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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28919038/covalent-ligand-discovery-against-druggable-hotspots-targeted-by-anti-cancer-natural-products
#1
Elizabeth A Grossman, Carl C Ward, Jessica N Spradlin, Leslie A Bateman, Tucker R Huffman, David K Miyamoto, Jordan I Kleinman, Daniel K Nomura
Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation...
September 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28943356/arabinosylation-modulates-the-growth-regulating-activity-of-the-peptide-hormone-cle40a-from-soybean
#2
Leo Corcilius, April H Hastwell, Mengbai Zhang, James Williams, Joel P Mackay, Peter M Gresshoff, Brett J Ferguson, Richard J Payne
Small post-translationally modified peptide hormones mediate crucial developmental and regulatory processes in plants. CLAVATA/ENDOSPERM-SURROUNDING REGION (CLE) genes are found throughout the plant kingdom and encode for 12-13 amino acid peptides that must often undergo post-translational proline hydroxylation and glycosylation with O-β1,2-triarabinose moieties before they become functional. Apart from a few recent examples, a detailed understanding of the structure and function of most CLE hormones is yet to be uncovered...
September 8, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28943358/custom-glycosylation-of-cells-and-proteins-using-cyclic-carbamate-derivatized-oligosaccharides
#3
Marek W J Whitehead, Nikolay Khanzhin, Lubor Borsig, Thierry Hennet
The structural complexity of glycosylation restrains the functional characterization of glycans. We present a versatile carbohydrate ligation technique based on the reaction of cyclic carbamates with primary amines. Cyclic-carbamate-derivatized carbohydrates can be added to primary amine-containing molecules in aqueous solution to yield glycoconjugates. This method enabled the presentation of carbohydrate epitopes on live animal cells, as shown by the acquisition of E-selectin binding sites on mouse MC-38 cells decorated with 3-fucosyllactose or 3-fucosyl-3-sialyllactose...
September 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28943357/divergent-jnk-phosphorylation-of-hdac3-in-triple-negative-breast-cancer-cells-determines-hdac-inhibitor-binding-and-selectivity
#4
Thomas W Hanigan, Shaimaa M Aboukhatwa, Taha Y Taha, Jonna Frasor, Pavel A Petukhov
Histone deacetylase (HDAC) catalytic activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACis) is unclear. In this study, we developed a method that identified a 3- to 16-fold increase in HDACi selectivity for HDAC3 in triple-negative breast cancer (TNBC) cells in comparison with luminal subtypes that was not predicted by current practice measurements with recombinant proteins...
September 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28943355/boron-based-inhibitors-of-the-nlrp3-inflammasome
#5
Alex G Baldwin, Jack Rivers-Auty, Michael J D Daniels, Claire S White, Carl H Schwalbe, Tom Schilling, Halah Hammadi, Panichakorn Jaiyong, Nicholas G Spencer, Hazel England, Nadia M Luheshi, Manikandan Kadirvel, Catherine B Lawrence, Nancy J Rothwell, Michael K Harte, Richard A Bryce, Stuart M Allan, Claudia Eder, Sally Freeman, David Brough
NLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca(2+) homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca(2+) homeostasis...
September 1, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28919040/heme-binding-biguanides-target-cytochrome-p450-dependent-cancer-cell-mitochondria
#6
Zhijun Guo, Irina F Sevrioukova, Ilia G Denisov, Xia Zhang, Ting-Lan Chiu, Dafydd G Thomas, Eric A Hanse, Rebecca A D Cuellar, Yelena V Grinkova, Vanessa Wankhede Langenfeld, Daniel S Swedien, Justin D Stamschror, Juan Alvarez, Fernando Luna, Adela Galván, Young Kyung Bae, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Beverly Norris, Craig M Flory, Robert J Schumacher, M Gerard O'Sullivan, Qing Cao, Haitao Chu, John D Lipscomb, William M Atkins, Kalpna Gupta, Ameeta Kelekar, Ian A Blair, Jorge H Capdevila, John R Falck, Stephen G Sligar, Thomas L Poulos, Gunda I Georg, Elizabeth Ambrose, David A Potter
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs...
August 29, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28919039/a-linear-diubiquitin-based-probe-for-efficient-and-selective-detection-of-the-deubiquitinating-enzyme-otulin
#7
Aurelia Weber, Paul R Elliott, Adan Pinto-Fernandez, Sarah Bonham, Benedikt M Kessler, David Komander, Farid El Oualid, Daniel Krappmann
The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor κB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN activity-based probe [ABP]) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. The OTULIN ABP displays high selectivity for OTULIN and does not label other M1-cleaving DUBs, including CYLD...
August 28, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28943354/hydroxyhomocitrulline-is-a-collagen-specific-carbamylation-mark-that-affects-cross-link-formation
#8
Yuki Taga, Keisuke Tanaka, Chieko Hamada, Masashi Kusubata, Kiyoko Ogawa-Goto, Shunji Hattori
Carbamylation is a non-enzymatic post-translational modification that physiologically occurs during aging and is a risk factor for various diseases. The most common product of carbamylation is homocitrulline (HCit), where a lysine (Lys) amino group has reacted with urea-derived cyanate. HCit has recently been detected in collagen; however, given that 15%-90% of total Lys in collagen is hydroxylated, it is unclear how hydroxylation affects collagen carbamylation. Here, we identified a collagen-specific carbamylation product, hydroxyhomocitrulline (HHCit), and showed that high levels of HHCit are correlated with age in rat tissue collagen and in vivo carbamylation in mice, as well as with the decline of kidney function in the serum of dialysis patients...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28919041/a-split-abl-kinase-for-direct-activation-in-cells
#9
Juan E Diaz, Charles W Morgan, Catherine E Minogue, Alexander S Hebert, Joshua J Coon, James A Wells
To dissect the cellular roles of individual kinases, it is useful to design tools for their selective activation. We describe the engineering of a split-cAbl kinase (sKin-Abl) that is rapidly activated in cells with rapamycin and allows temporal, dose, and compartmentalization control. Our design strategy involves an empirical screen in mammalian cells and identification of split site in the N lobe. This split site leads to complete loss of activity, which can be restored upon small-molecule-induced dimerization in cells...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28919037/a-link-between-linearmycin-biosynthesis-and-extracellular-vesicle-genesis-connects-specialized-metabolism-and-bacterial-membrane-physiology
#10
B Christopher Hoefler, Reed M Stubbendieck, N Kalyani Josyula, Sabrina M Moisan, Emma M Schulze, Paul D Straight
Specialized metabolites support bacterial competitive fitness as antibiotics, signals, pigments, and metal scavengers. Little is known about how specialized metabolites are processed and trafficked for their diverse competitive functions. Linearmycins A and B are linear polyketides with antifungal and antibacterial activity but are colony-localized in imaging mass spectrometry of Streptomyces sp. Mg1 (S. sp. Mg1). To decipher a connection between colony localization and antibiotic activity, we identified the linearmycin gene cluster and investigated linearmycin production and distribution by S...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28890318/total-biosynthesis-of-the-pyrrolo-4-2-benzodiazepine-scaffold-tomaymycin-on-an-in%C3%A2-vitro-reconstituted-nrps-system
#11
Alexander von Tesmar, Michael Hoffmann, Jan Pippel, Antoine Abou Fayad, Stefan Dausend-Werner, Armin Bauer, Wulf Blankenfeldt, Rolf Müller
In vitro reconstitution and biochemical analysis of natural product biosynthetic pathways remains a challenging endeavor, especially if megaenzymes of the nonribosomal peptide synthetase (NRPS) type are involved. In theory, all biosynthetic steps may be deciphered using mass spectrometry (MS)-based analyses of both the carrier protein-coupled intermediates and the free intermediates. We here report the "total biosynthesis" of the pyrrolo[4,2]benzodiazepine scaffold tomaymycin using an in vitro reconstituted NRPS system...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28890317/mitoneod-a-mitochondria-targeted-superoxide-probe
#12
Maria M Shchepinova, Andrew G Cairns, Tracy A Prime, Angela Logan, Andrew M James, Andrew R Hall, Sara Vidoni, Sabine Arndt, Stuart T Caldwell, Hiran A Prag, Victoria R Pell, Thomas Krieg, John F Mulvey, Pooja Yadav, James N Cobley, Thomas P Bright, Hans M Senn, Robert F Anderson, Michael P Murphy, Richard C Hartley
Mitochondrial superoxide (O2(⋅-)) underlies much oxidative damage and redox signaling. Fluorescent probes can detect O2(⋅-), but are of limited applicability in vivo, while in cells their usefulness is constrained by side reactions and DNA intercalation. To overcome these limitations, we developed a dual-purpose mitochondrial O2(⋅-) probe, MitoNeoD, which can assess O2(⋅-) changes in vivo by mass spectrometry and in vitro by fluorescence. MitoNeoD comprises a O2(⋅-)-sensitive reduced phenanthridinium moiety modified to prevent DNA intercalation, as well as a carbon-deuterium bond to enhance its selectivity for O2(⋅-) over non-specific oxidation, and a triphenylphosphonium lipophilic cation moiety leading to the rapid accumulation within mitochondria...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28890316/iron-biochemistry-is-correlated-with-amyloid-plaque-morphology-in-an-established-mouse-model-of-alzheimer-s-disease
#13
Neil D Telling, James Everett, Joanna F Collingwood, Jon Dobson, Gerrit van der Laan, Joseph J Gallagher, Jian Wang, Adam P Hitchcock
A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aβ) fibrils in the brain. Nevertheless, the links between Aβ and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aβ1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub-micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Aβ...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28867595/mitochondrial-ferredoxin-determines-vulnerability-of-cells-to-copper-excess
#14
Cindy Vallières, Sara L Holland, Simon V Avery
The essential micronutrient copper is tightly regulated in organisms, as environmental exposure or homeostasis defects can cause toxicity and neurodegenerative disease. The principal target(s) of copper toxicity have not been pinpointed, but one key effect is impaired supply of iron-sulfur (FeS) clusters to the essential protein Rli1 (ABCE1). Here, to find upstream FeS biosynthesis/delivery protein(s) responsible for this, we compared copper sensitivity of yeast-overexpressing candidate targets. Overexpression of the mitochondrial ferredoxin Yah1 produced copper hyper-resistance...
August 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28919036/blends-of-non-caloric-sweeteners-saccharin-and-cyclamate-show-reduced-off-taste-due-to-tas2r-bitter-receptor-inhibition
#15
Maik Behrens, Kristina Blank, Wolfgang Meyerhof
Non-caloric sweeteners are widely used for the formulation of calorie-reduced beverages for health-conscious consumers. However, disadvantages such as undesired off-tastes limit the use of non-nutritive sweeteners. Therefore, the food industry is constantly searching for novel sweeteners and frequently resorts to using blends combining non-caloric sweeteners in a single formulation. The earliest blend allowing higher sweetness levels with reduced bitter off-taste combined saccharin with cyclamate. However, the mechanism by which sweetener blends become superior to single compounds remained obscure...
August 23, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28807782/modulating-protein-protein-interactions-of-the-mitotic-polo-like-kinases-to-target-mutant-kras
#16
Ana J Narvaez, Suzan Ber, Alex Crooks, Amy Emery, Bryn Hardwick, Estrella Guarino Almeida, David J Huggins, David Perera, Meredith Roberts-Thomson, Roberta Azzarelli, Fiona E Hood, Ian A Prior, David W Walker, Richard Boyce, Robert G Boyle, Samuel P Barker, Christopher J Torrance, Grahame J McKenzie, Ashok R Venkitaraman
Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis...
July 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28807783/aggregation-and-its-influence-on-the-immunomodulatory-activity-of-synthetic-innate-defense-regulator-peptides
#17
Evan F Haney, Bing Catherine Wu, Kelsey Lee, Ashley L Hilchie, Robert E W Hancock
There is increasing interest in developing cationic host defense peptides (HDPs) and their synthetic derivatives as antimicrobial, immunomodulatory, and anti-biofilm agents. These activities are often evaluated without considering biologically relevant concentrations of salts or serum; furthermore certain HDPs have been shown to aggregate in vitro. Here we examined the effect of aggregation on the immunomodulatory activity of a synthetic innate defense regulator peptide, 1018 (VRLIVAVRIWRR-NH2). A variety of salts and solutes were screened to determine their influence on 1018 aggregation, revealing that this peptide "salts out" of solution in an anion-specific and concentration-dependent manner...
July 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28938091/targeting-metabolism-for-cancer-therapy
#18
REVIEW
Alba Luengo, Dan Y Gui, Matthew G Vander Heiden
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials...
September 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28938090/small-molecule-targets-in-immuno-oncology
#19
REVIEW
Dashyant Dhanak, James P Edwards, Ancho Nguyen, Peter J Tummino
Advances in understanding the role and molecular mechanisms underlying immune surveillance and control of (pre)malignancies is revolutionizing clinical practice in the treatment of cancer. Presently, multiple biologic drugs targeting the immune checkpoint proteins PD(L)1 or CTLA4 have been approved and/or are in advanced stages of clinical development for many cancers. In addition, combination therapy with these agents and other immunomodulators is being intensively explored with the aim of improving primary response rates or prolonging overall survival...
September 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28938089/drug-discovery-and-chemical-biology-of-cancer-epigenetics
#20
REVIEW
Scott Ribich, Darren Harvey, Robert A Copeland
Comprehensive whole-exome sequencing, DNA copy-number determination, and transcriptomic analyses of diverse cancers have greatly expanded our understanding of the biology of many tumor types. In addition to mutations in the common cell-of-origin specific driver mutations, these studies have also revealed a large number of loss-of-function and gain-of-function mutations in chromatin-modifying proteins (CMPs). This has revealed that epigenetic dysregulation is a common feature of most pediatric and adult cancers...
September 21, 2017: Cell Chemical Biology
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