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Cell Chemical Biology

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https://www.readbyqxmd.com/read/29337187/metabolomics-reveals-that-dietary-xenoestrogens-alter-cellular-metabolism-induced-by-palbociclib-letrozole-combination-cancer-therapy
#1
Benedikt Warth, Philipp Raffeiner, Ana Granados, Tao Huan, Mingliang Fang, Erica M Forsberg, H Paul Benton, Laura Goetz, Caroline H Johnson, Gary Siuzdak
Recently, the palbociclib/letrozole combination therapy was granted accelerated US FDA approval for the treatment of estrogen receptor (ER)-positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein and the estrogenic mycotoxin zearalenone. A global metabolomics approach was applied to unravel metabolite and pathway modifications...
January 10, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29337186/lipoprotein-signal-peptidase-inhibitors-with-antibiotic-properties-identified-through-design-of-a-robust-in%C3%A2-vitro-ht-platform
#2
Seiya Kitamura, Anna Owensby, Daniel Wall, Dennis W Wolan
As resistance to antibiotics increases, the exploration of new targets and strategies to combat pathogenic bacteria becomes more urgent. Ideal protein targets are required for viability across many species, are unique to prokaryotes to limit effects on the host, and have robust assays to quantitate activity and identify inhibitors. Lipoprotein signal peptidase (Lsp) is a transmembrane aspartyl protease required for lipoprotein maturation and comprehensively fits these criteria. Here, we have developed the first in vitro high-throughput assay to monitor proteolysis by Lsp...
January 10, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29307840/robust-prediction-of-resistance-to-trimethoprim-in-staphylococcus-aureus
#3
Philip W Fowler, Kevin Cole, N Claire Gordon, Angela M Kearns, Martin J Llewelyn, Tim E A Peto, Derrick W Crook, A Sarah Walker
The rise of antibiotic resistance threatens modern medicine; to combat it new diagnostic methods are required. Sequencing the whole genome of a pathogen offers the potential to accurately determine which antibiotics will be effective to treat a patient. A key limitation of this approach is that it cannot classify rare or previously unseen mutations. Here we demonstrate that alchemical free energy methods, a well-established class of methods from computational chemistry, can successfully predict whether mutations in Staphylococcus aureus dihydrofolate reductase confer resistance to trimethoprim...
January 4, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29307841/ros-mediated-15-hydroxyprostaglandin-dehydrogenase-degradation-via-cysteine-oxidation-promotes-nad-mediated-epithelial-mesenchymal-transition
#4
Weixuan Wang, Yadong Hu, Xiaofei Wang, Qingtao Wang, Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) levels decrease with aging as a result of aging-associated CD38 upregulation. Here, we established a cell model with decreased cellular NAD levels by overexpressing CD38 or treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase. We revealed that decreased NAD triggered reactive oxygen species (ROS)-mediated degradation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which drove cells to undergo epithelial-mesenchymal transition (EMT). Moreover, we showed that oxidation of the Cys44 residue to sulfonic acid in 15-PGDH led to its degradation via non-canonical ubiquitination-proteasome and autophagy pathways...
December 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29290624/acid-tolerant-monomeric-gfp-from-olindias-formosa
#5
Hajime Shinoda, Yuanqing Ma, Ryosuke Nakashima, Keisuke Sakurai, Tomoki Matsuda, Takeharu Nagai
The fluorescent protein (FP) color palette has greatly contributed to the visualization of molecular and cellular processes. However, most FPs lose fluorescence at a pH lower than their neutral pKa (∼6), and this has hampered their application in acidic organelles (pH ∼4.5-6.0). Currently, several cyan- and red-colored acid-tolerant FPs are available; however, there are few reports of acid-tolerant green FPs (GFPs) that are practically applicable to bioimaging. Here, we developed the acid-tolerant monomeric GFP "Gamillus" from the jellyfish Olindias formosa, with excellent brightness, maturation speed, and photostability...
December 23, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29290623/identification-of-new-activators-of-mitochondrial-fusion-reveals-a-link-between-mitochondrial-morphology-and-pyrimidine-metabolism
#6
Laia Miret-Casals, David Sebastián, José Brea, Eva M Rico-Leo, Manuel Palacín, Pedro M Fernández-Salguero, M Isabel Loza, Fernando Albericio, Antonio Zorzano
Mitochondria are dynamic organelles that produce most of the cellular ATP, and are involved in many other cellular functions such as Ca2+ signaling, differentiation, apoptosis, cell cycle, and cell growth. One key process of mitochondrial dynamics is mitochondrial fusion, which is catalyzed by mitofusins (MFN1 and MFN2) and OPA1. The outer mitochondrial membrane protein MFN2 plays a relevant role in the maintenance of mitochondrial metabolism, insulin signaling, and mutations that cause neurodegenerative disorders...
December 23, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29307839/target-identification-and-mechanism-of-action-of-picolinamide-and-benzamide-chemotypes-with-antifungal-properties
#7
Verena Pries, Christina Nöcker, Danish Khan, Philipp Johnen, Zebin Hong, Ashutosh Tripathi, Anna-Lena Keller, Michael Fitz, Francesca Perruccio, Ireos Filipuzzi, Sasikala Thavam, Thomas Aust, Ralph Riedl, Slava Ziegler, Fulvia Bono, Gabriel Schaaf, Vytas A Bankaitis, Herbert Waldmann, Dominic Hoepfner
Invasive fungal infections are accompanied by high mortality rates that range up to 90%. At present, only three different compound classes are available for use in the clinic, and these often suffer from low bioavailability, toxicity, and drug resistance. These issues emphasize an urgent need for novel antifungal agents. Herein, we report the identification of chemically versatile benzamide and picolinamide scaffolds with antifungal properties. Chemogenomic profiling and biochemical assays with purified protein identified Sec14p, the major phosphatidylinositol/phosphatidylcholine transfer protein in Saccharomyces cerevisiae, as the sole essential target for these compounds...
December 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29290622/a-decade-of-click-chemistry-in-protein-palmitoylation-impact-on-discovery-and-new-biology
#8
REVIEW
Xinxin Gao, Rami N Hannoush
Protein palmitoylation plays diverse roles in regulating the trafficking, stability, and activity of cellular proteins. The advent of click chemistry has propelled the field of protein palmitoylation forward by providing specific, sensitive, rapid, and easy-to-handle methods for studying protein palmitoylation. This year marks the 10th anniversary since the first click chemistry-based fatty acid probes for detecting protein lipid modifications were reported. The goal of this review is to highlight key biological advancements in the field of protein palmitoylation during the past 10 years...
December 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29276048/specific-inhibition-of-the-bifunctional-farnesyl-geranylgeranyl-diphosphate-synthase-in-malaria-parasites-via-a-new-small-molecule-binding-site
#9
Jolyn E Gisselberg, Zachary Herrera, Lindsey M Orchard, Manuel Llinás, Ellen Yeh
The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compound, MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS...
December 15, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29276047/overcoming-resistance-to-the-thz-series-of-covalent-transcriptional-cdk-inhibitors
#10
Yang Gao, Tinghu Zhang, Hideki Terai, Scott B Ficarro, Nicholas Kwiatkowski, Ming-Feng Hao, Bandana Sharma, Camilla L Christensen, Edmond Chipumuro, Kwok-Kin Wong, Jarrod A Marto, Peter S Hammerman, Nathanael S Gray, Rani E George
Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12...
December 15, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29276046/drug-target-commons-a-community-effort-to-build-a-consensus-knowledge-base-for-drug-target-interactions
#11
Jing Tang, Zia-Ur-Rehman Tanoli, Balaguru Ravikumar, Zaid Alam, Anni Rebane, Markus Vähä-Koskela, Gopal Peddinti, Arjan J van Adrichem, Janica Wakkinen, Alok Jaiswal, Ella Karjalainen, Prson Gautam, Liye He, Elina Parri, Suleiman Khan, Abhishekh Gupta, Mehreen Ali, Laxman Yetukuri, Anna-Lena Gustavsson, Brinton Seashore-Ludlow, Anne Hersey, Andrew R Leach, John P Overington, Gretchen Repasky, Krister Wennerberg, Tero Aittokallio
Knowledge of the full target space of bioactive substances, approved and investigational drugs as well as chemical probes, provides important insights into therapeutic potential and possible adverse effects. The existing compound-target bioactivity data resources are often incomparable due to non-standardized and heterogeneous assay types and variability in endpoint measurements. To extract higher value from the existing and future compound target-profiling data, we implemented an open-data web platform, named Drug Target Commons (DTC), which features tools for crowd-sourced compound-target bioactivity data annotation, standardization, curation, and intra-resource integration...
December 15, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29249694/objective-quantitative-data-driven-assessment-of-chemical-probes
#12
Albert A Antolin, Joseph E Tym, Angeliki Komianou, Ian Collins, Paul Workman, Bissan Al-Lazikani
Chemical probes are essential tools for understanding biological systems and for target validation, yet selecting probes for biomedical research is rarely based on objective assessment of all potential compounds. Here, we describe the Probe Miner: Chemical Probes Objective Assessment resource, capitalizing on the plethora of public medicinal chemistry data to empower quantitative, objective, data-driven evaluation of chemical probes. We assess >1.8 million compounds for their suitability as chemical tools against 2,220 human targets and dissect the biases and limitations encountered...
December 14, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29276045/phodags-enable-optical-control-of-diacylglycerol-sensitive-transient-receptor-potential-channels
#13
Trese Leinders-Zufall, Ursula Storch, Katherin Bleymehl, Michael Mederos Y Schnitzler, James A Frank, David B Konrad, Dirk Trauner, Thomas Gudermann, Frank Zufall
Diacylglycerol-sensitive transient receptor potential (TRP) channels play crucial roles in a wide variety of biological processes and systems, but their activation mechanism is not well understood. We describe an optical toolkit by which activation and deactivation of these ion channels can be controlled with unprecedented speed and precision through light stimuli. We show that the photoswitchable diacylglycerols PhoDAG-1 and PhoDAG-3 enable rapid photoactivation of two DAG-sensitive TRP channels, Trpc2 and TRPC6, upon stimulation with UV-A light, whereas exposure to blue light terminates channel activation...
December 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29249695/gdc-0879-a-brafv600e-inhibitor-protects-kidney-podocytes-from-death
#14
Jonas Sieber, Nicolas Wieder, Abbe Clark, Manuel Reitberger, Sofia Matan, Jeannine Schoenfelder, Jianming Zhang, Anna Mandinova, Joshua Adam Bittker, Juan Gutierrez, Ozan Aygün, Namrata Udeshi, Steven Carr, Peter Mundel, Andreas Werner Jehle, Anna Greka
Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds...
December 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29249693/site-specific-installation-of-succinyl-lysine-analog-into-histones-reveals-the-effect-of-h2bk34-succinylation-on-nucleosome-dynamics
#15
Yihang Jing, Zheng Liu, Gaofei Tian, Xiucong Bao, Toyotaka Ishibashi, Xiang David Li
Posttranslational modifications of histones play key roles in the dynamic regulation of chromatin structure. Lysine succinylation is a new type of histone modification, but its biological significance in chromatin structure and dynamics remains unknown. Here we develop a chemical approach to site-specifically install a succinyl lysine analog into histones. This analog serves as an ideal structural and functional mimic to natural succinyl lysine. The incorporation of this succinylation mimic into histone H2B at lysine 34, a succinylation site at the nucleosomal DNA-histone interface, leads to significant decrease in nucleosome stability in vitro, which is consistent with the defects in chromatin structure of a budding yeast strain containing a lysine-to-glutamate mutation at the corresponding residue of yeast histone H2B...
December 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29233521/the-elements-of-translational-chemical-biology
#16
REVIEW
Robert A Copeland, P Ann Boriack-Sjodin
A causal relationship between target activity modulation by small molecules and phenotypic consequence is the cornerstone of chemical biology and drug discovery. Here we articulate elements of translational chemical biology, as guideposts to ensure the appropriate use of chemical probes and the conclusions drawn from cellular studies with these molecules.
November 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29198567/conserved-lipid-and-small-molecule-modulation-of-coq8-reveals-regulation-of-the-ancient-kinase-like-ubib-family
#17
Andrew G Reidenbach, Zachary A Kemmerer, Deniz Aydin, Adam Jochem, Molly T McDevitt, Paul D Hutchins, Jaime L Stark, Jonathan A Stefely, Thiru Reddy, Alex S Hebert, Emily M Wilkerson, Isabel E Johnson, Craig A Bingman, John L Markley, Joshua J Coon, Matteo Dal Peraro, David J Pagliarini
Human COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 and its direct role in CoQ production remain unclear, in part due to lack of known endogenous regulators of COQ8 function and of effective small molecules for probing its activity in vivo. Here, we demonstrate that COQ8 possesses evolutionarily conserved ATPase activity that is activated by binding to membranes containing cardiolipin and by phenolic compounds that resemble CoQ pathway intermediates...
November 24, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29174541/engineered-multivalent-sensors-to-detect-coexisting-histone-modifications-in-living-stem-cells
#18
Aurore M-F Delachat, Nora Guidotti, Andreas L Bachmann, Antonio C A Meireles-Filho, Horst Pick, Carolin C Lechner, Cédric Deluz, Bart Deplancke, David M Suter, Beat Fierz
The regulation of fundamental processes such as gene expression or cell differentiation involves chromatin states, demarcated by combinatorial histone post-translational modification (PTM) patterns. The subnuclear organization and dynamics of chromatin states is not well understood, as tools for their detection and modulation in live cells are lacking. Here, we report the development of genetically encoded chromatin-sensing multivalent probes, cMAPs, selective for bivalent chromatin, a PTM pattern associated with pluripotency in embryonic stem cells (ESCs)...
November 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29198568/nosp-regulated-nosiheptide-production-responds-to-both-peptidyl-and-small-molecule-ligands-derived-from-the-precursor-peptide
#19
Jingjing Li, Yue Li, Guoqing Niu, Heng Guo, Yanping Qiu, Zhi Lin, Wen Liu, Huarong Tan
Nosiheptide, an archetypal member of thiopeptide antibiotics, arises from post-translational modifications of a ribosomally synthesized precursor peptide that contains an N-terminal leader peptide (LP) sequence and a C-terminal core peptide (CP) sequence. Despite extensive efforts concerning the biosynthesis of thiopeptide antibiotics, the regulatory mechanisms in this process remain poorly understood. Using the nosiheptide-producing Streptomyces actuosus strain as a model system, we report here that NosP, a Streptomyces antibiotic regulatory protein, serves as the only cluster-situated regulator and activates the transcription of all structural genes, which are organized into two divergently transcribed operons in the nos cluster, by binding to their intergenic region...
November 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29153851/apobec-enzymes-as-targets-for-virus-and-cancer-therapy
#20
REVIEW
Margaret E Olson, Reuben S Harris, Daniel A Harki
Human DNA cytosine-to-uracil deaminases catalyze mutations in both pathogen and cellular genomes. APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H restrict human immunodeficiency virus 1 (HIV-1) infection in cells deficient in the viral infectivity factor (Vif), and have the potential to catalyze sublethal levels of mutation in viral genomes in Vif-proficient cells. At least two APOBEC3 enzymes, and in particular APOBEC3B, are sources of somatic mutagenesis in cancer cells that drive tumor evolution and may manifest clinically as recurrence, metastasis, and/or therapy resistance...
November 14, 2017: Cell Chemical Biology
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