity by inhibiting complex carbohydrate hydrolyzing enzymes such as inhibition of the -amylase enzyme which is better than acarbose because the IC50 value of the extract is smaller. If the IC50 value is smaller then the enzyme inhibition is stronger. For further research, it is recommended to use a more specific enzyme, namely the -glucosidase enzyme.
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Kern, Gunther, Tiffany Palmer, David E. Ehmann, Adam B. Shapiro, Beth Andrews, Gregory S. Basarab, Peter Doig, et al. "Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914." Journal of Biological Chemistry 290, no. 34 (July 6, 2015): 20984–94. http://dx.doi.org/10.1074/jbc.m115.663534.
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We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467–474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β.
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Betari, Nibal, Kristoffer Sahlholm, Yuta Ishizuka, Knut Teigen, and Jan Haavik. "Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis." Future Medicinal Chemistry 12, no. 16 (August 2020): 1461–74. http://dx.doi.org/10.4155/fmc-2020-0127.
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Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2 H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure–activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.
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OUELLET, Marc, Jean-Pierre FALGUEYRET, and M. David PERCIVAL. "Detergents profoundly affect inhibitor potencies against both cyclo-oxygenase isoforms." Biochemical Journal 377, no. 3 (February 1, 2004): 675–84. http://dx.doi.org/10.1042/bj20030969.
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The sensitivity of Coxs (cyclo-oxygenases) to inhibition is known to be highly dependent on assay conditions. In the present study, the inhibitor sensitivities of purified Cox-1 and -2 were determined in a colorimetric assay using the reducing agent N,N,N´,N´-tetramethyl-p-phenylenediamine. With the detergent genapol X-100 (2 mM) present, the potencies of nimesulide, ibuprofen, flufenamic acid, niflumic acid and naproxen were increased over 100-fold against Cox-2 and titration curve shapes changed, so that maximal inhibition now approached 100%. Indomethacin, diclofenac and flosulide were not changed in potency. Similar effects of genapol were observed with inhibitors of Cox-1. DuP-697 and two analogues became more than 10-fold less potent against Cox-2 with genapol present. Tween-20, Triton X-100 and phosphatidylcholine, but not octylglucoside, gave qualitatively similar effects as genapol. Similar detergent-dependent changes in inhibitor potency were also observed using a [14C]arachidonic acid HPLC assay. The increases in potency of ibuprofen, flufenamic acid, isoxicam and niflumic acid towards Cox-2 and ibuprofen towards Cox-1 were accompanied by a change from time-independent to time-dependent inhibition. The interactions of Cox inhibitors has been described in terms of multiple binding step mechanisms. The genapol-dependent increase in inhibitor potency for ketoprofen was associated with an increase in the rate constant for the conversion of the initial enzyme–inhibitor complex to a second, more tightly bound form. The loss of potency for some inhibitors is probably due to inhibitor partitioning into detergent micelles. The present study identifies detergents as another factor that must be considered when determining inhibitor potencies against both Cox isoforms.
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Davies, Gareth, Hannah Semple, Megan McCandless, Jonathan Cairns, and Geoffrey A. Holdgate. "High-Throughput Mechanism of Inhibition." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 2 (January 22, 2021): 248–56. http://dx.doi.org/10.1177/2472555220983809.
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Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a modulator of enzyme activity requires an understanding of the enzyme’s mechanism and the mode of interaction of compounds. This allows an understanding of how physiological conditions in disease-relevant cells will affect inhibitor potency. As a result, there is increasing interest in evaluating hit compounds from high-throughput screens to determine their mode of interaction with the target. This work revisits the common inhibition modalities and illustrates the impact of substrate concentration relative to Km upon the pattern of changes in IC50 that are expected for increasing substrate concentration. It proposes a new, high-throughput approach for assessing mode of inhibition, incorporating analyses based on a minimal descriptive model, to deliver a workflow that allows rapid and earlier compound classification immediately after high-throughput screening.
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Haehner, Thomas, Ulrich Massing, Torsten Diesinger, and Dieter Müller-Enoch. "Inhibition of Cytochrome P450 Mediated Enzyme Activity by Alkylphosphocholines." Zeitschrift für Naturforschung C 59, no. 7-8 (August 1, 2004): 599–605. http://dx.doi.org/10.1515/znc-2004-7-826.
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AbstractThe inhibitory potency of four alkylphospholipids: rac-1-O-phosphocholine-2-hydroxy-octadecane (rac-2-OH), rac-1-O-phosphocholine-2-O-acetyl-octadecane (rac-2-O-acetyl), rac-1- O-phosphocholine-2-amino-octadecane (rac-2-NH2) and rac-1-O-phosphocholine-2-N-acetyloctadecane (rac-2-N-acetyl), on the cytochrome P450-dependent monooxygenase activity has been evaluated. The IC50 values of the alkylphosphocholines with 7-ethoxycoumarin as substrate in liver microsomal fractions of PB-treated rats and with a reconstituted CYP2B1: NADPH-P450-reductase system are in the range of 3.2D5.0 μм and 2.8D3.5 μм, respectively. Lineweaver-Burk plots with the inhibitors in concentrations that were found to cause roughly a 50% inhibition and with 7-ethoxycoumarin as substrate revealed for all four alkylphospholipids a competitive inhibition type. The degree of the competitive inhibition is quantified by the Ki values. With liver microsomal fractions of PB-treated rats, the Ki values of rac-2-OH (Ki = 1.36 μм) and rac-2-O-acetyl (Ki = 1.33 μm) differs slightly from those of rac-2-NH2 (Ki = 2.2 μм) and rac-2-N-acetyl (Ki = 2.2 μм), but with the reconstituted CYP2B1: NADPHP450- reductase system all Ki values are in the small range of 1.8 D 2.6 μм, indicating that the short substituted group at the 2-position (OH; O-acetyl; NH2; N-acetyl) of the long chain octadecanol part of the phosphodiesters exhibit no essential role on the strong inhibitory potency of these alkylphosphocholines on the 7-ethoxycoumarin-O-deethylase activity.
Dissertations / Theses on the topic "Enzyme Inhibition Potency"
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Wyszynski, Filip Jan. "Dissecting tunicamycin biosynthesis : a potent carbohydrate processing enzyme inhibitor." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:3a7a509d-dba0-4d5b-9a39-a883c872d758.
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Tunicamycin nucleoside antibiotics were the first known to target the formation of peptidoglycan precursor lipid I in bacterial cell wall biosynthesis. They have also been used extensively as inhibitors of protein N-glycosylation in eukaryotes, blocking the biogenesis of early intermediate dolichyl-pyrophosphoryl-N-acetylglucosamine. Despite their unusual structures and useful biological properties, little is known about their biosynthesis. Elucidating the metabolic pathway of tunicamycins and gaining an understanding of the enzymes involved in key bond forming processes would not only be of great academic value in itself, it would also unlock a comprehensive toolbox of biosynthetic machinery for the production of tunicamycin analogues which have the potential to act as novel therapeutic antibiotics or as specific inhibitors of medicinally important NDP-dependent glycosyltransferases. I – Cloning the tunicamycin biosynthetic gene cluster. We report identification of the tunicamycin biosynthetic genes in Streptomyces chartreusis following genome sequencing and a chemically-guided strategy for in silico genome mining that allowed rapid identification and unification of an operon fractured across contigs. Heterologous expression established a likely minimal gene set necessary for antibiotic production, from which a detailed metabolic pathway for tunicamycin biosynthesis is proposed. II – Natural product isolation and degradation. We have developed efficient methods for the isolation of tunicamycins from liquid culture in preparative quantities. A subsequent relay synthesis furnished advanced biosynthetic intermediates for use as precursors in the production of tunicamycin analogues and as substrates for the in vitro characterisation of individual Tun enzymes. III – Functional characterisation of tun gene products. Individual tun gene products were over-expressed and purified from recombinant E. coli hosts, allowing in vitro functional studies to take place. An NMR assay of biosynthetic enzyme TunF showed it acted as a UDP-GlcNAc-4-epimerase. Putative glycosyltransferase TunD showed hydrolytic activity towards substrate UDP-GlcNAc but failed to accept to the expected natural acceptor substrate, providing unexpected insights into the ordering of biosynthetic events in the tunicamycin pathway. Initial studies into the over-expression of the putative sugar N-deacetylase TunE were also described. IV – Towards synthesis of tunicamycin fragments. Investigations into a novel synthesis of D-galactosamine – a structural motif within tunicamycin – led to the unexpected observation of inverted regioselectivity upon RhII-catalysed C-H insertion of a D-mannose-derived sulfamate. This was the first example of N-insertion at the beta- rather than gamma-C-H based on conformation alone and warranted further investigation. The X-ray structure of a key sulfamate precursor offered valuable insights as to the source of this unique selectivity.
Book chapters on the topic "Enzyme Inhibition Potency"
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Armitage, Ian, Ashley McCarron, and Lei Zhu. "Process Development and GMP Production of a Potent NEDD8-Activating Enzyme (NAE) Inhibitor: Pevonedistat." In ACS Symposium Series, 13–62. Washington, DC: American Chemical Society, 2016. http://dx.doi.org/10.1021/bk-2016-1240.ch002.
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Crawley, G. C., S. J. Foster, R. M. McMillan, and E. R. H. Walker. "Discovery of ZD2138, a Potent, Selective, Well-Tolerated, Nonredox Inhibitor of the Enzyme 5-Lipoxygenase." In The Search for Anti-Inflammatory Drugs, 191–231. Boston, MA: Birkhäuser Boston, 1995. http://dx.doi.org/10.1007/978-1-4615-9846-6_7.
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Frey, Perry A., and Adrian D. Hegeman. "Enzyme Inhibition." In Enzymatic Reaction Mechanisms. Oxford University Press, 2007. http://dx.doi.org/10.1093/oso/9780195122589.003.0009.
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One aspect of the importance of enzymes in biology can be appreciated by considering the attention that continues to be focused on the inhibition of enzymatic activity. Historically, inhibitors played important roles in the elucidation of metabolic pathways. An example was the use of malonate as a metabolic inhibitor, leading to the accumulation of succinate in metabolizing cell extracts. Malonate proved to be an inhibitor of succinate dehydrogenase, and its effect on metabolism revealed the importance of succinate as a metabolic intermediate and of succinate dehydrogenase in metabolism. In this way, malonate as an inhibitor played an important role in the elucidation of the tricarboxylic acid cycle. Countless competitive inhibitors have been applied in various ways to the characterization of active sites. Clues to the binding properties and specificities of active sites can be deduced by systematically varying the structures of competitive inhibitors and comparing the inhibition constants. In another application, competitive inhibitors are often used to shield active sites against the effects of group selective chemical modification. Because biological processes are catalyzed by enzymes, inhibitors can be used to manage biochemical dynamics to the advantage of humans. Examples include pharmaceutical agents and agricultural insecticides and herbicides, which are often inhibitors of specific enzymes. Many targets for ethical drugs are enzymes. For these reasons, the development of enzyme inhibitors is an important objective in pharmaceutical and agricultural research and development. We explained the simplest kinetic properties of reversible inhibitors in chapter 2, and in chapter 1, we discussed the use of competitive reversible inhibitors and affinity-labeling agents for characterizing active sites. The importance of inhibitors in the pharmaceutical and agricultural industries has led to the discovery and invention of compounds that inhibit enzymes by special mechanisms and with very high binding affinities. These inhibitors often displayed special kinetic properties, which led to the development of kinetic paradigms, including slow-binding inhibition and tight-binding inhibition. In chapter 1, we introduced the theoretical significance of transition-state analogs as potent inhibitors of enzymes, and this theory has led to practical applications in the design of inhibitors. In this chapter, we consider some of the special applications of inhibitors in the pharmaceutical and agricultural industries.
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Zeeshan Bhatti, Muhammad, and Aman Karim. "Plant Natural Products: A Promising Source of Hyaluronidase Enzyme Inhibitors." In Extracellular Matrix - Developments and Therapeutics [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.98814.
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Hyaluronidase enzyme degrades hyaluronan, the primary component of the extracellular matrix found in connective tissues animals and on the surface of certain pathogenic bacteria. The degradation of hyaluronan is linked to a wide range of physiological and pathological process. Inhibiting the hyaluronidase enzyme is thus significant as an approach to treat a variety of diseases and health conditions such as anti-fertility, anti-tumor, antimicrobial, and anti-venom/toxin agents. HAase inhibitors of different chemical types have been identified include both synthetic compounds and constituents obtained from naturally sources. Plant natural products as HAase inhibitors are unique due to their structural features and diversity. Medicinal plants have historically been used as contraceptives, antidote for snakebites and to promote wound healing. In recent years, small molecules, particularly plant natural products (alkaloids, flavonoids, polyphenol and flavonoids, triterpenes and steroids) possessing potent HAase have been discovered. A number of plant species from various families, which have folk medicinal claims for these ailments (related to hyaluronan disturbances) were scientifically proven for their potential to block HAase enzymes.
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Cordes, Eugene H. "The perils of Primaxin." In Hallelujah Moments, 85–102. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780190080457.003.0006.
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Primaxin is one of the most effective antibiotics introduced into medical practice in the past few decades. It is a single-pill combination of two agents, an unusual β-lactam antibiotic and an inhibitor of an obscure kidney enzyme that abolished the efficacy of the β-lactam in that organ. The initial discovery was a β-lactam antibiotic (think penicillin, amoxicillin) named thienamycin from a fermentation broth. Thienamycin had marvelous antibiotic properties, potent against many microorganisms resistant to earlier β lactams, but was notoriously unstable. Once the unusual structure of thienamycin was unraveled, structural modifications were started. A critical chemical modification resulted in a new agent, imipenem, that retained the antibiotic properties of thienamycin but was stable. A second drug discovery effort resulted in an inhibitor of the kidney enzyme, cilistatin. A combination of the two created Primaxin.
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Hunt, John. "Discovery of BMS-387032, a Potent Cyclin-Dependent Kinase Inhibitor in Clinical Development." In Enzyme Inhibitors Series, 251–64. CRC Press, 2006. http://dx.doi.org/10.1201/9781420005400.ch11.
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Cordes, Eugene H. "Diabetes breakthroughs: Thornberry and Weber." In Hallelujah Moments, 153–86. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780190080457.003.0010.
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Januvia and Janumet are important additions to the array of drugs that are employed to treat type 2 diabetes. Januvia (sitagliptin) works by an entirely novel mechanism: it is a potent and specific inhibitor of an enzyme known as DPP-4 (dipeptidyl peptidase-4). DPP-4 promotes the destruction of a peptide known as GLP-1 (glucagon-like-peptide-1), an incretin. Incretins are agents that stimulate the secretion of insulin and repress the secretion of glucagon. Both actions tend to normalize glucose levels. Indeed, clinical trials with GLP-1 have shown that this peptide normalizes blood glucose levels in both the fed and fasted states. GLP-1 must be given by injection and is not suitable for routine use by diabetic patients. However, an inhibitor of the enzyme that degrades GLP-1 is the functional equivalent of administration of GLP-1. Januvia acts in exactly this way. Janumet is a combination product in which Januvia is combined with metformin, an effective anti-diabetes agent that has been employed for many years. There are now a number of gliptins (DPP-4 inhibitors) in clinical use for type 2 diabetes.
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Cordes, Eugene H. "Fludalanine: nice try but no hallelujah." In Hallelujah Moments, 139–52. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780190080457.003.0009.
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Fludalanine was one of the most promising antibiotics of its generation: a simple inexpensive molecule having a novel mechanism of action highly effective against problem bacteria. It ultimately failed as a consequence of potential toxicity to patients resulting from one of its metabolites. The starting point for fludalanine is the simple molecule D-fluoroalanine, a potent inhibitor of alanine racemase, the enzyme that supplies the amino acid D-alanine for bacterial wall synthesis. D-Alanine has no role in human metabolism. Fludalanine is derived from D-fluoroalanine by an isotopic substitution designed to slow its rate of metabolism. Remarkably, at high concentrations of fludalanine, bacteria actually use the antibiotic for cell wall synthesis. To prevent that, another inhibitor of a distinct enzyme required for bacterial cell wall synthesis, pentizidone, was combined with fludalanine: problem solved. However, long-term safety studies in rodents revealed that fludalanine caused vacuole formation in the brain, called spongy brain. The toxicity was traced back to a metabolite of fludalanine, and the toxicity of that molecule in rodents was established. Unhappily, levels of that metabolite proved too high in patients to ensure their safety. That was the end of a highly promising effort to add an important antibiotic to clinical practice.
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Green, Darren, and Philip A. Kalra. "Cardiorenal syndrome." In Oxford Textbook of Medicine, edited by Jeremy Dwight, 3421–28. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0350.
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Concurrent renal and cardiovascular disease is common. Renal disease is a potent cardiovascular risk factor and consequently cardiovascular disease is the most important cause of mortality in patients with end-stage renal disease. This increased risk is mediated by vascular disease (coronary calcification, endothelial dysfunction, dyslipidaemia, and others), left ventricular hypertrophy, risk of arrhythmias, and left ventricular systolic and diastolic dysfunction. These interactions are further complicated by the presence of anaemia in advanced renal disease. The coexistence of renal disease and heart failure presents a major therapeutic challenge and requires careful attention to fluid status and renal function. Diuretic resistance is common and the important prognostic benefit of angiotensin-converting enzyme inhibition in this high-risk group is often neglected. Cardiovascular drugs, particularly antiarrhythmic agents such as digoxin, sotalol, and flecainide, should be used with caution in patients with renal disease.
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Green, Darren, and Philip A. Kalra. "Cardiorenal syndrome." In Oxford Textbook of Medicine, 2728. Oxford University Press, 2010. http://dx.doi.org/10.1093/med/9780199204854.003.16514.
Full textAbstract:
Concurrent renal and cardiovascular disease is common. Renal disease is a potent cardiovascular risk factor and consequently cardiovascular disease is the most important cause of mortality in patients with endstage renal disease. This increased risk is mediated by vascular disease (coronary calcification, endothelial dysfunction, dyslipidaemia, etc.), left ventricular hypertrophy, risk of arrhythmias and left ventricular systolic and diastolic dysfunction. These interactions are further complicated by the presence of anaemia in advanced renal disease. The coexistence of renal disease and heart failure presents a major therapeutic challenge and requires careful attention to fluid status and renal function. Diuretic resistance is common and the important prognostic benefit of angiotensin converting enzyme (ACE) inhibition in this high-risk group is often neglected. Cardiovascular drugs, in particular antiarrhythmic agents such as digoxin, sotalol, and flecainide, should be used with caution in patients with renal disease. Patients with severe cardiac and renal disease require a multidisciplinary approach to their management.
Conference papers on the topic "Enzyme Inhibition Potency"
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Fatchiyah, Fatchiyah, and Shella Clarista Natasia. "Inhibition potency of HMGR enzyme against hypercholesterolemia by bioactive peptides of CSN1S2 protein from caprine milk." In THE 8TH ANNUAL BASIC SCIENCE INTERNATIONAL CONFERENCE: Coverage of Basic Sciences toward the World’s Sustainability Challanges. Author(s), 2018. http://dx.doi.org/10.1063/1.5062812.
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Preissner, K. T., and P. Sie. "S PROTEIN/VITRONECTIN NEUTRALIZES THE ANTICOAGULANT ACTIVITY OF GLYCOSAMINOGLYCANS IN THE INHIBITION OF THROMBIN BY HEPARIN COFACTOR II." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643633.
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The complement inhibitor S protein, which is identical to the adhesive protein vitronectin, functions as heparin-neutralizing factor by protecting thrombin against fast inactivation by antithrombin III. The interference of S protein with glycos-aminoglycan-catalyzed inhibition of thrombin by heparin cofactor II was investigated in a purified system. In the presence of 0.3 μg/ml heparin, or 0.5 μg/ml pentosan polyphosphate (SP 54), or 2 μg/ml dermatan sulfate, S protein induced a concentration-dependent reduction of the inhibition rate of thrombin by heparin cofactor II. This resulted in a decrease of the apparent pseudo-first order rate constants by about 17-fold (heparin), or about 7-fold (SP 54), but only by about 2-fold for dermatan sulfate at a physiological ratio of S protein to heparin cofactor II. Likewise, S protein significantly counteracted the anticoagulant activity of heparin and SP 54 bot not of dermatan sulfate when tested in an inhibition assay using various concentrations of glycosaminoglycans. For heparin, the activity of S protein at the point of 50% inhibition of thrombin was expressed in the range 0.06-0.6 μg/ml (0.01-0.1 U/ml) and for SP 54 in the range 0.3-2 pg/ml. Exposure of the glycos-aminoglycan-binding region of S protein by reduction and carb-oxymethylation of the protein even increased the neutralizing activity of S protein towards heparin and SP 54. S protein not only was found together with thrombin in a binary complex. S protein also became incorporated into a ternary complex with thrombin and heparin cofactor II as judged by crossed immunoelectrophoresis, regardless whether complex formation was initiated by heparin or dermatan sulfate. These findings underline the role of S protein as potent glycosaminoglycan-neutral-izing protein in plasma and as scavenger protein which may bind to enzyme-inhibitor complexes of the coagulation system.
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Timmons, Sheila, and Jack Hawiger. "REGULATION OF PLATELET RECEPTORS FOR FIBRINOGEN AND VON WILLEBRAND FACTOR BY PROTEIN KINASE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644674.
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Positive and negative regulation of platelet receptors for adhesive proteins, fibrinogen (F) and von Willebrand Factor (vWF) determines whether binding of these ligands will or will not take place. We have shown previously that ADP stimulates and cyclic AMP inhibits binding of F and vWF to human platelets. Now we show that positive regulation of F and vWF binding to platelets via the glycoprotein 11b/1111a complex is dependent on platelet Protein Kinase C, a calcium- and phospholipid-dependent enzyme. A potent activator of Protein Kinase C, phorbol-12-myristoyl-13-acetate (PMA) induced saturable and specific binding of F and vWF which was inhibited by synthetic peptides, gamma chain .dodecapeptide (gamma 400-411) and RGDS. The phosphorylation of 47kDa protein (P47), a marker of Protein Kinase C activation in platelets, preceded binding of F and vWF induced with PMA as well as with ADP and thrombin. Sphingosine, an inhibitor of Protein Kinase C, blocked binding of F and vWF to platelets stimulated with PMA, ADP, and thrombin. Inhibition of binding was concentration-dependent and it was accompanied by inhibition of platelet aggregation. Thus, stimulation of Protein Kinase C is required for exposure of platelet receptors for adhesive proteins whereas inhibition of Protein Kinase C prevents receptorexposure. Protein Kinase C fulfills the role of an intraplatelet signal transducer, regulating receptors for adhesive proteins, and constitutes a target for pharmacologic modulation of the adhesive interactions of platelets.
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Niederst, P. N., M. Asbach, M. Ott, and R. E. Zimmermann. "IN VITRO REACTION MODELS OF THROMBIN AND ITS PHYSIOLOGICAL INHIBITOR ANTITHROMBIN III IN THE PRESENCE OF HEPARIN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644356.
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Antithrombin III (AT III) neutralizes thrombin and other serine proteases of plasma coagulation system by forming a stable 1:1 covalent complex. The inhibition rates are greatly increased by the potent catalyst heparin. The catalytic mechanism of heparin was studied in the presence of dextran sulfate (DS), a thrombin-binding sulfated Polysaccharid. DS did not influence the reaction of AT III with heparin and the amidolytic activity of thrombin, but preincubation with thrombin could inhibit the catalytic activity of heparin in the reaction of thrombin with AT III. We conclude that the reaction of heparin with enzyme and inhibitor, thus forming a ternary complex, is necessary for its catalytic activity.It is known that heparin also converts AT III from an inhibitor to a substrate for thrombin in a dose dependent manner. By cleavage of the reaction site bound Arg(385)-Ser(386) an AT III-fragment (MG 50000 d) occurs, which has a decreased affinity to heparin and does not inhibit F I la. At physiological ionic strength we have only measured a small percentage of AT 111-proteolysis (4%, 1 U/ml Hep). The extent of AT III-fragment formation could be enhanced by lowering the ionic strength (max 44%, 1 U/ml Hep., 1=0,02).
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Agarwal, Kailash C. "NEW INSIGHTS INTO THE ANTIPLATELET ACTIVITY OF FORSKOLIN: ROLE OF PLASMA ADENOSINE AND SPECIES DIFFERENCES." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643584.
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Forskolin stimulates adenylate cyclase by interacting with the catalytic subunit and inhibits platelet aggregation. This inhibition is greatly potentiated by adenosine (Ado) which stimulates adenylate cyclase through membrane-bound Ado receptors. Forskolin is 2-4 fold more potent as an inhibitor of collagen-induced rat platelet aggregation as compared to human platelets (IC50 values, in rat PRP, 0.5-0.8 μM; in human PRP, 1.5-2 μM). However, if the blood is pretreated with adenosine deaminase (ADA), an enzyme that degrades Ado to inosine, the inhibitory action of forskolin is greatly reduced producing similar effects both in human and rat PRPs (IC50, 2-3 μM) and whole blood (IC50, 4.6 μM). Both 5’-methylthioadenosine (MTA, 50-100 μM), an antagonist of Ado receptors, and 2’,5’-dideoxyadenosine (DDA, 100 μM), an inhibitor of adenylate cyclase, reverse the inhibition of platelet aggregation in rat PRP, whereas, no reversal is seen in human PRP. When Ado in the rat plasma is degraded by ADA pretreatment, DDA or MTA shows no reversal as seen in human PRP. The inhibitory action of forskolin (1-2 μM), which is only weakly inhibitory alone (<20%) in human whole blood, can be greatly potentiated (100% inhibition) by the inhibitors of nucleoside transport, dipyridamole (10 μM) or dilazep (2 μM). Only slight potentiation is seen in rat whole blood suggesting that rat plasma Ado levels are not affected significantly perhaps due to weakly active erythrocytic nucleoside transport system. Sato and Ui (In: Physiology and Pharmacology of Adenosine, Daly et al, Eds. Raven Press, 1983, 1-11), have shown that rat plasma contains much higher Ado levels (7.55 ± 0.51 pM) than human plasma (0.29 ± 0.08 μM). These studies demonstrate that plasma adenosine plays an important role in the forskolin antiplatelet activity which can be greatly potentiated in human whole blood by the clinically used drugs, dipyridamole and dilazep. (Supported by US PHS Grant CA 07340).
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Teng, C. M., and F. N. Ko. "COMPARISON OF THE PLATELET AGGREGATION INDUCED BY THREE THROMBIN-LIKE ENZYMES OF SNAKE VENOMS AND THROMBIN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644535.
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Acutin was isolated from Agkistrodon acutus venom and batroxobin and thrombocytin were isolated from Bothrops atrox venom. These three thrombin-like enzymes had different specificity for platelet activation and fibrinogen clotting. The clotting activities were 700, 170 and 7 μ/mg for batroxobin, acutin and thrombocytin, respectively. They induced aggregation and ATP release of washed rabbit platelets. The aggregating activities were 102, 104 and 105 times less than that of thrombin for thrombocytin, acutin and batroxobin, respectively basing on the clotting unit. The platelet -activating potency was correlated with their effectiveness on the retractility and elasticity of the clots. Platelet aggregation induced by thrombin or thrombocytin could be inhibited by heparin with antithrombin III while that by acutin or batroxobin could not. The thrombin-like enzymes did not induce aggregation of thrombin-degranulated platelets even fibrinogen was added. Indomethacin showed weak inhibition on the aggregation while the ADP - scavenging system, creatine phosphate/creatine phosphokinase, or apyrase inhibited the aggregation induced by the three thrombin-like enzymes but not that by thrombin. In the presence of EGTA, only thrombin could induce ATP release from platelets. It is concluded that the aggregation induced by thrombin-like enzymes is different from that of thrombin and mainly due to ADP released from platelets.
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Orthner, Carolyn L., Prabir Bhattacharya, and Dudley K. Strikland. "PURIFICATION AND CHARACTERIZATION OF A PROTEIN C ACTIVATOR FROM THE VENOM OF AGKISTRODON CONTORTRIX CONTORTRIX." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643813.
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There are two recent reports on the purification and properties of a protein C activator (PCA) from the venom of the Southern copperhead snalce. The purification of a 37,000 Mr nonenzymatic PCA (Martinoli and Stocker, Thrcmb. Res. 43, 253, 1976) as well as of a 20,000 Mr thrombin-like enzyme (Klein and Walker, Biochem. ,25, 4175, 1986) have been described. The purpose of this investigation was to purify and further characterize the PCA(s) from this vencm. A PCA has been isolated by sulphopropyl-Sephadex followed by gel filtration chromatography resulting in approximately a 100-fold purification with a 50% yield. PCA appeared as a single band on SDS-PAGE with an estimated Mr of 32,000 or 37,000 in the absence or presence of β-mercaptoethanol, respectively. High pressure gel permeation cinematography of PCA in Tris-buffered saline, pH 7.5 resulted in a single protein peak with a Mr of 39,000 which was coincident with activity. PCA was a potent activator of human protein C (PC) with a Km for PC of 0.6uM and a Vm of 0.02 sec-1. In addition, PCA catalyzed the arnidolysis of Tosyl-gly-pro-arg-p-nitroanilide (TGPRpNA) with a Km of 1.1 irM and a Vim of 66 sec-1. The rate of arnidolysis of five other pept idyl-arginyl-pNA substrates each tested at 1.0 mM was < 10% that of TGPRpNA. PCA was inhibited by nitrophenylguanidi-nobenzoate (NPGB), phenylmethylsulphonylflouride, D-phe-pro-arg-chloromethyi_ketone (PPACK) and soybean trypsin inhibitor indicating that PCA is a serine protease. The active site concentration of PCA as measured by NPGB titration was 90% that of the protein concentration. Measurement of the rate of PCA inhibition at varying levels of PPACK indicated that it had a Ki of 34uM .and an aUcylation rate constant of 0.09 min-1. PCA activation of PC was completely inhibited by CaC12 with an apparent Ki of 99uM. Since neither PCA arnidolysis of TGPRpNA nor inhibition by PPACK was affected by Ca2+, the effect of this metal was likely on the substrate PC. In summary, a PCA has been purified to homogeneity and has properties which are distinct from those reported. PCA premises to be a useful enzyme in studies of PC and its activation.
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Yoshimura, Chihoko, Hiromi Muraoka, Hiroaki Ochiiwa, Shingo Tsuji, Akihiro Hashimoto, Toru Takenaka, Hiromi Kazuno, et al. "Abstract C176: TAS4464, a novel, highly potent, and selective inhibitor of NEDD8 activating enzyme demonstrates sustained target inhibition and antitumor activity in a preclinical model." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-c176.
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Mouas, Toma, amel djedouani, ghada boukerzaza, chawki Benssuici, and manel bouabellou. "EFFICIENT SYNTHESIS OF DHA TRANSITION METAL CHELATES AS POTENT ANTIOXIDANTS, ENZYME INHIBITOR AND ANTIMICROBIAL AGENTS." In 1st International Electronic Conference on Biomedicine. Basel, Switzerland: MDPI, 2021. http://dx.doi.org/10.3390/ecb2021-10262.
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Hijikata-Okunomiya, A., S. Okamoto, R. Kikumoto, and Y. Tamao. "STEREOGEOMETRY OP THE ACTIVE SITES OF SERINE ENZYMES GATHERED FROM SYNTHETIC THROMBIN-INHIBITORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644606.
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MD-805 is a potent thrombin-inhibitor having the structure of tri-pods; Arg skeletone, N-terminal side and C-terminal side. MD-805 showed weaker inhibitory activity to other enzymes than thrombin. In this report, to gather more detailed informations about the structural features of serine enzymes concerning the specificity, we experimentally examined the structure-activity relationship (SAR) of a number of arginine derivatives including MD-805 and theoretically generated a MD-805-trypsin complex model using the results of X-ray crystallography of MD-805 and BPTI-trypsin complex by calculation in principle to minimize van der Waals contacts, and thus we discussed to interpret SAR from the molecular level. SAR of C-terminal side of arginine derivatives was obtained with the inhibitory activity to trypsin, plasmin, and glandular kallikrein and compared with the previous results of thrombin, the followings being indicated: (1) The hydrophobic binding pocket (HBP), which was reported by us to be at least partly similar in stereogeometry between trypsin and thrombin, had the depth corresponded to the length of ethylpiperidine, (2) concerning the site (termed the P site) next to HBP, there were large differences in stereogeometry between trypsin and thrombin; the P site of trypsin could accept propyl and phenyl group attached to 4-position of piperidine, while that of thrombin was unable to accept them and (3) the P sites of plasmin and glandular kallikrein resembled that of trypsin in being able to accept phenyl group. MD-805-trypsin complex model supported the reasonable understanding that the stereogeometrical similarity in HBP between thrombin and trypsin was attributable to the high homology in amino acid sequences in Ser-195 loop and that the dissimilarity in the P sites between thrombin and the others was attributable to 9 amino acids insertion found only in thrombin (Loop B). Furthermore, many dansylarginine derivatives showed very strong inhibition for pseudocholinesterase, however, SAR for C-terminal side of these derivatives revealed the similarity and dissimilarity in HBP and the P site between pseudocholinesterase and the proteases described above.