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Enzyme inhibitor

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https://www.readbyqxmd.com/read/28098782/auranofin-inhibits-the-enzyme-activity-of-pasteurella-multocida-toxin-pmt-in-human-cells-and-protects-cells-from-intoxication
#1
Stefan Carle, Thorsten Brink, Joachim H C Orth, Klaus Aktories, Holger Barth
The AB-type protein toxin from Pasteurella multocida (PMT) contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR) is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins) in the cytosol of cells...
January 13, 2017: Toxins
https://www.readbyqxmd.com/read/28098447/the-stories-tryptophans-tell-exploring-protein-dynamics-of-heptosyltransferase-i-from-escherichia-coli
#2
Joy M Cote, Carlos Andres Ramirez-Mondragon, Zarek S Siegel, Daniel Joseph Czyzyk, Jiali Gao, Yuk Yin Sham, Ishita Mukerji, Erika A Taylor
Heptosyltransferase I (HepI) catalyzes the addition of a single L-glycero-β-D-manno-heptose sugar (heptose) onto the membrane incorporated Kdo2-Lipid A as part of the biosynthesis of the core region of lipopolysaccharide (LPS). Gram-negative bacteria with gene knockouts of HepI have reduced virulence with enhanced susceptibility to hydrophobic antibiotics, making design of inhibitors against HepI of interest. Previous studies have shown that HepI protein dynamics are partially rate limiting, and therefore disruption of protein dynamics might provide a new strategy for inhibiting HepI...
January 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28098164/uncovering-the-sumoylation-and-ubiquitylation-crosstalk-in-human-cells-using-sequential-peptide-immunopurification
#3
Frédéric Lamoliatte, Francis P McManus, Ghizlane Maarifi, Mounira K Chelbi-Alix, Pierre Thibault
Crosstalk between the SUMO and ubiquitin pathways has recently been reported. However, no approach currently exists to determine the interrelationship between these modifications. Here, we report an optimized immunoaffinity method that permits the study of both protein ubiquitylation and SUMOylation from a single sample. This method enables the unprecedented identification of 10,388 SUMO sites in HEK293 cells. The sequential use of SUMO and ubiquitin remnant immunoaffinity purification facilitates the dynamic profiling of SUMOylated and ubiquitylated proteins in HEK293 cells treated with the proteasome inhibitor MG132...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28097911/design-synthesis-and-docking-study-of-novel-coumarin-ligands-as-potential-selective-acetylcholinesterase-inhibitors
#4
Fatih Sonmez, Belma Zengin Kurt, Isil Gazioglu, Livia Basile, Aydan Dag, Valentina Cappello, Tiziana Ginex, Mustafa Kucukislamoglu, Salvatore Guccione
New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28097901/skin-whitening-agents-medicinal-chemistry-perspective-of-tyrosinase-inhibitors
#5
Thanigaimalai Pillaiyar, Manoj Manickam, Vigneshwaran Namasivayam
Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28097874/through-scaffold-modification-to-3-5-diaryl-4-5-dihydroisoxazoles-new-potent-and-selective-inhibitors-of-monoamine-oxidase-b
#6
Rita Meleddu, Simona Distinto, Roberto Cirilli, Stefano Alcaro, Matilde Yanez, Maria Luisa Sanna, Angela Corona, Claudia Melis, Giulia Bianco, Peter Matyus, Filippo Cottiglia, Elias Maccioni
3,5-Diaryl-4,5-dihydroisoxazoles were synthesized and evaluated as monoamine oxidase (MAO) enzyme inhibitors and iron chelators. All compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was preliminarily evaluated for its ability to bind iron II and III cations, indicating that neither iron II nor iron III is coordinated. The best compounds racemic mixtures were separated and single enantiomers inhibitory activity evaluated...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28097769/high-resolution-crystal-structures-of-human-kynurenine-aminotransferase-i-bound-to-plp-cofactor-and-in-complex-with-aminooxyacetate
#7
Naveed A Nadvi, Noeris K Salam, Joohong Park, Fady N Akladios, Vimal Kapoor, Charles A Collyer, Mark D Gorrell, And W Bret Church
In this study we report two high-resolution structures of the pyridoxal 5' phosphate (PLP)-dependent enzyme kynurenine aminotransferase-I (KAT-I). One is the native structure with the cofactor in the PLP form bound to Lys247 with the highest resolution yet available for KAT-I at 1.28 Å resolution, and the other with the general PLP-dependent aminotransferase inhibitor, aminooxyacetate (AOAA) covalently bound to the cofactor at 1.54 Å. Only small conformational differences are observed in the vicinity of the aldimine (oxime) linkage with which the PLP forms the Schiff base with Lys247 in the 1...
January 18, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28097295/association-of-systemic-medication-use-with-intraocular-pressure-in-a-multiethnic-asian-population-the-singapore-epidemiology-of-eye-diseases-study
#8
Henrietta Ho, Yuan Shi, Jacqueline Chua, Yih-Chung Tham, Sing Hui Lim, Tin Aung, Tien Yin Wong, Ching-Yu Cheng
Importance: There is limited understanding of the associations between systemic medication use and intraocular pressure (IOP) in the general population. Objective: To examine the association between systemic medication use and IOP in a multiethnic Asian population. Design, Setting, and Participants: In this post hoc analysis of the Singapore Epidemiology of Eye Diseases study, a population-based study of 10 033 participants (78.7% response rate) from 3 racial/ethnic groups (Chinese [recruited from February 9, 2009, through December 19, 2011], Malays [recruited from August 16, 2004, though July 10, 2006], and Indians [recruited from May 21, 2007, through December 29, 2009]), participants with glaucoma, previous ocular surgery, or trauma and an IOP asymmetry greater than 5 mm Hg between eyes were excluded...
January 12, 2017: JAMA Ophthalmology
https://www.readbyqxmd.com/read/28096973/a-fission-yeast-cell-based-system-for-multidrug-resistant-hiv-1-proteases
#9
Zsigmond Benko, Dong Liang, Ge Li, Robert T Elder, Anindya Sarkar, Jun Takayama, Arun K Ghosh, Richard Y Zhao
BACKGROUND: HIV-1 protease (PR) is an essential enzyme for viral production. Thus, PR inhibitors (PIs) are the most effective class of anti-HIV drugs. However, the main challenge to the successful use of PI drugs in patient treatment is the emergence of multidrug resistant PRs (mdrPRs). This study aimed to develop a fission yeast cell-based system for rapid testing of new PIs that combat mdrPRs. RESULTS: Three mdrPRs were isolated from HIV-infected patients that carried seven (M7PR), ten (M10PR) and eleven (M11PR) PR gene mutations, respectively...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28096675/the-role-of-heme-oxygenase-1-ho-1-in-the-regulation-of-inflammatory-reaction-neuronal-cell-proliferation-and-apoptosis-in-rats-after-intracerebral-hemorrhage-ich
#10
Xuezheng Fan, Linshen Mu
OBJECTIVE: To investigate the role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH). METHODS: Thirty-six adult Sprague Dawley (SD) male rats were randomly divided into sham operation, ICH and zinc protoporphyrin (ZPP) group. Rats (except for the sham operation group) were given 50 μL stereotactic injection of autologous blood from the femoral artery into the caudate nucleus, to establish an ICH model...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28096572/current-and-emerging-treatments-for-hypercholesterolemia-a-focus-on-statins-and-proprotein-convertase-subtilisin-kexin-type-9-inhibitors-for-perioperative-clinicians
#11
REVIEW
Terrence L Trentman, Steven G Avey, Harish Ramakrishna
Statins are a mainstay of hyperlipidemia treatment. These drugs inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and have beneficial effects on atherosclerosis including plaque stabilization, reduction of platelet activation, and reduction of plaque proliferation and inflammation. Statins also have a benefit beyond atherosclerotic plaque, including anticoagulation, vasodilatation, antioxidant effects, and reduction of mediators of inflammation. In the perioperative period, statins appear to contribute to improved outcomes via these mechanisms...
October 2016: Journal of Anaesthesiology, Clinical Pharmacology
https://www.readbyqxmd.com/read/28096549/decatamariic-acid-a-new-mitochondrial-respiration-inhibitor-discovered-by-pesticidal-screening-using-drug-sensitive-saccharomyces-cerevisiae
#12
Yoshihiro Watanabe, Takuya Suga, Satomi Narusawa, Masato Iwatsuki, Kenichi Nonaka, Takuji Nakashima, Yasuo Shinohara, Takahiro Shiotsuki, Naoya Ichimaru, Hideto Miyoshi, Yukihiro Asami, Satoshi Ōmura, Kazuro Shiomi
A new decalin, decatamariic acid, was isolated from a cultured broth of the fungus Aspergillus tamarii FKI-6817. Its absolute configuration was elucidated by NMR and electronic circular dichroism. Decatamariic acid (10 μM) elicited ~50% inhibition of the ATP production in mitochondria isolated from wild-type Saccharomyces cerevisiae without affecting the activities of respiratory enzymes. The action manner of this compound may be interesting as a possible seed for new pesticides.The Journal of Antibiotics advance online publication, 18 January 2017; doi:10...
January 18, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28096482/chronic-disease-management-interventions-for-people-with-chronic-kidney-disease-in-primary-care-a-systematic-review-and-meta-analysis
#13
Lauren Galbraith, Casey Jacobs, Brenda R Hemmelgarn, Maoliosa Donald, Braden Manns, Min Jun
BACKGROUND: Primary care providers manage the majority of patients with chronic kidney disease (CKD), although the most effective chronic disease management (CDM) strategies for these patients are unknown. We assessed the efficacy of CDM interventions used by primary care providers managing patients with CKD. METHODS: MEDLINE, EMBASE and CENTRAL were systematically searched (inception to November 2014) for randomized controlled trials (RCTs) assessing education-based and computer-assisted CDM interventions targeting primary care providers managing patients with CKD in the community...
January 16, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28096371/cox2-mpges1-pge2-pathway-regulates-pd-l1-expression-in-tumor-associated-macrophages-and-myeloid-derived-suppressor-cells
#14
Victor Prima, Lyudmila N Kaliberova, Sergey Kaliberov, David T Curiel, Sergei Kusmartsev
In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)-mediated inhibition of activated PD-1(+) T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti-PD-L1 and -PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow-derived myeloid cells...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28095641/melatonin-ameliorates-alcohol-induced-bile-acid-synthesis-by-enhancing-mir-497-expression
#15
Yong Deuk Kim, Seung-Lark Hwang, Eun-Joo Lee, Hyeong-Mi Kim, Myung-Jin Chung, Ahmed K Elfadl, Sung-Eun Lee, Balachandar Nedumaran, Robert A Harris, Kyu-Shik Jeong
Alcoholic liver disease is a major cause of chronic liver disease worldwide and cannabinoid receptor type 1 (CB1R) is involved in a diverse metabolic diseases. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are a potent regulator of biological conditions. Melatonin plays a crucial role in regulating diverse physiological functions and metabolic homeostasis. MicroRNAs are key regulators of various biological processes. Herein, we demonstrate that melatonin improves bile acid synthesis in the liver of alcohol-fed mice by controlling miR-497 expression...
January 17, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28095176/a-flexible-workflow-for-automated-bioluminescent-kinase-selectivity-profiling
#16
Tracy Worzella, Matt Butzler, Jacquelyn Hennek, Seth Hanson, Laura Simdon, Said Goueli, Cris Cowan, Hicham Zegzouti
Kinase profiling during drug discovery is a necessary process to confirm inhibitor selectivity and assess off-target activities. However, cost and logistical limitations prevent profiling activities from being performed in-house. We describe the development of an automated and flexible kinase profiling workflow that combines ready-to-use kinase enzymes and substrates in convenient eight-tube strips, a bench-top liquid handling device, ADP-Glo Kinase Assay (Promega, Madison, WI) technology to quantify enzyme activity, and a multimode detection instrument...
November 1, 2016: Journal of Laboratory Automation
https://www.readbyqxmd.com/read/28094799/activation-of-wnt-%C3%AE-catenin-signalling-via-gsk3-inhibitors-direct-differentiation-of-human-adipose-stem-cells-into-functional-hepatocytes
#17
Jieqiong Huang, Xinyue Guo, Weihong Li, Haiyan Zhang
The generation of hepatocytes that are derived from human adipose stem cells (hASCs) represents an alternative to human hepatocytes for individualized therapeutic and pharmaceutical applications. However, the mechanisms facilitating hepatocyte differentiation from hASCs are not well understood. Here, we show that upon exposure to glycogen synthase kinase 3 (GSK3) inhibitors alone, the expression of definitive endoderm specific genes GATA4, FOXA2, and SOX17 in hASCs significantly increased in a manner with activation of Wnt/β-catenin signalling...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28094552/glucose-metabolism-in-cancer-and-ischemia-possible-therapeutic-consequences-of-the-warburg-effect
#18
Spela Salamon, Eva Podbregar, Peter Kubatka, Dietrich Büsselberg, Martin Caprnda, Radka Opatrilova, Vanda Valentova, Mariusz Adamek, Peter Kruzliak, Matej Podbregar
The Warburg effect states that the main source of energy for cancer cells is not aerobic respiration, but glycolysis-even in normoxia. The shift from one to the other is governed by mutually counteracting enzymes: pyruvate dehydrogenase and pyruvate dehydrogenase kinase (PDK). Anaerobic metabolism of cancer cells promotes cell proliferation, local tissue immunosuppression, resistance to hypoxic conditions, and metastatic processes. By switching glucose back to oxidative metabolism, these effects might be reversed...
January 17, 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28094550/pharmacophore-modelling-atom-based-3d-qsar-generation-and-virtual-screening-of-molecules-projected-for-mpges-1-inhibitory-activity
#19
S Misra, M Saini, H Ojha, D Sharma, K Sharma
COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors...
January 17, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28094391/advantages-of-an-optical-nanosensor-system-for-the-mechanistic-analysis-of-a-novel-topoisomerase-i-targeting-drug-a-case-study
#20
Marie B Andersen, Cinzia Tesauro, María Gonzalez, Emil L Kristoffersen, Concepción Alonso, Gloria Rubiales, Andrea Coletta, Rikke Frøhlich, Magnus Stougaard, Yi-Ping Ho, Francisco Palacios, Birgitta R Knudsen
The continuous need for the development of new small molecule anti-cancer drugs calls for easily accessible sensor systems for measuring the effect of vast numbers of new drugs on their potential cellular targets. Here we demonstrate the use of an optical DNA biosensor to unravel the inhibitory mechanism of a member of a new family of small molecule human topoisomerase I inhibitors, the so-called indeno-1,5-naphthyridines. By analysing human topoisomerase I catalysis on the biosensor in the absence or presence of added drug complemented with a few traditional assays, we demonstrate that the investigated member of the indeno-1,5-naphthyridine family inhibited human topoisomerase I activity by blocking enzyme-DNA dissociation...
January 17, 2017: Nanoscale
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