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Cell Chemical Biology

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...
October 13, 2016: Cell Chemical Biology
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...
October 7, 2016: Cell Chemical Biology
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...
September 28, 2016: Cell Chemical Biology
Fernando Corrêa, Kevin H Gardner
Information transmission in biological signaling networks is commonly considered to be a unidirectional flow of information between protein partners. According to this view, many bacterial response regulator proteins utilize input receiver (REC) domains to "switch" functional outputs, using REC phosphorylation to shift pre-existing equilibria between inactive and active conformations. However, recent data indicate that output domains themselves also shift such equilibria, implying a "mutual inhibition" model...
August 9, 2016: Cell Chemical Biology
Benjamin M Vincent, Jean-Baptiste Langlois, Raja Srinivas, Alex K Lancaster, Ruth Scherz-Shouval, Luke Whitesell, Bruce Tidor, Stephen L Buchwald, Susan Lindquist
To cause disease, a microbial pathogen must adapt to the challenges of its host environment. The leading fungal pathogen Candida albicans colonizes nutrient-poor bodily niches, withstands attack from the immune system, and tolerates treatment with azole antifungals, often evolving resistance. To discover agents that block these adaptive strategies, we screened 300,000 compounds for inhibition of azole tolerance in a drug-resistant Candida isolate. We identified a novel indazole derivative that converts azoles from fungistatic to fungicidal drugs by selective inhibition of mitochondrial cytochrome bc1...
August 6, 2016: Cell Chemical Biology
Jakob Fuhrmann, Venkataraman Subramanian, Douglas J Kojetin, Paul R Thompson
Protein arginine phosphorylation is a recently discovered modification that affects multiple cellular pathways in Gram-positive bacteria. In particular, the phosphorylation of arginine residues by McsB is critical for regulating the cellular stress response. Given that the highly efficient protein arginine phosphatase YwlE prevents arginine phosphorylation under non-stress conditions, we hypothesized that this enzyme negatively regulates arginine phosphorylation and acts as a sensor of cell stress. To evaluate this hypothesis, we developed the first suite of highly potent and specific SO3-amidine-based YwlE inhibitors...
August 6, 2016: Cell Chemical Biology
Kai Liu, Chen Yu, Min Xie, Ke Li, Sheng Ding
Regenerative medicine aims to repair and regenerate injured tissues and restore their impaired functions. Recent developments in stem cell biology have attracted significant interest in their applications in regenerative medicine. Chemical approaches using small molecules have yielded exciting results in induction and differentiation of pluripotent stem cells, lineage conversion of somatic cells, and ex vivo as well as in vivo modulation of adult stem cells. In this review, we discuss recent progress, new insights, and future challenges of the chemical approaches in stem cell biology and regenerative medicine...
August 6, 2016: Cell Chemical Biology
Felix Broecker, Christopher E Martin, Erik Wegner, Jochen Mattner, Ju Yuel Baek, Claney L Pereira, Chakkumkal Anish, Peter H Seeberger
Infections with Clostridium difficile increasingly cause morbidity and mortality worldwide. Bacterial surface glycans including lipoteichoic acid (LTA) were identified as auspicious vaccine antigens to prevent colonization. Here, we report on the potential of synthetic LTA glycans as vaccine candidates. We identified LTA-specific antibodies in the blood of C. difficile patients. Therefore, we evaluated the immunogenicity of a semi-synthetic LTA-CRM197 glycoconjugate. The conjugate elicited LTA-specific antibodies in mice that recognized natural LTA epitopes on the surface of C...
August 6, 2016: Cell Chemical Biology
Adrian R Ferré-D'Amaré
Sequence-specific nucleic acid binding proteins do not recognize one sequence out of all possibilities; rather, they bind to many sequences with a range of affinities. In this issue of Cell Chemical Biology, Lin et al. (2016), describe the entire landscape of affinities between different RNA molecules and an RNA-binding protein, thus providing a comprehensive description of the factors affecting specificity.
October 20, 2016: Cell Chemical Biology
James A Shayman
Prostaglandins have been characterized as the metabolic products of arachidonic acid released from glycerophospholipids following hydrolysis by phospholipase A2s and enzymatic oxidation by the COX1 and COX2. In this issue of Cell Chemical Biology, Liu et al. (2016) examine the metabolism of 2-arachidonoyl-lyso-phosphatidylcholine and 2-arachidonoyl-lyso-phosphatidylethanolamine by COX2 and conversion to glycerolipid linked prostanoids, raising a series of interesting and important questions.
October 20, 2016: Cell Chemical Biology
Joan B Broderick, James D Moody
The human gut microbiome is the source of not only microbial diversity, but also of interesting chemical reactions and enzymology. An excellent example of this is CutC, an enzyme that makes trimethylamine (TMA). In this issue of Cell Chemical Biology, Bodea et al. (2016) show how CutC uses a glycyl radical to perform C-N bond cleavage needed for TMA production.
October 20, 2016: Cell Chemical Biology
Milka Kostic
Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our October 2016 selection includes systematic structural, biochemical, and cellular characterization of B-RAF inhibitors; connecting bacterial transporters with their physiologically relevant ligands; and rewiring yeast metabolism for industrial scale production of isoprenoids.
October 20, 2016: Cell Chemical Biology
John J Chen, Joseph C Genereux, Eul Hyun Suh, Vincent F Vartabedian, Bibiana Rius, Song Qu, Maria T A Dendle, Jeffery W Kelly, R Luke Wiseman
Transthyretin (TTR) is a tetrameric serum protein associated with multiple systemic amyloid diseases. In these disorders, TTR aggregates in extracellular environments through a mechanism involving rate-limiting dissociation of the tetramer to monomers, which then misfold and aggregate into soluble oligomers and amyloid fibrils that induce toxicity in distal tissues. Using an assay established herein, we show that highly destabilized, aggregation-prone TTR variants are secreted as both native tetramers and non-native conformations that accumulate as high-molecular-weight oligomers...
October 20, 2016: Cell Chemical Biology
Hui-Yun Liu, Qi Zhao, Tian-Peng Zhang, Yue Wu, Yun-Xia Xiong, Shi-Ke Wang, Yuan-Long Ge, Jin-Hui He, Peng Lv, Tian-Miao Ou, Jia-Heng Tan, Ding Li, Lian-Quan Gu, Jian Ren, Yong Zhao, Zhi-Shu Huang
G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel single-chain variable fragment (scFv) antibody, D1, with high binding selectivity for parallel G-quadruplexes in vitro and in vivo. Genome-wide chromatin immunoprecipitation using D1 and deep-sequencing revealed the consensus sequence for parallel G-quadruplex formation, which is characterized by G-rich sequence with a short loop size (<3 nt)...
October 20, 2016: Cell Chemical Biology
Jörg O Schulze, Giorgio Saladino, Katrien Busschots, Sonja Neimanis, Evelyn Süß, Dalibor Odadzic, Stefan Zeuzem, Valerie Hindie, Amanda K Herbrand, María-Natalia Lisa, Pedro M Alzari, Francesco L Gervasio, Ricardo M Biondi
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates...
October 20, 2016: Cell Chemical Biology
Jakob Franke, Christian Hertweck
Thioesters play essential roles in many biosynthetic pathways to fatty acids, esters, polyketides, and non-ribosomal peptides. Coenzyme A (CoA) and related phosphopantetheine thioesters are typically employed as activated acyl units for diverse C-C, C-O, and C-N coupling reactions. To study and control these enzymatic assembly lines in vitro and in vivo structurally simplified analogs such as N-acetylcysteamine (NAC) thioesters have been developed. This review gives an overview on experimental strategies enabled by synthetic NAC thioesters, such as the elucidation of complex biosynthetic pathways and enzyme mechanisms as well as precursor-directed biosynthesis and mutasynthesis...
October 20, 2016: Cell Chemical Biology
Hsuan-Chun Lin, Jing Zhao, Courtney N Niland, Brandon Tran, Eckhard Jankowsky, Michael E Harris
RNA binding proteins (RBPs) are typically involved in non-equilibrium cellular processes, and specificity can arise from differences in ground state, transition state, or product states of the binding reactions for alternative RNAs. Here, we use high-throughput methods to measure and analyze the RNA association kinetics and equilibrium binding affinity for all possible sequence combinations in the precursor tRNA binding site of C5, the essential protein subunit of Escherichia coli RNase P. The results show that the RNA sequence specificity of C5 arises due to favorable RNA-protein interactions that stabilize the transition state for association and bound enzyme-substrate complex...
October 20, 2016: Cell Chemical Biology
Laurie-Anne Payet, Mélanie Leroux, John C Willison, Akio Kihara, Ludovic Pelosi, Fabien Pierrel
Coenzyme Q (Q) is a redox lipid that is central for the energetic metabolism of eukaryotes. The biosynthesis of Q from the aromatic precursor 4-hydroxybenzoic acid (4-HB) is understood fairly well. However, biosynthetic details of how 4-HB is produced from tyrosine remain elusive. Here, we provide key insights into this long-standing biosynthetic problem by uncovering molecular details of the first and last reactions of the pathway in the yeast Saccharomyces cerevisiae, namely the deamination of tyrosine to 4-hydroxyphenylpyruvate by Aro8 and Aro9, and the oxidation of 4-hydroxybenzaldehyde to 4-HB by Hfd1...
October 20, 2016: Cell Chemical Biology
Harikanth Venkannagari, Patricia Verheugd, Jarkko Koivunen, Teemu Haikarainen, Ezeogo Obaji, Yashwanth Ashok, Mohit Narwal, Taina Pihlajaniemi, Bernhard Lüscher, Lari Lehtiö
Members of the human diphtheria toxin-like ADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation (MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available...
October 20, 2016: Cell Chemical Biology
Xueping Liu, Hoeke Abele Baarsma, Chung Hwee Thiam, Corinna Montrone, Barbara Brauner, Gisela Fobo, Julia-Sophie Heier, Sven Duscha, Melanie Königshoff, Veronique Angeli, Andreas Ruepp, Monica Campillos
Phenotypic drug discovery offers some advantages over target-based methods, mainly because it allows drug leads to be tested in systems that more closely model distinct disease states. However, a potential disadvantage is the difficulty of linking the observed phenotype to a specific cellular target. To address this problem, we developed DePick, a computational target de-convolution tool to determine targets specifically linked to small-molecule phenotypic screens. We applied DePick to eight publicly available screens and predicted 59 drug target-phenotype associations...
October 20, 2016: Cell Chemical Biology
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