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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28712747/selectivity-and-kinetic-requirements-of-hdac-inhibitors-as-progranulin-enhancers-for-treating-frontotemporal-dementia
#1
Angela She, Iren Kurtser, Surya A Reis, Krista Hennig, Jenny Lai, Audrey Lang, Wen-Ning Zhao, Ralph Mazitschek, Bradford C Dickerson, Joachim Herz, Stephen J Haggarty
Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression...
July 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28712746/formation-of-an-angular-aromatic-polyketide-from-a-linear-anthrene-precursor-via-oxidative-rearrangement
#2
Guixi Gao, Xiangyang Liu, Min Xu, Yemin Wang, Fei Zhang, Lijun Xu, Jin Lv, Qingshan Long, Qianjin Kang, Hong-Yu Ou, Ying Wang, Jürgen Rohr, Zixin Deng, Ming Jiang, Shuangjun Lin, Meifeng Tao
Bacterial aromatic polyketides are a group of natural products synthesized by polyketide synthases (PKSs) that show diverse structures and biological activities. They are structurally subclassified into linear, angular, and discoid aromatic polyketides, the formation of which is commonly determined by the shaping and folding of the poly-β-keto intermediates under the concerted actions of the minimal PKSs, cyclases and ketoreductases. Murayaquinone, found in several streptomycetes, possesses an unusual tricyclic angular aromatic polyketide core containing a 9,10-phenanthraquinone...
July 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28712745/the-ligand-binding-landscape-of-diacylglycerol-kinases
#3
Caroline E Franks, Sean T Campbell, Benjamin W Purow, Thurl E Harris, Ku-Lung Hsu
Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through ATP-dependent phosphorylation of the lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to study isoform-specific functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, ATP and small-molecule binding motifs of representative members from all five DGK subtypes...
July 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28669526/attenuating-staphylococcus-aureus-virulence-by-targeting-flotillin-protein-scaffold-activity
#4
Gudrun Koch, Charlotte Wermser, Ivan C Acosta, Lara Kricks, Stephanie T Stengel, Ana Yepes, Daniel Lopez
Scaffold proteins are ubiquitous chaperones that bind proteins and facilitate physical interaction of multi-enzyme complexes. Here we used a biochemical approach to dissect the scaffold activity of the flotillin-homolog protein FloA of the multi-drug-resistant human pathogen Staphylococcus aureus. We show that FloA promotes oligomerization of membrane protein complexes, such as the membrane-associated RNase Rny, which forms part of the RNA-degradation machinery called the degradosome. Cells lacking FloA had reduced Rny function and a consequent increase in the targeted sRNA transcripts that negatively regulate S...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28669525/mechanisms-of-skin-toxicity-associated-with-metabotropic-glutamate-receptor-5-negative-allosteric-modulators
#5
Falgun Shah, Antonia F Stepan, Alison O'Mahony, Sharlene Velichko, Alexandra E Folias, Christopher Houle, Christopher L Shaffer, John Marcek, Jessica Whritenour, Robert Stanton, Ellen L Berg
Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648376/sam68-allows-selective-targeting-of-human-cancer-stem-cells
#6
Yannick D Benoit, Ryan R Mitchell, Ruth M Risueño, Luca Orlando, Borko Tanasijevic, Allison L Boyd, Lili Aslostovar, Kyle R Salci, Zoya Shapovalova, Jennifer Russell, Masakatsu Eguchi, Diana Golubeva, Monica Graham, Anargyros Xenocostas, Michael R Trus, Ronan Foley, Brian Leber, Tony J Collins, Mickie Bhatia
Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs. Disruption of CBP-β-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction...
June 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648378/steroidogenic-metabolism-of-galeterone-reveals-a-diversity-of-biochemical-activities
#7
Mohammad Alyamani, Zhenfei Li, Michael Berk, Jianneng Li, Jingjie Tang, Sunil Upadhyay, Richard J Auchus, Nima Sharifi
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ(5),3β-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ(4)-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3β-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5β-reduced metabolites...
June 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648380/privileged-electrophile-sensors-a-resource-for-covalent-drug-development
#8
REVIEW
Marcus John Curtis Long, Yimon Aye
This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles...
June 10, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648379/targeted-protein-degradation-from-chemical-biology-to-drug-discovery
#9
REVIEW
Philipp M Cromm, Craig M Crews
Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches...
June 10, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28648377/chemical-tools-for-studying-tlr-signaling-dynamics
#10
REVIEW
Timo Oosenbrug, Michel J van de Graaff, Maaike E Ressing, Sander I van Kasteren
The detection of infectious pathogens is essential for the induction of antimicrobial immune responses. The innate immune system detects a wide array of microbes using a limited set of pattern-recognition receptors (PRRs). One family of PRRs with a central role in innate immunity are the Toll-like receptors (TLRs). Upon ligation, these receptors initiate signaling pathways culminating in the release of pro-inflammatory cytokines and/or type I interferons (IFN-I). In recent years, it has become evident that the specific subcellular location and timing of TLR activation affect signaling outcome...
June 9, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28625738/mechanisms-of-paradoxical-activation-of-ampk-by-the-kinase-inhibitors-su6656-and-sorafenib
#11
Fiona A Ross, Simon A Hawley, F Romana Auciello, Graeme J Gowans, Abdelmadjid Atrih, Douglas J Lamont, D Grahame Hardie
SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1...
June 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28602761/joining-forces-the-chemical-biology-medicinal-chemistry-continuum
#12
REVIEW
Alleyn T Plowright, Christian Ottmann, Michelle Arkin, Yves P Auberson, Henk Timmerman, Herbert Waldmann
The scientific advances being made across all disciplines are creating ever-increasing opportunities to enhance our knowledge of biological systems and how they relate to human disease. One of the central driving forces in discovering new medicines is medicinal chemistry, where the design and synthesis of novel compounds has led to multiple drugs. Chemical biology, sitting at the interface of many disciplines, has now emerged as a major contributor to the understanding of biological systems and is becoming an integral part of drug discovery...
June 1, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644957/chemical-probes-for-visualizing-intact-animal-and-human-brain-tissue
#13
REVIEW
Hei Ming Lai, Wai-Lung Ng, Steve M Gentleman, Wutian Wu
Newly developed tissue clearing techniques can be used to render intact tissues transparent. When combined with fluorescent labeling technologies and optical sectioning microscopy, this allows visualization of fine structure in three dimensions. Gene-transfection techniques have proved very useful in visualizing cellular structures in animal models, but they are not applicable to human brain tissue. Here, we discuss the characteristics of an ideal chemical fluorescent probe for use in brain and other cleared tissues, and offer a comprehensive overview of currently available chemical probes...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644956/sirt4-is-a-regulator-of-insulin-secretion
#14
Elma Zaganjor, Sejal Vyas, Marcia C Haigis
In a recent issue of Cell Metabolism, Anderson et al. (2017) report that SIRT4 regulates insulin sensitivity in the pancreas via activation of methylcrotonyl-CoA carboxylase 1 (MCCC1) by removal of dicarboxyacyl-lysine modifications. Thus, SIRT4 activates leucine catabolism and causes decreased secretion of insulin from the pancreas.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644955/turning-on-proteasomes
#15
Jan Henrik Krahn, Farnusch Kaschani, Markus Kaiser
While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644954/bacteria-and-the-fate-of-estrogen-in-the-environment
#16
William B Whitman
In this issue of Cell Chemical Biology, Chen et al. (2017) report that 4-hydroxyestrone and pyridinestrone acid are intermediates in the 4,5-seco pathway of aerobic estrogen degradation by the bacterium Sphingomonas. The authors identify a gene for 4-hydroxyestrone 4,5-dioxygenase and find it to be widely distributed in diverse proteobacteria, suggesting that this pathway is environmentally significant.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644953/helping-induced-hpscs-clean-up-their-act
#17
Ho-Chang Jeong, Hyuk-Jin Cha
Inhibition of the tumorigenic potential of human pluripotent stem cells (hPSCs) remains critically important for safe hPSC-based therapy. In this issue of Cell Chemical Biology, Kuang et al. (2017) reveal that the phospho-D-peptide D-3 efficiently induces death of residual hPSCs, but not of differentiated progenies, through high alkaline phosphatase activity in hPSCs.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644952/acsf3-and-mal-onate-adapted-mitochondria
#18
David B Lombard, Yingming Zhao
In this issue of Cell Chemical Biology, Bowman and colleagues show that the mitochondrial enzyme ACSF3 generates malonyl-CoA from malonate, in turn regulating metabolic flux and mitochondrial protein malonylation (Bowman et al., 2017). The study reveals a mechanism to generate mitochondrial malonyl-CoA and how this molecule impacts mitochondrial biology.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644951/principles-of-chemical-biology-from-sexy-fatty-acids-and-ebv-probes-to-anti-acid-antibiotic-via-post-biotics-and-host-microbe-metabolic-complementarity
#19
(no author information available yet)
This month: The role of fatty acids in sex determination; a probe to monitor and inhibit EBNA1 at the same time; a biological role for post-biotics; what happens when you mix microbes, hosts, and drugs; and an antibiotic that cross-protects with acid.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28602760/how-to-increase-brightness-of-near-infrared-fluorescent-proteins-in-mammalian-cells
#20
Anton A Shemetov, Olena S Oliinyk, Vladislav V Verkhusha
Numerous near-infrared (NIR) fluorescent proteins (FPs) were recently engineered from bacterial photoreceptors but lack of their systematic comparison makes researcher's choice rather difficult. Here we evaluated side-by-side several modern NIR FPs, such as blue-shifted smURFP and miRFP670, and red-shifted mIFP and miRFP703. We found that among all NIR FPs, miRFP670 had the highest fluorescence intensity in various mammalian cells. For instance, in common HeLa cells miRFP703, mIFP, and smURFP were 2-, 9-, and 53-fold dimmer than miRFP670...
June 22, 2017: Cell Chemical Biology
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