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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28434876/dual-targeting-small-molecule-inhibitors-of-the-staphylococcus-aureus-fmn-riboswitch-disrupt-riboflavin-homeostasis-in-an-infectious-setting
#1
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...
April 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
#2
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...
April 17, 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
#3
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...
April 13, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28434875/covalent-protein-labeling-at-glutamic-acids
#4
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...
April 13, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28416275/cisplatin-analogs-confer-protection-against-cyanide-poisoning
#5
Anjali K Nath, Xu Shi, Devin L Harrison, Jordan E Morningstar, Sari Mahon, Adriano Chan, Patrick Sips, Jangwoen Lee, Calum A MacRae, Gerry R Boss, Matthew Brenner, Robert E Gerszten, Randall T Peterson
Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cyanide kills organisms as diverse as insects, fish, and humans within seconds to hours. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro...
April 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28416276/synthesis-and-degradation-of-adenosine-5-tetraphosphate-by-nicotinamide-and-nicotinate-phosphoribosyltransferases
#6
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...
April 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28163016/discovering-targets-of-non-enzymatic-acylation-by-thioester-reactivity-profiling
#7
Rhushikesh A Kulkarni, Andrew J Worth, Thomas T Zengeya, Jonathan H Shrimp, Julie M Garlick, Allison M Roberts, David C Montgomery, Carole Sourbier, Benjamin K Gibbs, Clementina Mesaros, Yien Che Tsai, Sudipto Das, King C Chan, Ming Zhou, Thorkell Andresson, Allan M Weissman, W Marston Linehan, Ian A Blair, Nathaniel W Snyder, Jordan L Meier
Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of non-enzymatic acylation, including several enzymes in lower glycolysis...
January 31, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28431225/retraction-notice-to-targeting-mycobacterial-enzymes-with-natural-products
#8
Elwira Sieniawska
No abstract text is available yet for this article.
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28431224/adp-ribosylation-goes-normal-serine-as-the-major-site-of-the-modification
#9
Qiang Liu, Bogdan I Florea, Dmitri V Filippov
Proteins containing adenosine diphosphate ribosylserine as a posttranslational modification are widespread and formed via HPF1-assisted, PARP-1-mediated PARylation as Bonfiglio et al. (2017) report in a recent issue of Molecular Cell.
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28431223/pink1-based-screen-shines-light-on-autophagy-enhancers-for-parkinson-s-disease
#10
Dominik Haddad, Ken Nakamura
In this issue of Cell Chemical Biology, Zhang et al. (2017) report a zebrafish model of Parkinson's disease (PD), incorporating the PD-protein PINK1 and rotenone, a toxin linked to PD. Using it as a drug-screening platform, they identify trifluoperazine and other piperazine phenothiazines as protective compounds that enhance autophagy independent of PINK1.
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28431222/principles-of-chemical-biology-from-magic-to-gut-fungi-via-plug-and-play-biosensors
#11
(no author information available yet)
This month: New MAGIC linking mitochondrial biology and proteostasis, split RNA polymerase based biosensors, and a role that fungi play in human gut microbiome.
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28431221/a-shout-out-to-chemical-biology-a-multidisciplinary-field-par-excellence
#12
EDITORIAL
Milka Kostic
No abstract text is available yet for this article.
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28392148/molecular-insight-into-evolution-of-symbiosis-between-breast-fed-infants-and-a-member-of-the-human-gut-microbiome-bifidobacterium-longum
#13
Chihaya Yamada, Aina Gotoh, Mikiyasu Sakanaka, Mitchell Hattie, Keith A Stubbs, Ayako Katayama-Ikegami, Junko Hirose, Shin Kurihara, Takatoshi Arakawa, Motomitsu Kitaoka, Shujiro Okuda, Takane Katayama, Shinya Fushinobu
Breast-fed infants generally have a bifidobacteria-rich microbiota with recent studies indicating that human milk oligosaccharides (HMOs) selectively promote bifidobacterial growth. Bifidobacterium bifidum possesses a glycoside hydrolase family 20 lacto-N-biosidase for liberating lacto-N-biose I from lacto-N-tetraose, an abundant HMO unique to human milk, while Bifidobacterium longum subsp. longum has a non-classified enzyme (LnbX). Here, we determined the crystal structure of the catalytic domain of LnbX and provide evidence for creation of a novel glycoside hydrolase family, GH136...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28392147/pyroptosis-and-apoptosis-pathways-engage-in-bidirectional-crosstalk-in-monocytes-and-macrophages
#14
Cornelius Y Taabazuing, Marian C Okondo, Daniel A Bachovchin
Pyroptosis is a lytic form of programmed cell death mediated by the inflammatory caspase-1, -4, and -5. We recently discovered that small-molecule inhibitors of the serine peptidases DPP8 and DPP9 (DPP8/9) induce pro-caspase-1-dependent pyroptosis in monocytes and macrophages. Notably, DPP8/9 inhibitors, unlike microbial agents, absolutely require caspase-1 to induce cell death. Therefore, DPP8/9 inhibitors are useful probes to study caspase-1 in cells. Here, we show that, in the absence of the pyroptosis-mediating substrate gasdermin D (GSDMD), caspase-1 activates caspase-3 and -7 and induces apoptosis, demonstrating that GSDMD is the only caspase-1 substrate that induces pyroptosis...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28392146/a-small-molecule-inhibitor-of-bax-and-bak-oligomerization-prevents-genotoxic-cell-death-and-promotes-neuroprotection
#15
Xin Niu, Hetal Brahmbhatt, Philipp Mergenthaler, Zhi Zhang, Jing Sang, Michael Daude, Fabian G R Ehlert, Wibke E Diederich, Eve Wong, Weijia Zhu, Justin Pogmore, Jyoti P Nandy, Maragani Satyanarayana, Ravi K Jimmidi, Prabhat Arya, Brian Leber, Jialing Lin, Carsten Culmsee, Jing Yi, David W Andrews
Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28392145/hdac-inhibitor-induced-mitotic-arrest-is-mediated-by-eg5-kif11-acetylation
#16
Dhanusha A Nalawansha, Inosha D Gomes, Magdalene K Wambua, Mary Kay H Pflum
Histone deacetylase 1 (HDAC1) is an epigenetic enzyme that regulates key cellular processes, such as cell proliferation, apoptosis, and cell survival, by deacetylating histone substrates. Aberrant expression of HDAC1 is implicated in multiple diseases, including cancer. As a consequence, HDAC inhibitors have emerged as effective anti-cancer drugs. HDAC inhibitor-induced G0/G1 cell-cycle arrest has been attributed to epigenetic transcriptional changes mediated by histone acetylation. However, the mechanism of G2/M arrest remains poorly understood...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28366621/rescue-of-pink1-deficiency-by-stress-dependent-activation-of-autophagy
#17
Yuxi Zhang, David T Nguyen, Ellen M Olzomer, Gin P Poon, Nicholas J Cole, Anita Puvanendran, Brigitte R Phillips, Daniel Hesselson
Stimulating autophagy is a promising therapeutic strategy for slowing the progression of neurodegenerative disease. Neurons are insensitive to current approaches based on mTOR inhibition for activating autophagy, and instead may rely on the Parkinson's disease-associated proteins PINK1 and PARKIN to activate the autophagy-lysosomal pathway in response to mitochondrial damage. We developed a multifactorial zebrafish drug-screening platform combining Pink1 deficiency with an environmental toxin to compromise mitochondrial function and trigger dopaminergic neuron loss...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28366620/a-ratiometric-sensor-for-imaging-insulin-secretion-in-single-%C3%AE-cells
#18
Martina Schifferer, Dmytro A Yushchenko, Frank Stein, Andrey Bolbat, Carsten Schultz
Despite the urgent need for assays to visualize insulin secretion there is to date no reliable method available for measuring insulin release from single cells. To address this need, we developed a genetically encoded reporter termed RINS1 based on proinsulin superfolder GFP (sfGFP) and mCherry fusions for monitoring insulin secretion. RINS1 expression in MIN6 β cells resulted in proper processing yielding single-labeled insulin species. Unexpectedly, glucose or drug stimulation of insulin secretion in β cells led to the preferential release of the insulin-sfGFP construct, while the mCherry-fused C-peptide remained trapped in exocytic granules...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28343940/lithocholic-acid-hydroxyamide-destabilizes-cyclin-d1-and-induces-g0-g1-arrest-by-inhibiting-deubiquitinase-usp2a
#19
Katarzyna Magiera, Marcin Tomala, Katarzyna Kubica, Virginia De Cesare, Matthias Trost, Bartosz J Zieba, Neli Kachamakova-Trojanowska, Marcin Les, Grzegorz Dubin, Tad A Holak, Lukasz Skalniak
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28330605/polyubiquitin-photoactivatable-crosslinking-reagents-for-mapping-ubiquitin-interactome-identify-rpn1-as-a-proteasome-ubiquitin-associating-subunit
#20
Michal Chojnacki, Wissam Mansour, Dharjath S Hameed, Rajesh K Singh, Farid El Oualid, Rina Rosenzweig, Mark A Nakasone, Zanlin Yu, Fabian Glaser, Lewis E Kay, David Fushman, Huib Ovaa, Michael H Glickman
Ubiquitin (Ub) signaling is a diverse group of processes controlled by covalent attachment of small protein Ub and polyUb chains to a range of cellular protein targets. The best documented Ub signaling pathway is the one that delivers polyUb proteins to the 26S proteasome for degradation. However, studies of molecular interactions involved in this process have been hampered by the transient and hydrophobic nature of these interactions and the lack of tools to study them. Here, we develop Ub-phototrap (Ub(PT)), a synthetic Ub variant containing a photoactivatable crosslinking side chain...
April 20, 2017: Cell Chemical Biology
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