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Start Over Author "Michael C" Journal journal of biological chemistry
1,107 results on '"Michael C"'

8. Dual cyclooxygenase–fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site

Author

Goodman, Michael C, Xu, Shu, Rouzer, Carol A, Banerjee, Surajit, Ghebreselasie, Kebreab, Migliore, Marco, Piomelli, Daniele, and Marnett, Lawrence J

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Chemical Sciences, Prevention, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Amidohydrolases, Catalytic Domain, Cyclooxygenase Inhibitors, Isoenzymes, Phenylcarbamates, Phenylpropionates, Prostaglandin-Endoperoxide Synthases, Protein Binding, Stereoisomerism, Substrate Specificity, cyclooxygenase, enzyme catalysis, enzyme inhibitor, enzyme kinetics, enzyme structure, fatty acid metabolism, inflammation, polyunsaturated fatty acid, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H2 (PGH2). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH2 analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·(S)-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, (S)-ARN2508 is more potent than (R)-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to (R)-flurbiprofen, (R)-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for (S)-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of (S)-flurbiprofen.

Published
2018

12. The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

Author

Koo, Chek Ziu, Harrison, Neale, Noy, Peter J., Szyroka, Justyna, Matthews, Alexandra L., Hsia, Hung-En, Müller, Stephan A., Tüshaus, Johanna, Goulding, Joelle, Willis, Katie, Apicella, Clara, Cragoe, Bethany, Davis, Edward, Keles, Murat, Malinova, Antonia, McFarlane, Thomas A., Morrison, Philip R., Nguyen, Hanh T.H., Sykes, Michael C., Ahmed, Haroon, Di Maio, Alessandro, Seipold, Lisa, Saftig, Paul, Cull, Eleanor, Pliotas, Christos, Rubinstein, Eric, Poulter, Natalie S., Briddon, Stephen J., Holliday, Nicholas D., Lichtenthaler, Stefan F., and Tomlinson, Michael G.

Published
2020
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17. p16 Protein and Gigaxonin Are Associated with the Ubiquitination of NFκB in Cisplatin-induced Senescence of Cancer Cells*

Author

Veena, Mysore S, Wilken, Reason, Zheng, Jun-Ying, Gholkar, Ankur, Venkatesan, Natarajan, Vira, Darshni, Ahmed, Sameer, Basak, Saroj K, Dalgard, Clifton L, Ravichandran, Sandhiya, Batra, Raj K, Kasahara, Noriyuki, Elashoff, David, Fishbein, Michael C, Whitelegge, Julian P, Torres, Jorge Z, Wang, Marilene B, and Srivatsan, Eri S

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Rare Diseases, Dental/Oral and Craniofacial Disease, Cancer, Active Transport, Cell Nucleus, Antineoplastic Agents, Cell Line, Tumor, Cell Nucleus, Cellular Senescence, Cisplatin, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p16, Cytoskeletal Proteins, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, Human papillomavirus 16, Humans, NF-kappa B, Prognosis, Ubiquitination, Cancer Stem Cells, Chemoresistance, Head and Neck Cancer, Gigaxonin, NFB, p16 Suppressor Gene, NFκB, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

The molecular mechanism of p16-mediated senescence in cisplatin-treated cancer cells is not fully understood. Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFκB. Chromatin immunoprecipitation assays show that this modification is associated with the inhibition of NFκB interacting with its DNA binding sequences, leading to decreased expression of NFκB-transcribed proteins. LCMS proteomic analysis of LAP-TAP-purified proteins from HeLa cells containing a tetracycline-inducible GFP-S peptide-NFκB expression system identified gigaxonin, an ubiquitin E3 ligase adaptor, as an NFκB-interacting protein. Immunoblotting and siRNA studies confirmed the NFκB-gigaxonin interaction and the dependence of this binding on p16-NFκB binding. Using gel shift assays, we have confirmed p16-NFκB and gigaxonin-NFκB interactions. Furthermore, we have observed increased NFκB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression. Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0.0000542), indicating the importance of nuclear p16 expression in prognosis. Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors. However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors. These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFκB.

Published
2014

21. An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein

Author

Glidden, Michael D., Aldabbagh, Khadijah, Phillips, Nelson B., Carr, Kelley, Chen, Yen-Shan, Whittaker, Jonathan, Phillips, Manijeh, Wickramasinghe, Nalinda P., Rege, Nischay, Swain, Mamuni, Peng, Yi, Yang, Yanwu, Lawrence, Michael C., Yee, Vivien C., Ismail-Beigi, Faramarz, and Weiss, Michael A.

Published
2018
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32. Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate

Author

Foryst-Ludwig, Anna, Kreissl, Michael C., Benz, Verena, Brix, Sarah, Smeir, Elia, Ban, Zsofia, Januszewicz, Elżbieta, Salatzki, Janek, Grune, Jana, Schwanstecher, Anne-Kathrin, Blumrich, Annelie, Schirbel, Andreas, Klopfleisch, Robert, Rothe, Michael, Blume, Katharina, Halle, Martin, Wolfarth, Bernd, Kershaw, Erin E., and Kintscher, Ulrich

Published
2015
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49. The basis for non-canonical ROK family function in the N-acetylmannosamine kinase from the pathogen Staphylococcus aureus

Author

Michael C. Newton-Vesty, Renwick C. J. Dobson, Santosh Panjikar, Christopher R Horne, James W. B. Moir, Rachel A. North, Rosmarie Friemann, Michael D. W. Griffin, James S Davies, Ramaswamy Subramanian, David Coombes, and Thanuja Gangi Setty

Subjects
0301 basic medicine, Staphylococcus aureus, Amino Acid Motifs, Repressor, Substrate analog, Crystallography, X-Ray, Biochemistry, Substrate Specificity, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Catalytic Domain, Transferase, Molecular Biology, Binding Sites, 030102 biochemistry & molecular biology, biology, Protein Stability, Kinase, Active site, Hexosamines, Cell Biology, Recombinant Proteins, Protein Structure, Tertiary, Sialic acid, Kinetics, Phosphotransferases (Alcohol Group Acceptor), Zinc, Open reading frame, 030104 developmental biology, chemistry, Structural biology, Protein Structure and Folding, Biocatalysis, biology.protein
Abstract

In environments where glucose is limited, some pathogenic bacteria metabolize host-derived sialic acid as a nutrient source. N-Acetylmannosamine kinase (NanK) is the second enzyme of the bacterial sialic acid import and degradation pathway and adds phosphate to N-acetylmannosamine using ATP to prime the molecule for future pathway reactions. Sequence alignments reveal that Gram-positive NanK enzymes belong to the Repressor, ORF, Kinase (ROK) family, but many lack the canonical Zn-binding motif expected for this function, and the sugar-binding EXGH motif is altered to EXGY. As a result, it is unclear how they perform this important reaction. Here, we study the Staphylococcus aureus NanK (SaNanK), which is the first characterization of a Gram-positive NanK. We report the kinetic activity of SaNanK along with the ligand-free, N-acetylmannosamine-bound and substrate analog GlcNAc-bound crystal structures (2.33, 2.20, and 2.20 Å resolution, respectively). These demonstrate, in combination with small-angle X-ray scattering, that SaNanK is a dimer that adopts a closed conformation upon substrate binding. Analysis of the EXGY motif reveals that the tyrosine binds to the N-acetyl group to select for the "boat" conformation of N-acetylmannosamine. Moreover, SaNanK has a stacked arginine pair coordinated by negative residues critical for thermal stability and catalysis. These combined elements serve to constrain the active site and orient the substrate in lieu of Zn binding, representing a significant departure from canonical NanK binding. This characterization provides insight into differences in the ROK family and highlights a novel area for antimicrobial discovery to fight Gram-positive and S. aureus infections.

Published
2020
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50. A genome-wide analysis of targets of macrolide antibiotics in mammalian cells

Author

Chaitan Khosla, Michael C. Bassik, Ayse Okesli-Armlovich, Amita Gupta, and David W. Morgens

Subjects
0301 basic medicine, Josamycin, MAP Kinase Signaling System, Mitochondrial translation, Bioenergetics, Mitochondrion, MAP Kinase Kinase Kinase 4, p38 Mitogen-Activated Protein Kinases, Biochemistry, Oxidative Phosphorylation, 03 medical and health sciences, Mitochondrial unfolded protein response, medicine, Animals, Humans, Protein kinase A, Molecular Biology, Protein Synthesis Inhibitors, 030102 biochemistry & molecular biology, Kinase, Chemistry, Drug Resistance, Microbial, Cell Biology, Anti-Bacterial Agents, Erythromycin, 030104 developmental biology, Gene Expression Regulation, Protein Biosynthesis, Cancer cell, Unfolded Protein Response, Macrolides, Mitogen-Activated Protein Kinases, K562 Cells, Glycolysis, medicine.drug, K562 cells
Abstract

Macrolide antibiotics, such as erythromycin and josamycin, are natural polyketide products harboring 14- to 16-membered macrocyclic lactone rings to which various sugars are attached. These antibiotics are used extensively in the clinic because of their ability to inhibit bacterial protein synthesis. More recently, some macrolides have been shown to also possess anti-inflammatory and other therapeutic activities in mammalian cells. To better understand the targets and effects of this drug class in mammalian cells, we used a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate cellular sensitivity to josamycin. Among the most sensitizing hits were proteins involved in mitochondrial translation and the mitochondrial unfolded protein response, glycolysis, and the mitogen-activated protein kinase signaling cascade. Further analysis revealed that cells treated with josamycin or other antibacterial agents exhibited impaired oxidative phosphorylation and metabolic shifts to glycolysis. Interestingly, we observed that knockdown of the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene, which contributes to p38 mitogen-activated protein kinase signaling, sensitized cells only to josamycin but not to other antibacterial agents. There is a growing interest in better characterizing the therapeutic effects and toxicities of antibiotics in mammalian cells to guide new applications in both cellular and clinical studies. To our knowledge, this is the first report of an unbiased genome-wide screen to investigate the effects of a clinically used antibiotic on human cells.

Published
2020
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