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Cell Chemical Biology

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https://www.readbyqxmd.com/read/27889409/bioactive-compound-screen-for-pharmacological-enhancers-of-apolipoprotein-e-in-primary-human-astrocytes
#1
Gina M Finan, Ronald Realubit, Sungkwon Chung, Dieter Lütjohann, Nan Wang, John R Cirrito, Charles Karan, Tae-Wan Kim
Pharmacological screening in physiologically relevant brain cells is crucial for identifying neuroactive compounds that better translate into in vivo biology and efficacious therapeutics. Pharmacological enhancement of apolipoprotein E (apoE), a cholesterol-transporting apolipoprotein, has been proposed as a promising therapeutic approach for Alzheimer's disease. Several nuclear receptor agonists were initially shown to increase brain apoE levels together with ATP-binding cassette transporter 1 (ABCA1), but their underlying mechanisms remain unclear...
November 18, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27889408/an-rna-based-fluorescent-biosensor-for-high-throughput-analysis-of-the-cgas-cgamp-sting-pathway
#2
Debojit Bose, Yichi Su, Assaf Marcus, David H Raulet, Ming C Hammond
In mammalian cells, the second messenger (2'-5',3'-5') cyclic guanosine monophosphate-adenosine monophosphate (2',3'-cGAMP), is produced by the cytosolic DNA sensor cGAMP synthase (cGAS), and subsequently bound by the stimulator of interferon genes (STING) to trigger interferon response. Thus, the cGAS-cGAMP-STING pathway plays a critical role in pathogen detection, as well as pathophysiological conditions including cancer and autoimmune disorders. However, studying and targeting this immune signaling pathway has been challenging due to the absence of tools for high-throughput analysis...
November 18, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27866909/unsaturated-fatty-acid-synthesis-in-the-gastric-pathogen-helicobacter-pylori-proceeds-via-a-backtracking-mechanism
#3
Hongkai Bi, Lei Zhu, Jia Jia, Liping Zeng, John E Cronan
Helicobacter pylori is a Gram-negative bacterium that inhabits the upper gastrointestinal tract in humans, and the presence of this pathogen in the gut microbiome increases the risk of peptic ulcers and stomach cancer. H. pylori depends on unsaturated fatty acid (UFA) biosynthesis for maintaining membrane structure and function. Although some of the H. pylori enzymes involved in UFA biosynthesis are functionally homologous with the enzymes found in Escherichia coli, we show here that an enzyme HP0773, now annotated as FabX, uses an unprecedented backtracking mechanism to not only dehydrogenate decanoyl-acyl carrier protein (ACP) in a reaction that parallels that of acyl-CoA dehydrogenase, the first enzyme of the fatty acid β-oxidation cycle, but also isomerizes trans-2-decenoyl-ACP to cis-3-decenoyl-ACP, the key UFA synthetic intermediate...
November 16, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27889407/whole-cell-cancer-vaccines-induce-large-antibody-responses-to-carbohydrates-and-glycoproteins
#4
Li Xia, David S Schrump, Jeffrey C Gildersleeve
Whole-cell cancer vaccines are a promising strategy for treating cancer, but the characteristics of a favorable immune response are not fully understood. New insights could enable development of better vaccines, discovery of new antigens, and identification of biomarkers of efficacy. Using glyco-antigen microarrays, we demonstrate that GVAX Pancreas (a granulocyte macrophage colony-stimulating factor-modified whole-cell tumor vaccine) induces large immunoglobulin G and immunoglobulin M responses to many antigens, including tumor-associated carbohydrates, blood group antigens, α-Gal, and bovine fetuin...
November 10, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27866911/structural-insight-into-the-enzymatic-formation-of-bacterial-stilbene
#5
Takahiro Mori, Takayoshi Awakawa, Koichiro Shimomura, Yuri Saito, Dengfeng Yang, Hiroyuki Morita, Ikuro Abe
In contrast to stilbene biosynthesis by type III polyketide synthase in plants, in bacteria stilbene is produced by the collaboration of two enzymes in Photorhabdus luminescens: the unusual β-ketosynthase StlD catalyzes the condensation of the β-ketoacyl starter with an α,β-unsaturated-acyl substrate (two C-C bond-forming reactions) to produce isopropylstyrylcyclohexanedione, which is subsequently converted to stilbene by the aromatase StlC. Here we report the in vitro characterizations of StlD and StlC, and the X-ray crystal structures of StlD...
November 9, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27866910/proteome-wide-profiling-of-clinical-parp-inhibitors-reveals-compound-specific-secondary-targets
#6
Claire E Knezevic, Gabriela Wright, Lily L Remsing Rix, Woosuk Kim, Brent M Kuenzi, Yunting Luo, January M Watters, John M Koomen, Eric B Haura, Alvaro N Monteiro, Caius Radu, Harshani R Lawrence, Uwe Rix
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively...
November 9, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27866908/biosynthetic-pathway-connects-cryptic-ribosomally-synthesized-posttranslationally-modified-peptide-genes-with-pyrroloquinoline-alkaloids
#7
Peter A Jordan, Bradley S Moore
In an era where natural product biosynthetic gene clusters can be rapidly identified from sequenced genomes, it is unusual for the biosynthesis of an entire natural product class to remain unknown. Yet, the genetic determinates for pyrroloquinoline alkaloid biosynthesis have remained obscure despite their abundance and deceptive structural simplicity. In this work, we have identified the biosynthetic gene cluster for ammosamides A-C, pyrroloquinoline alkaloids from Streptomyces sp. CNR-698. Through direct cloning, heterologous expression and gene deletions we have validated the ammosamide biosynthetic gene cluster and demonstrated that these seemingly simple molecules are derived from a surprisingly complex set of biosynthetic genes that are also found in the biosynthesis of lymphostin, a structurally related pyrroloquinoline alkaloid from Salinispora and Streptomyces...
November 9, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27863219/cancer-cell-drug-response-transcriptomes-in-3d
#8
Krister Wennerberg
The relevance of different in vitro culture models of cancer cells is a hot topic, but few systematic and definitive analyses in this area exist. In this issue of Cell Chemical Biology, Senkowski et al. (2016) address this issue by studying the transcriptomic profiles of drug-treated cancer cells cultured in two-dimensional and three-dimensional cultures. They describe biological findings with potential therapeutic implications and provide a unique data resource to mine.
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27863218/discovery-of-ibomycin-a-potent-antifungal-weapon
#9
J Andrew Alspaugh
In this issue of Cell Chemical Biology, Robbins et al. (2016) identify ibomycin, a unique compound with antifungal activity. Microbial physiological and genetic studies suggest that endocytic trafficking might be the site of action for this lead antifungal compound.
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27863217/eukaryotic-ribosome-as-a-target-for-cardiovascular-disease
#10
Simone Pellegrino, Gulnara Yusupova
Cardiovascular diseases have been associated with genetic variants and increased plasma level of the secreted protein PCSK9. In this issue of Cell Chemical Biology, Petersen et al. (2016) describe an inhibitor of PCSK9 secretion in human cells that, surprisingly, targets the 80S ribosome.
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27863216/exposing-the-unique-connection-between-metabolism-and-virulence-in-staphylococcus-aureus
#11
Andy Weiss, Renee M Fleeman, Lindsey N Shaw
In this issue of Cell Chemical Biology, Choby et al. (2016) use a small molecule inhibitor active against fermenting S. aureus to unravel a unique connection between virulence factor production and central metabolism. In so doing, the authors uncover Fe-S cluster assembly proteins as a novel antibacterial target, and deliver a first-in-class scaffold for optimization against anaerobically growing cells.
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27863215/from-glioblastoma-to-hepatitis-c-it-s-a-metabolism-thing
#12
Milka Kostic
Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our November 2016 selection includes the discovery that cholesterol supply is a weak link in glioblastoma metabolism and the finding that nuclear hormone receptors are in the center of the complicated relationship we have with the hepatitis C virus.
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27840070/selective-jak3-inhibitors-with-a-covalent-reversible-binding-mode-targeting-a-new-induced-fit-binding-pocket
#13
Michael Forster, Apirat Chaikuad, Silke M Bauer, Julia Holstein, Matthew B Robers, Cesear R Corona, Matthias Gehringer, Ellen Pfaffenrot, Kamran Ghoreschi, Stefan Knapp, Stefan A Laufer
Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27818300/multicolor-electron-microscopy-for-simultaneous-visualization-of-multiple-molecular-species
#14
Stephen R Adams, Mason R Mackey, Ranjan Ramachandra, Sakina F Palida Lemieux, Paul Steinbach, Eric A Bushong, Margaret T Butko, Ben N G Giepmans, Mark H Ellisman, Roger Y Tsien
Electron microscopy (EM) remains the primary method for imaging cellular and tissue ultrastructure, although simultaneous localization of multiple specific molecules continues to be a challenge for EM. We present a method for obtaining multicolor EM views of multiple subcellular components. The method uses sequential, localized deposition of different lanthanides by photosensitizers, small-molecule probes, or peroxidases. Detailed view of biological structures is created by overlaying conventional electron micrographs with pseudocolor lanthanide elemental maps derived from distinctive electron energy-loss spectra of each lanthanide deposit via energy-filtered transmission electron microscopy...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27818299/a-semi-synthetic-oligosaccharide-conjugate-vaccine-candidate-confers-protection-against-streptococcus-pneumoniae-serotype-3-infection
#15
Sharavathi Guddehalli Parameswarappa, Katrin Reppe, Andreas Geissner, Petra Ménová, Subramanian Govindan, Adam D J Calow, Annette Wahlbrink, Markus W Weishaupt, Bopanna Ponnappa Monnanda, Roland Lawrence Bell, Liise-Anne Pirofski, Norbert Suttorp, Leif Erik Sander, Martin Witzenrath, Claney Lebev Pereira, Chakkumkal Anish, Peter H Seeberger
The identification of immunogenic glycotopes that render glycoconjugate vaccines protective is key to improving vaccine efficacy. Synthetic oligosaccharides are an attractive alternative to the heterogeneous preparations of purified polysaccharides that most marketed glycoconjugate vaccines are based on. To investigate the potency of semi-synthetic glycoconjugates, we chose the least-efficient serotype in the current pneumococcal conjugate vaccine Prevnar 13, Streptococcus pneumoniae serotype 3 (ST3). Glycan arrays containing synthetic ST3 repeating unit oligosaccharides were used to screen a human reference serum for antibodies and to define the recognition site of two ST3-specific protective monoclonal antibodies...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27773629/rna-dna-triplex-formation-by-long-noncoding-rnas
#16
REVIEW
Yue Li, Junetha Syed, Hiroshi Sugiyama
Long noncoding RNAs (lncRNAs) play a pivotal role in the regulation of biological processes through various mechanisms that are not fully understood. Proposed mechanisms include regulation based on RNA-protein interactions, as well as RNA-RNA interactions and RNA-DNA interactions. Here, we focus on one possible mechanism that lncRNA might be using to impact biological function, the RNA-DNA triplex formation. We summarize currently available examples of lncRNA triplex formation and discuss the details surrounding orientation of triplex formation as one of the key properties guiding this process...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27773628/a-small-molecule-inhibitor-of-iron-sulfur-cluster-assembly-uncovers-a-link-between-virulence-regulation-and-metabolism-in-staphylococcus-aureus
#17
Jacob E Choby, Laura A Mike, Ameya A Mashruwala, Brendan F Dutter, Paul M Dunman, Gary A Sulikowski, Jeffrey M Boyd, Eric P Skaar
The rising problem of antimicrobial resistance in Staphylococcus aureus necessitates the discovery of novel therapeutic targets for small-molecule intervention. A major obstacle of drug discovery is identifying the target of molecules selected from high-throughput phenotypic assays. Here, we show that the toxicity of a small molecule termed '882 is dependent on the constitutive activity of the S. aureus virulence regulator SaeRS, uncovering a link between virulence factor production and energy generation. A series of genetic, physiological, and biochemical analyses reveal that '882 inhibits iron-sulfur (Fe-S) cluster assembly most likely through inhibition of the Suf complex, which synthesizes Fe-S clusters...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27746129/discovery-of-ibomycin-a-complex-macrolactone-that-exerts-antifungal-activity-by-impeding-endocytic-trafficking-and-membrane-function
#18
Nicole Robbins, Michaela Spitzer, Wenliang Wang, Nicholas Waglechner, Dhruv J Patel, Jonathan S O'Brien, Linda Ejim, Obi Ejim, Mike Tyers, Gerard D Wright
Natural products are invaluable historic sources of drugs for infectious diseases; however, the discovery of novel antimicrobial chemical scaffolds has waned in recent years. Concurrently, there is a pressing need for improved therapeutics to treat fungal infections. We employed a co-culture screen to identify ibomycin, a large polyketide macrolactone that has preferential killing activity against Cryptococcus neoformans. Using chemical and genome methods, we determined the structure of ibomycin and identified the biosynthetic cluster responsible for its synthesis...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27746128/a-small-molecule-anti-secretagogue-of-pcsk9-targets-the-80s-ribosome-to-inhibit-pcsk9-protein-translation
#19
Donna N Petersen, Julie Hawkins, Wanida Ruangsiriluk, Kimberly A Stevens, Bruce A Maguire, Thomas N O'Connell, Benjamin N Rocke, Markus Boehm, Roger B Ruggeri, Tim Rolph, David Hepworth, Paula M Loria, Philip A Carpino
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin...
November 17, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27746127/the-calcineurin-variant-cna%C3%AE-1-controls-mouse-embryonic-stem-cell-differentiation-by-directing-mtorc2-membrane-localization-and-activation
#20
Jesús M Gómez-Salinero, Marina M López-Olañeta, Paula Ortiz-Sánchez, Javier Larrasa-Alonso, Alberto Gatto, Leanne E Felkin, Paul J R Barton, Inmaculada Navarro-Lérida, Miguel Ángel Del Pozo, Pablo García-Pavía, Balaji Sundararaman, Giovanna Giovinazo, Gene W Yeo, Enrique Lara-Pezzi
Embryonic stem cells (ESC) have the potential to generate all the cell lineages that form the body. However, the molecular mechanisms underlying ESC differentiation and especially the role of alternative splicing in this process remain poorly understood. Here, we show that the alternative splicing regulator MBNL1 promotes generation of the atypical calcineurin Aβ variant CnAβ1 in mouse ESCs (mESC). CnAβ1 has a unique C-terminal domain that drives its localization mainly to the Golgi apparatus by interacting with Cog8...
November 17, 2016: Cell Chemical Biology
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