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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28085251/differential-ability-of-five-dna-glycosylases-to-recognize-and-repair-damage-on-nucleosomal-dna
#1
Eric D Olmon, Sarah Delaney
Damage to genomic DNA leads to mutagenesis and disease. Repair of single base damage is initiated by DNA glycosylases, the first enzymes in the base excision repair pathway. Although eukaryotic packaging of chromosomal DNA in nucleosomes is known to decrease DNA glycosylase efficiency, the impact on individual glycosylases is unclear. Here, we present a model system in which we examine the repair of site-specific base damage in well-characterized nucleosome core particles by five different DNA glycosylases...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28085246/genetic-organization-of-anabaenopeptin-and-spumigin-biosynthetic-gene-clusters-in-the-cyanobacterium-sphaerospermopsis-torques-reginae-itep-024
#2
Stella T Lima, Danillo O Alvarenga, Augusto Etchegaray, David P Fewer, Jouni Jokela, Alessandro M Varani, Miriam Sanz, Felipe A Dörr, Ernani Pinto, Kaarina Sivonen, Marli F Fiore
Cyanobacteria produce a broad range of natural products many of which are potent protease inhibitors. Biosynthetic gene clusters encoding the production of novel protease inhibitors belonging to the spumigin and anabaenopeptin family of non-ribosomal peptides were identified in the genome of the bloom-forming cyanobacterium Sphaerospermopsis torques-reginae ITEP-024. The genetic architecture and gene organization of both non-ribosomal peptide biosynthetic clusters were compared in parallel with their chemical structure variations obtained by liquid chromatography (LC-MS/MS)...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28084722/novel-triazole-piperazine-hybrid-molecules-induce-apoptosis-via-activation-of-the-mitochondrial-pathway-and-exhibit-anti-tumor-efficacy-in-osteosarcoma-xenograft-nude-mice-model
#3
Chandra Bhushan Mishra, Raj Kumar Mongre, Shikha Kumari, Dong Kee Jeong, Manisha Tiwari
Mitochondria imparts crucial role in the regulation of programmed cell death, reactive oxygen species (ROS) generation besides serving as a primary energy source. Mitochondria appeared as an important target for therapy of cancer due to its significant contribution in cell survival and death. Here, we report the design and synthesis of a novel series of triazole-piperazine hybrids as potent anticancer agents. MCS-5 emerged as an excellent anticancer agent which showed better anticancer activity than standard drug Doxorubicin in-vitro and in-vivo studies...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28059499/inactivation-of-the-nuclear-orphan-receptor-coup-tfii-by-small-chemicals
#4
Rémy Le Guével, Frédérik Oger, Celia P Martinez-Jimenez, Maud Bizot, Céline Gheeraert, François Firmin, Maheul Ploton, Miroslava Kretova, Gaëlle Palierne, Bart Staels, Peter Barath, Iannis Talianidis, Philippe Lefebvre, Jérôme Eeckhoute, Gilles Salbert
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan member of the nuclear receptor family of transcription factors whose activities are modulated upon binding of small molecules into an hydrophobic ligand-binding pocket (LBP). Although the LBP of COUP-TFII is filled with aromatic amino-acid side chains, alternative modes of ligand binding could potentially lead to regulation of the orphan receptor. Here, we screened a synthetic and natural compound library in a yeast one-hybrid assay and identified 4-methoxynaphthol as an inhibitor of COUP-TFII...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28045490/an-allosteric-inhibitor-scaffold-targeting-the-pif-pocket-of-atypical-protein-kinase-c-isoforms
#5
Jose M Arencibia, Wolfgang Fröhner, Magdalena Krupa, Daniel Pastor-Flores, Piotr Merker, Thomas Oellerich, Sonja Neimanis, Christian Schmithals, Verena Köberle, Evelyn Süß, Stefan Zeuzem, Holger Stark, Albrecht Piiper, Dalibor Odadzic, Jörg O Schulze, Ricardo M Biondi
There is a current and pressing need for improved cancer therapies. The use of small molecule kinase inhibitors and their application in combinatorial regimens represent an approach to personalized targeted cancer therapy. A number of AGC kinases, including atypical Protein Kinase C enzymes (PKCs), are validated drug targets for cancer treatment. Most drug development programs for protein kinases focus on the development of drugs that bind at the ATP-binding site. Alternatively, allosteric drugs have great potential for the development of future innovative drugs...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28032983/two-flavoenzymes-catalyze-the-post-translational-generation-of-5-chlorotryptophan-and-2-aminovinyl-cysteine-during-nai-107-biosynthesis
#6
Manuel A Ortega, Dillon P Cogan, Subha Mukherjee, Neha Garg, Bo Li, Gabrielle N Thibodeaux, Sonia I Maffioli, Stefano Donadio, Margherita Sosio, Jerome Escano, Leif Smith, Satish K Nair, Wilfred A van der Donk
Lantibiotics are ribosomally synthesized and post-translationally modified antimicrobial peptides containing thioether rings. In addition to these cross-links, the clinical candidate lantibiotic NAI-107 also possesses a C-terminal S-[(Z)-2-aminovinyl]-d-cysteine (AviCys) and a unique 5-chloro-l-tryptophan (ClTrp) moiety linked to its potent bioactivity. Bioinformatic and genetic analyses on the NAI-107 biosynthetic gene cluster identified mibH and mibD as genes encoding flavoenzymes responsible for the formation of ClTrp and AviCys, respectively...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28060484/a-highly-promiscuous-%C3%A3-ketoacyl-acp-synthase-kas-iii-like-protein-is-involved-in-pactamycin-biosynthesis
#7
Mostafa E Abugrain, Corey J Brumsted, Andrew R Osborn, Benjamin Philmus, Taifo Mahmud
β-Ketoacyl-acyl carrier protein (β-Ketoacyl-ACP) synthase (KAS) III catalyzes the first step in fatty acid biosynthesis, involving a Claisen condensation of the acetyl-CoA starter unit with the first extender unit, malonyl-ACP, to form acetoacetyl-ACP. KAS III-like proteins have also been reported to catalyze acyltransferase reactions using coenzyme A esters or discrete ACP-bound substrates. Here, we report the in vivo and in vitro characterizations of a KAS III-like protein (PtmR), which directly transfers a 6-methylsalicylyl moiety from an iterative type I polyketide synthase to an aminocyclopentitol unit in pactamycin biosynthesis...
January 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28051309/chemical-modifications-to-rna-a-new-layer-of-gene-expression-regulation
#8
Jinghui Song, Chengqi Yi
The first chemical modification to RNA was discovered nearly 60 years ago; to date, more than 100 chemically distinct modifications have been identified in cellular RNA. With the recent development of novel chemical and/or biochemical methods, dynamic modifications to RNA have been identified in the transcriptome, including N(6)-methyladenosine (m(6)A), inosine (I), 5-methylcytosine (m(5)C), pseudouridine (Ψ), 5-hydroxymethylcytosine (hm(5)C), and N(1)-methyladenosine (m(1)A). Collectively, the multitude of RNA modifications are termed epitranscriptome, leading to the emerging field of epitranscriptomics...
January 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28045484/development-of-autologous-c5-vaccine-nanoparticles-to-reduce-intravascular-hemolysis-in-vivo
#9
Lingjun Zhang, Wen Qiu, Stephen Crooke, Yan Li, Areeba Abid, Bin Xu, M G Finn, Feng Lin
The complement system is emerging as a new target for treating many diseases. For example, Eculizumab, a humanized monoclonal antibody against complement component 5 (C5), has been approved for paroxysmal nocturnal hemoglobinuria (PNH) in which patient erythrocytes are lysed by complement. In this study, we developed vaccines to elicit autologous anti-C5 antibody production in mice for complement inhibition. Immunization of mice with a conservative C5 xenoprotein raised high titers of IgG's against the xenogenous C5, but these antibodies did not reduce C5 activity in the blood...
January 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28075556/biosynthesis-of-the-methylthioxylose-capping-motif-of-lipoarabinomannan-in-mycobacterium-tuberculosis
#10
Shiva Kumar Angala, Michael R McNeil, Libin Shi, Maju Joe, Ha Pham, Sophie Zuberogoitia, Jerome Nigou, Claudia M Boot, Todd L Lowary, Martine Gilleron, Mary Jackson
Lipoarabinomannan (LAM) is a lipoglycan found in abundant quantities in the cell envelope of all mycobacteria. The non-reducing arabinan termini of LAM display species-specific structural micro-heterogeneity that impacts the biological activity of the entire molecule. Mycobacterium tuberculosis, for instance, produces mannoside caps made of one to three α(1→2)-Manp-linked residues that may be further substituted with an α(1→4)-linked methylthio-D-xylose (MTX) residue. While the biological functions and catalytic steps leading to the formation of the mannoside caps of M...
January 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28075554/an-engineered-allele-of-afsq1-facilitates-the-discovery-and-investigation-of-cryptic-natural-products
#11
Martin Daniel-Ivad, Nabeela Hameed, Stephanie Tan, Rachna Dhanjal, Daniel Socko, Patricia Pak, Tomas Gverzdys, Marie A Elliot, Justin R Nodwell
New approaches to antimicrobial discovery are needed to address the growing threat of antibiotic resistance. The Streptomyces genus, a proven source of antibiotics, is recognized as having a large reservoir of untapped secondary metabolic genes, many of which are likely to produce uncharacterized compounds. However, most of these compounds are currently inaccessible, as they are not expressed under standard laboratory conditions. Here we present a novel methodology for activating these 'cryptic' metabolites by heterologously expressing a constitutively active pleiotropic regulator...
January 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28068062/sequence-defined-backbone-modifications-regulate-antibacterial-activity-of-oligoteas
#12
Mintu Porel, Dana N Thornlow, Christine M Artim, Christopher A Alabi
In response to the urgent need for new antibiotic development strategies, antimicrobial peptides (AMPs) and other synthetic polymers are being actively investigated as promising alternatives to traditional antibiotics. Although most AMPs display lytic activity against several types of bacteria, they have poor toxicology profiles and are susceptible to proteolysis in vivo. While many synthetic variants have been created to mimic AMPs by tuning the hydrophobic to cationic ratio of the side-chain groups, few have decoupled the effects of charge from hydrophobicity in discrete systems, and none have investigated the effect of backbone hydrophobicity...
January 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28068060/structural-and-functional-basis-of-c-methylation-of-coumarin-scaffolds-by-novo
#13
Joanna C Sadler, Chun-Wa Chung, Julie E Mosley, Glenn A Burley, Luke D Humphreys
C-methylation of aromatic small molecules by C-methyltransferases (C-MTs) is an important biological trans-formation that involves C-C bond formation using S-adenosyl-L-methionine (SAM) as the methyl donor. Here, two advanc-es in the mechanistic understanding of C-methylation of the 8-position of coumarin substrates catalyzed by the C-MT No-vO from Streptomyces Spheroides are described. First, a crystal structure of NovO reveals the Arg116-Asn117 and His120-Arg121 motifs are essential for coumarin substrate binding...
January 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28068059/subcellular-redox-targeting-bridging-in-vitro-and-in-vivo-chemical-biology
#14
Marcus J C Long, Jesse R Poganik, Souradyuti Ghosh, Yimon Aye
Networks of redox sensor proteins within discrete microdomains regulate the flow of redox signaling. Yet, the inherent reactivity of redox signals complicates the study of specific redox events and pathways by traditional methods. Herein, we review designer chemistries capable of measuring flux and/or mimicking subcellular redox signaling at the cellular and organismal level. Such efforts have begun to decipher the logic underlying organelle-, site-, and target-specific redox signaling in vitro and in vivo...
January 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28068058/extensive-turnover-of-compatible-solutes-in-cyanobacteria-revealed-by-deuterium-oxide-d2o-stable-isotope-probing
#15
Richard Baran, Rebecca Lau, Benjamin P Bowen, Spencer Diamond, Nick Jose, Ferran Garcia-Pichel, Trent R Northen
Cyanobacteria are important primary producers of organic matter in diverse environments on a global scale. While mechanisms of CO2 fixation are well understood, the distribution of the flow of fixed organic carbon within individual cells and complex microbial communities is less well characterized. To obtain a general overview of metabolism, we describe the use of deuterium oxide (D2O) to measure deuterium incorporation into the intracellular metabolites of two physiologically diverse cyanobacteria: a terrestrial filamentous strain (Microcoleus vaginatus PCC 9802) and a euryhaline unicellular strain (Synechococcus sp...
January 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/27984693/global-n-glycan-site-occupancy-of-hiv-1-gp120-by-metabolic-engineering-and-high-resolution-intact-mass-spectrometry
#16
Weston B Struwe, Alexandra Stuckmann, Anna-Janina Behrens, Kevin Pagel, Max Crispin
A vital step in HIV vaccine development strategies has been the observation that some infected individuals generate broadly neutralizing antibodies that target the glycans on the surface of HIV-1 gp120. These antibodies target glycan epitopes on viral envelope spikes, and yet the positions and degree of occupancy of glycosylation sites is diverse. Therefore, there is a need to understand glycosylation occupancy on recombinant immunogens. The sheer number of potential glycosylation sites and degree of chemical heterogeneity impedes assessing the global sequon occupancy of gp120 glycoforms...
January 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28032990/iterative-focused-screening-with-biological-fingerprints-identifies-selective-asc-1-inhibitors-distinct-from-traditional-high-throughput-screening
#17
Peter S Kutchukian, Lee Warren, Brian C Magliaro, Adam Amoss, Jason A Cassaday, Gregory O'Donnell, Brian Squadroni, Paul Zuck, Danette Pascarella, J Chris Culberson, Andrew J Cooke, Danielle Hurzy, Kelly-Ann Sondra Schlegel, Fiona Thomson, Eric N Johnson, Victor N Uebele, Jeffrey D Hermes, Sophie Parmentier-Batteur, Michael Finley
N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine-serine-cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs...
January 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28055183/deciphering-the-functions-of-protein-o-glcnacylation-with-chemistry
#18
Matthew Worth, Hao Li, Jiaoyang Jiang
O-GlcNAcylation is the modification of serine and threonine residues with β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. This dynamic modification is attached by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA), and is a critical regulator of various cellular processes. Furthermore, O-GlcNAcylation is dysregulated in many diseases, such as diabetes, cancer, and Alzheimer's disease. However, the precise role of this modification and its cycling enzymes (OGT and OGA) in normal and disease states remains elusive...
January 5, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28055182/arylsulfatase-k-is-the-lysosomal-2-sulfoglucuronate-sulfatase
#19
Omkar P Dhamale, Roger Lawrence, Elena M Wiegmann, Bhahwal A Shah, Kanar Al-Mafraji, William C Lamanna, Torben Lübke, Thomas Dierks, Geert-Jan Boons, Jeffrey D Esko
The degradation of glycosaminoglycans (GAGs) involves a series of exolytic glycosidases and sulfatases that act sequentially on the non-reducing end of the polysaccharide chain. Enzymes have been cloned that catalyze all of the known linkages with the exception of the removal of the 2-O-sulfate group from 2-sulfoglucuronate, which is found in heparan sulfate and dermatan sulfate. Here we show using synthetic disaccharide substrates that arylsulfatase K is the glucuronate-2-sulfatase. Arylsulfatase K acts selectively on 2-sulfoglucuronate and lacks activity against 2-sulfoiduronate, whereas iduronate-2-sulfatase (IDS) desulfates synthetic disaccharides containing 2-sulfoiduronate but not 2-sulfoglucuronate...
January 5, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28055181/fluorescent-branched-rnas-for-high-throughput-analysis-of-dbr1-enzyme-kinetics-and-inhibition
#20
Adam Katolik, Nathaniel E Clark, Nobuhiro Tago, Eric J Montemayor, P John Hart, Masad J Damha
We have developed fluorescent 2',5' branched RNAs (bRNA) that permit real time monitoring of RNA lariat (intron) debranching enzyme (Dbr1) kinetics. These compounds contain fluorescein (FAM) on the 5' arm of the bRNA that is effectively quenched by a vicinal dabcyl moiety on the 2' arm. Dbr1-mediated hydrolysis of the 2',5' linkage liberates the dabcyl-containing 2' arm, and induces a large increase in FAM fluorescence, thus resulting in a dark-to-bright reporter system for Dbr1 hydrolysis. We show that unlabeled bRNAs with non-native 2',5'-phosphodiester linkages, such as phosphoramidate or phosphorothioate, can inhibit Dbr1-mediated debranching with IC50 values in the low nanomolar range...
January 5, 2017: ACS Chemical Biology
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