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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28529131/the-structure-of-the-guanidine-ii-riboswitch
#1
Lin Huang, Jia Wang, David M J Lilley
The guanidine-II (mini-ykkC) riboswitch is the smallest of the guanidine-responsive riboswitches, comprising two stem loops of similar sequence. We have solved high-resolution crystal structures of both stem loops for the riboswitch from Gloeobacter violaceus. The stem loops have a strong propensity to dimerize by intimate loop-loop interaction. The dimerization creates specific binding pockets for two guanidine molecules, explaining their cooperative binding. Within the binding pockets the ligands are hydrogen bonded to a guanine at O6 and N7, and to successive backbone phosphates...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28529132/efficient-selective-removal-of-human-pluripotent-stem-cells-via-ecto-alkaline-phosphatase-mediated-aggregation-of-synthetic-peptides
#2
Yi Kuang, Kenji Miki, Callum J C Parr, Karin Hayashi, Ikue Takei, Jie Li, Mio Iwasaki, Masato Nakagawa, Yoshinori Yoshida, Hirohide Saito
The incomplete differentiation of human induced pluripotent stem cells (iPSCs) poses a serious safety risk owing to their potential tumorigenicity, hindering their clinical application. Here, we explored the potential of phospho-D-peptides as novel iPSC-eliminating agents. Alkaline phosphatases overexpressed on iPSCs dephosphorylate phospho-D-peptides into hydrophobic peptides that aggregate and induce cell death. We isolated a peptide candidate, D-3, that selectively and rapidly induced toxicity in iPSCs within 1 hr but had little influence on various non-iPSCs, including primary hepatocytes and iPSC-derived cardiomyocytes...
May 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28479296/the-mammalian-malonyl-coa-synthetase-acsf3-is-required-for-mitochondrial-protein-malonylation-and-metabolic-efficiency
#3
Caitlyn E Bowman, Susana Rodriguez, Ebru S Selen Alpergin, Michelle G Acoba, Liang Zhao, Thomas Hartung, Steven M Claypool, Paul A Watkins, Michael J Wolfgang
Malonyl-coenzyme A (malonyl-CoA) is a central metabolite in mammalian fatty acid biochemistry generated and utilized in the cytoplasm; however, little is known about noncanonical organelle-specific malonyl-CoA metabolism. Intramitochondrial malonyl-CoA is generated by a malonyl-CoA synthetase, ACSF3, which produces malonyl-CoA from malonate, an endogenous competitive inhibitor of succinate dehydrogenase. To determine the metabolic requirement for mitochondrial malonyl-CoA, ACSF3 knockout (KO) cells were generated by CRISPR/Cas-mediated genome editing...
April 26, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525771/return-of-the-ice-age-caspases-safeguard-against-inflammatory-cell-death
#4
Marcin Poreba, Guy Salvesen
In a recent issue of Cell Chemical Biology, Taabazuing et al. (2017) reveal a bidirectional interplay between pathways leading to apoptosis and pyroptosis, two forms of regulated cell death with opposing inflammatory outcomes. The outcome is sealed by differential cleavage of the key pyroptosis execution substrate gasdermin D such that inflammatory caspases activate it but apoptotic caspases prevent its activation.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525770/-expand-and-click-a-new-method-for-labeling-hiv-1-envelope-glycoproteins
#5
Melissa V Fernandez, Eric O Freed
In this issue of Cell Chemical Biology, Sakin et al. (2017) investigate the nanoscale behavior of the HIV-1 envelope (Env) glycoprotein complex by using genetic code expansion, bioorthogonal amino acids, synthetic dyes, and click chemistry. This minimally invasive approach allows the measurement of native Env cellular distribution and dynamics.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525769/turning-the-light-on-in-the-phenotypic-drug-discovery-black-box
#6
John G Moffat
In this issue, Drawnel et al. (2017) introduce the concept of a "molecular phenotype" and demonstrate how "big data" coming from gene expression profiling, combined with signaling pathway information, small-molecule chemical information, preclinical animal models, and clinical samples can empower phenotypic discovery at several critical levels.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525768/hsp60-takes-a-hit-inhibition-of-mitochondrial-protein-folding
#7
Sundararajan Venkatesh, Carolyn K Suzuki
In this issue of Cell Chemical Biology,Wiechmann et al. (2017) identify mitochondrial chaperonin HSP60 as a direct target of myrtucommulone (MC), a nonprenylated acylphloroglucinol that is well known for its apoptotic activity in cancer cells. The authors propose MC as a chemical probe to study HSP60 biology and a potential chemotherapeutic agent in treating cancer and other HSP60-associated diseases.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525767/uncovering-the-cellular-target-of-agelastatin-a
#8
Yongho Park, Brian B Liau
McClary et al. (2017) identify the eukaryotic ribosome as a cellular target of agelastatin A, resolving the long-standing mystery surrounding the cytotoxic natural product's mechanism of action. Structural and modeling studies further pinpointed the molecule's binding site to the ribosome peptidyl transferase center, revealing key molecular interactions that drive binding.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525766/rationalizing-the-right-ratios
#9
Johannes Arp, Pierre Stallforth
The three hydroxamate siderophores, avaroferrin, bisucaberin, and putrebactin are synthesized by the same key enzyme AvbD. Rütschlin et al. (2017) show that the ratio of these three compounds is not governed by the enzyme's substrate specificity but rather by the substrate pool. This ensures a large metabolic flexibility and adaptability to new environments.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525765/covalent-probe-finds-carboxylic-acid
#10
Alexander Jones, Xiaoyun Zhang, Xiaoguang Lei
In this issue of Cell Chemical Biology, Martín-Gago et al. (2017a) disclose a new strategy for the selective covalent targeting of binding site carboxylic acids within the proteome using the isoxazolium salt as a warhead. This discovery paves the way for developing new protein ligation methods as well as covalent drug candidates.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525764/two-are-better-than-one-dual-targeting-of-riboswitches-by-metabolite-analogs
#11
Stefanie Sandra Krajewski, Dmitry Ignatov, Jörgen Johansson
In this issue of Cell Chemical Biology, Wang et al. (2017) examine the effect of the novel synthetic molecule ribocil-C and the natural compound roseoflavin in Gram-positive pathogens. In methicillin-resistant Staphylococcus aureus (MRSA), ribocil-C and roseoflavin target two autonomous riboswitches simultaneously, thereby inhibiting de novo synthesis and uptake of riboflavin.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525763/principles-of-chemical-biology-from-antibiotic-resistance-to-rna-targeted-therapy-via-autoxidation-and-lipid-droplets
#12
(no author information available yet)
This month: Ribosome mutations and multi-antibiotic resistance, role of autoxidation in ferroptosis, ceramide metabolism, and finding RNA drug targets.
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28457707/mitochondrial-chaperonin-hsp60-is-the-apoptosis-related-target-for-myrtucommulone
#13
Katja Wiechmann, Hans Müller, Stefanie König, Natalie Wielsch, Aleš Svatoš, Johann Jauch, Oliver Werz
The acylphloroglucinol myrtucommulone A (MC) causes mitochondrial dysfunctions by direct interference leading to apoptosis in cancer cells, but the molecular targets involved are unknown. Here, we reveal the chaperonin heat-shock protein 60 (HSP60) as a molecular target of MC that seemingly modulates HSP60-mediated mitochondrial functions. Exploiting an unbiased, discriminative protein fishing approach using MC as bait and mitochondrial lysates from leukemic HL-60 cells as target source identified HSP60 as an MC-binding protein...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28457706/a-versatile-tool-for-live-cell-imaging-and-super-resolution-nanoscopy-studies-of-hiv-1-env-distribution-and-mobility
#14
Volkan Sakin, Janina Hanne, Jessica Dunder, Maria Anders-Össwein, Vibor Laketa, Ivana Nikić, Hans-Georg Kräusslich, Edward A Lemke, Barbara Müller
The envelope glycoproteins (Env) of HIV-1 mediate cell entry through fusion of the viral envelope with a target cell membrane. Intramembrane mobility and clustering of Env trimers at the viral budding site are essential for its function. Previous live-cell and super-resolution microscopy studies were limited by lack of a functional fluorescent Env derivative, requiring antibody labeling for detection. Introduction of a bio-orthogonal amino acid by genetic code expansion, combined with click chemistry, offers novel possibilities for site-specific, minimally invasive labeling...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28457705/inhibition-of-eukaryotic-translation-by-the-antitumor-natural-product-agelastatin-a
#15
Brandon McClary, Boris Zinshteyn, Mélanie Meyer, Morgan Jouanneau, Simone Pellegrino, Gulnara Yusupova, Anthony Schuller, Jeremy Chris P Reyes, Junyan Lu, Zufeng Guo, Safiat Ayinde, Cheng Luo, Yongjun Dang, Daniel Romo, Marat Yusupov, Rachel Green, Jun O Liu
Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28434878/molecular-phenotyping-combines-molecular-information-biological-relevance-and-patient-data-to-improve-productivity-of-early-drug-discovery
#16
Faye Marie Drawnel, Jitao David Zhang, Erich Küng, Natsuyo Aoyama, Fethallah Benmansour, Andrea Araujo Del Rosario, Sannah Jensen Zoffmann, Frédéric Delobel, Michael Prummer, Franziska Weibel, Coby Carlson, Blake Anson, Roberto Iacone, Ulrich Certa, Thomas Singer, Martin Ebeling, Marco Prunotto
Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28434877/one-enzyme-three-metabolites-shewanella-algae-controls-siderophore-production-via-the-cellular-substrate-pool
#17
Sina Rütschlin, Sandra Gunesch, Thomas Böttcher
Shewanella algae B516 produces avaroferrin, an asymmetric hydroxamate siderophore, which has been shown to inhibit swarming motility of Vibrio alginolyticus. We aimed to elucidate the biosynthesis of this siderophore and to investigate how S. algae coordinates the production of avaroferrin and its two symmetric counterparts. We reconstituted the reaction in vitro with the main enzyme AvbD and the putative biosynthetic precursors, and demonstrate that multispecificity of this enzyme results in the production of all three cyclic hydroxamate siderophores that were previously isolated as natural products from S...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28434876/dual-targeting-small-molecule-inhibitors-of-the-staphylococcus-aureus-fmn-riboswitch-disrupt-riboflavin-homeostasis-in-an-infectious-setting
#18
Hao Wang, Paul A Mann, Li Xiao, Charles Gill, Andrew M Galgoci, John A Howe, Artjohn Villafania, Christopher M Barbieri, Juliana C Malinverni, Xinwei Sher, Todd Mayhood, Megan D McCurry, Nicholas Murgolo, Amy Flattery, Matthias Mack, Terry Roemer
Riboswitches are bacterial-specific, broadly conserved, non-coding RNA structural elements that control gene expression of numerous metabolic pathways and transport functions essential for cell growth. As such, riboswitch inhibitors represent a new class of potential antibacterial agents. Recently, we identified ribocil-C, a highly selective inhibitor of the flavin mononucleotide (FMN) riboswitch that controls expression of de novo riboflavin (RF, vitamin B2) biosynthesis in Escherichia coli. Here, we provide a mechanistic characterization of the antibacterial effects of ribocil-C as well as of roseoflavin (RoF), an antimetabolite analog of RF, among medically significant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28434875/covalent-protein-labeling-at-glutamic-acids
#19
Pablo Martín-Gago, Eyad K Fansa, Michael Winzker, Sandip Murarka, Petra Janning, Carsten Schultz-Fademrecht, Matthias Baumann, Alfred Wittinghofer, Herbert Waldmann
Covalent labeling of amino acids in proteins by reactive small molecules, in particular at cysteine SH and lysine NH groups, is a powerful approach to identify and characterize proteins and their functions. However, for the less-reactive carboxylic acids present in Asp and Glu, hardly any methodology is available. Employing the lipoprotein binding chaperone PDE6δ as an example, we demonstrate that incorporation of isoxazolium salts that resemble the structure and reactivity of Woodward's reagent K into protein ligands provides a novel method for selective covalent targeting of binding site carboxylic acids in whole proteomes...
May 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28416276/synthesis-and-degradation-of-adenosine-5-tetraphosphate-by-nicotinamide-and-nicotinate-phosphoribosyltransferases
#20
Adolfo Amici, Ambra A Grolla, Erika Del Grosso, Roberta Bellini, Michele Bianchi, Cristina Travelli, Silvia Garavaglia, Leonardo Sorci, Nadia Raffaelli, Silverio Ruggieri, Armando A Genazzani, Giuseppe Orsomando
Adenosine 5'-tetraphosphate (Ap4) is a ubiquitous metabolite involved in cell signaling in mammals. Its full physiological significance remains unknown. Here we show that two enzymes committed to NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPT), can both catalyze the synthesis and degradation of Ap4 through their facultative ATPase activity. We propose a mechanism for this unforeseen additional reaction, and demonstrate its evolutionary conservation in bacterial orthologs of mammalian NAMPT and NAPT...
May 18, 2017: Cell Chemical Biology
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