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ACS Chemical Biology

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https://www.readbyqxmd.com/read/29156135/fluorescent-probes-of-dna-repair
#1
David L Wilson, Eric T Kool
DNA repair is now understood to play a key role in a variety of disease states, most notably cancer. Tools for studying DNA have typically relied on traditional biochemical methods which are often laborious and indirect. Efforts to study the biology and therapeutic relevance of DNA repair pathways can be limited by such methods. Recently, specific fluorescent probes have been developed to aid in the study of DNA repair. Fluorescent probes offer the advantage of being able to directly assay for DNA repair activity in a simple, mix-and-measure format...
November 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29155548/site-selective-rna-splicing-nanozyme-dnazyme-and-rtcb-conjugates-on-a-gold-nanoparticle
#2
Jessica R Petree, Kevin Yehl, Kornelia Galior, Roxanne Glazier, Brendan Deal, Khalid Salaita
Modifying RNA through either splicing or editing is a fundamental biological process for creating protein diversity from the same genetic code. Developing novel chemical biology tools for RNA editing has potential to transiently edit genes and to provide a better understanding of RNA biochemistry. Current techniques used to modify RNA include the use of ribozymes, adenosine deaminase and tRNA endonucleases. Herein, we report a nanozyme that is capable of splicing of virtually any RNA stem-loop. This nanozyme is comprised of a gold nanoparticle functionalized with three enzymes: two catalytic DNA strands with ribonuclease function and an RNA ligase...
November 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29140075/strictosidine-synthase-triggered-enantioselective-synthesis-of-n-substituted-s-3-14-18-19-tetrahydroangustines-as-novel-topoisomerase-i-inhibitors
#3
Yunrui Cai, Huajian Zhu, Zaccary Alperstein, Wenjun Yu, Artem Cherkasov, Hongbin Zou
Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and these have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved Topoisomerase I (Top1) inhibitors. The enzyme STR1, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities...
November 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29096064/a-mononuclear-iron-dependent-methyltransferase-catalyzes-initial-steps-in-assembly-of-the-apratoxin-a-polyketide-starter-unit
#4
Meredith A Skiba, Andrew P Sikkema, Nathan A Moss, Collin L Tran, Rebecca M Sturgis, Lena Gerwick, William H Gerwick, David H Sherman, Janet L Smith
Natural product biosynthetic pathways contain a plethora of enzymatic tools to carry out difficult biosynthetic transformations. Here, we discover an unusual mononuclear iron-dependent methyltransferase that acts in the initiation steps of apratoxin A biosynthesis (AprA MT1). Fe(3+)-replete AprA MT1 catalyzes one or two methyl transfer reactions on the substrate malonyl-ACP (acyl carrier protein), whereas Co(2+), Fe(2+), Mn(2+), and Ni(2+) support only a single methyl transfer. MT1 homologues exist within the "GNAT" (GCN5-related N-acetyltransferase) loading modules of several modular biosynthetic pathways with propionyl, isobutyryl, or pivaloyl starter units...
November 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29083855/repair-of-a-site-specific-dna-cleavage-old-school-lessons-for-cas9-mediated-gene-editing
#5
Danielle N Gallagher, James E Haber
CRISPR/Cas9-mediated gene editing may involve nonhomologous end-joining to create various insertion/deletions (indels) or may employ homologous recombination to modify precisely the target DNA sequence. Our understanding of these processes has been guided by earlier studies using other site-specific endonucleases, both in model organisms such as budding yeast and in mammalian cells. We briefly review what has been gleaned from such studies using the HO and I-SceI endonucleases and how these findings guide current gene editing strategies...
November 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29131570/identification-and-characterisation-of-dual-inhibitors-of-the-usp25-28-deubiquitinating-enzyme-subfamily
#6
Jonathan D Wrigley, Gerald Gavory, Iain Simpson, Marian Preston, Helen Plant, Jenna Bradley, Anne U Goeppert, Ewelina Rozycka, Gareth Davies, Jarrod Walsh, Andrea Valentine, Keeva McClelland, Krzysztofa Ewa Odrzywol, Jonathan Renshaw, Joanna Boros, Jonathan Tart, Lindsey Leach, Thorsten Nowak, Richard A Ward, Timothy Harrison, David M Andrews
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and whilst displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29131568/diisonitrile-natural-product-sf2768-functions-as-a-chalkophore-that-mediates-copper-acquisition-in-streptomyces-thioluteus
#7
Lijuan Wang, Mengyi Zhu, Qingbo Zhang, Xu Zhang, Panlei Yang, Zihui Liu, Yun Deng, Yiguang Zhu, Xueshi Huang, Li Han, Shengqing Li, Jing He
A non-ribosomal peptide synthetase (NRPS) gene cluster (sfa) was identified in Streptomyces thioluteus to direct the biosynthesis of the diisonitrile antibiotic SF2768. Its biosynthetic pathway was reasonably proposed based on bioinformatics analysis, metabolic profiles of mutants and the elucidation of the intermediate and shunt product structures. Bioinformatics-based alignment found a putative ATP-binding cassette (ABC) transporter related to iron import within the biosynthetic gene cluster, which implied that the product might be a siderophore...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29088528/microfluidic-enabled-intracellular-delivery-of-membrane-impermeable-inhibitors-to-study-target-engagement-in-human-primary-cells
#8
Jing Li, Bu Wang, Brian M Juba, Michael Vazquez, Steve W Kortum, Betsy S Pierce, Michael Pacheco, Lee Roberts, Joseph W Strohbach, Lyn H Jones, Erik Hett, Atli Thorarensen, Jean-Baptiste Telliez, Armon Sharei, Mark Bunnage, Jonathan Brian Gilbert
Biochemical screening is a major source of lead generation for novel targets. However, during the process of small molecule lead optimization, compounds with excellent biochemical activity may show poor cellular potency, making structure-activity relationships difficult to decipher. This may be due to low membrane permeability of the molecule, resulting in insufficient intracellular drug concentration. The Cell Squeeze platform increases permeability regardless of compound structure by mechanically disrupting the membrane, which can overcome permeability limitations and bridge the gap between biochemical and cellular studies...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29125738/profiling-of-protein-o-glcnacylation-in-murine-cd8-effector-and-memory-like-t-cells
#9
Aime Lopez Aguilar, Yu Gao, Xiaomeng Hou, Gregoire Lauvau, John R Yates, Peng Wu
During an acute infection, antigenic stimulation leads to activation, expansion, and differentiation of naïve CD8(+) T cells, first into cytotoxic effector cells and eventually into long-lived memory cells. T cell antigen receptors (TCRs) detect antigens on antigen-presenting cells (APCs) in the form of antigenic peptides bound to major histocompatibility complex I (MHC-I)-encoded molecules and initiate TCR signal transduction network. This process is mediated by phosphorylation of many intracellular signaling proteins...
November 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29125730/development-of-a-protease-biosensor-based-on-a-dimerization-dependent-red-fluorescent-protein
#10
Aaron C Mitchell, Spencer C Alford, Sean A Hunter, Deepti Kannan, R Andres Parra Sperberg, Cheryl H Chang, Jennifer R Cochran
Dysregulated activity of the protease matriptase is a key contributor to aggressive tumor growth, cancer metastasis, osteoarthritis, and iron overload disease. Methods for the detection and quantification of matriptase activity and inhibition would be useful tools. To address this need, we developed a matriptase-sensitive protein biosensor based on a dimerization-dependent red fluorescent protein (ddRFP) reporter system. In this platform, two adjoining protein domains, connected by a protease-labile linker, produce fluorescence when assembled and are non-fluorescent when the linker is cleaved by matriptase...
November 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29112373/structure-activity-relationships-of-the-s-linked-glycocin-sublancin
#11
Subhanip Biswas, Chantal V Garcia De Gonzalo, Lindsay M Repka, Wilfred A van der Donk
Sublancin is a 37-amino acid antimicrobial peptide belonging to the glycocin family of natural products. It contains two helices that are held together by two disulfide bonds as well as an unusual S-glucosidic linkage to a Cys in a loop connecting the helices. We report the reconstitution of the biosynthetic pathway to this natural product in Escherichia coli. This technology enabled the evaluation of the structure-activity relationships of the solvent-exposed residues in the helices. The biosynthetic machinery proved tolerant of changes in both helices, and the bioactivity studies of the resulting mutants show that two residues in helix B are important for bioactivity, Asn31 and Arg33...
November 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29121465/co-culture-of-marine-invertebrate-associated-bacteria-and-interdisciplinary-technologies-enable-biosynthesis-and-discovery-of-a-new-antibiotic-keyicin
#12
Navid Adnani, Marc Chevrette, Srikar N Adibhatla, Fan Zhang, Qing Yu, Doug R Braun, Justin Nelson, Scott W Simpkins, Bradon R McDonald, Chad L Myers, Jeff S Piotrowski, Christopher J Thompson, Cameron R Currie, Lingjun Li, Scott R Rajski, Tim S Bugni
Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such "cryptic" or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions...
November 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29121460/diverse-class-2-crispr-cas-effector-proteins-for-genome-engineering-applications
#13
Neena K Pyzocha, Sidi Chen
CRISPR-Cas genome editing technologies have revolutionized modern molecular biology by making targeted DNA edits simple and scalable. These technologies are developed by domesticating naturally occurring microbial adaptive immune systems that display wide diversity of functionality for targeted nucleic acid cleavage. Several CRISPR-Cas single effector enzymes have been characterized and engineered for use in mammalian cells. The unique properties of the single effector enzymes can make a critical difference in experimental use or targeting specificity...
November 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29087175/global-awakening-of-cryptic-biosynthetic-gene-clusters-in-burkholderia-thailandensis
#14
Ashish Gupta, Renesh Bedre, Sudarshan Singh Thapa, Afsana Sabrin, Guannan Wang, Maheshi Dassanayake, Anne Grove
Many bacteria encode biosynthetic proteins that produce a vast array of natural products. These compounds are often synthesized during host invasion as they function as virulence factors. In addition, such secondary metabolites have yielded numerous molecular scaffolds with pharmaceutical and clinical importance. The gene clusters that encode proteins responsible for synthesis of these compounds are typically silenced or "cryptic" under laboratory growth conditions, hampering discovery of novel lead compounds...
November 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29058870/using-a-specific-rna-protein-interaction-to-quench-the-fluorescent-rna-spinach
#15
Laura Roszyk, Sebastian Kollenda, Sven Hennig
RNAs are involved in interaction networks with other biomolecules and are crucial for proper cell function. Yet their biochemical analysis remains challenging. For Förster Resonance Energy Transfer (FRET), a common tool to study such interaction networks, two interacting molecules have to be fluorescently labeled. "Spinach" is a genetically encodable RNA aptamer that starts to fluoresce upon binding of an organic molecule. Therefore, it is a biological fluorophore tag for RNAs. However, spinach has never been used in a FRET assembly before...
November 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29053920/turn-on-fluorene-push-pull-probes-with-high-brightness-and-photostability-for-visualizing-lipid-order-in-biomembranes
#16
Janah Shaya, Mayeul Collot, Frédéric Bénailly, Najiba Mahmoud, Yves Mély, Benoît Y Michel, Andrey S Klymchenko, Alain Burger
The rational design of environmentally sensitive dyes with superior properties is critical for elucidating the fundamental biological processes and understanding the biophysical behavior of cell membranes. In this study, a novel group of fluorene-based push-pull probes was developed for imaging membrane lipids. The design of these fluorogenic conjugates is based on a propioloyl linker to preserve the required spectroscopic features of the core dye. This versatile linker allowed the introduction of a polar deoxyribosyl head, a lipophilic chain, and an amphiphilic/anchoring group to tune the cell membrane binding and internalization...
November 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29112372/tuning-the-color-palette-of-fluorescent-copper-sensors-through-systematic-heteroatom-substitution-at-rhodol-cores
#17
Shang Jia, Karla M Ramos-Torres, Safacan Kolemen, Cheri M Ackerman, Christopher J Chang
Copper is an essential nutrient for sustaining life, and emerging data have expanded the roles of this metal in biology from its canonical functions as a static enzyme cofactor to dynamic functions as a transition metal signal. At the same time, loosely bound, labile copper pools can trigger oxidative stress and damaging events that are detrimental if misregulated. The signal/stress dichotomy of copper motivates the development of new chemical tools to study its spatial and temporal distributions in native biological contexts such as living cells...
November 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29111666/switching-cyclic-nucleotide-selective-activation-of-pka-holoenzyme-reveals-distinct-roles-of-tandem-cnb-domains
#18
Daniel He, Robin Lorenz, Choel Kim, Friedrich W Herberg, Chinten James Lim
The cAMP- and cGMP-dependent protein kinases (PKA and PKG) are key effectors of cyclic nucleotide signaling. Both share structural features that include tandem cyclic nucleotide-binding (CNB) domains, CNB-A and CNB-B, yet their functions are separated through preferential activation by either cAMP or cGMP. Based on structural studies and modeling, key CNB contact residues have been identified for both kinases. In this study, we explored the requirements for conversion of PKA activation from cAMP-dependent to cGMP-dependent...
November 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29073357/luciferase-activity-of-insect-fatty-acyl-coa-synthetases-with-synthetic-luciferins
#19
David M Mofford, Kate L Liebmann, Ganapathy Subramanian Sankaran, G S Kiran Kumar Reddy, G Randheer Reddy, Stephen C Miller
Long-chain fatty acyl-CoA synthetases (ACSLs) are homologues of firefly luciferase but are incapable of emitting light with firefly luciferin. Recently, we found that an ACSL from the fruit fly Drosophila melanogaster is a latent luciferase that will emit light with the synthetic luciferin CycLuc2. Here, we have profiled a panel of three insect ACSLs with a palette of >20 luciferin analogues. An ACSL from the nonluminescent beetle Agrypnus binodulus (AbLL) was found to be a second latent luciferase with distinct substrate specificity...
November 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29072450/ebselen-mechanisms-of-glutamate-dehydrogenase-and-glutaminase-enzyme-inhibition
#20
Yan Yu, Yanhong Jin, Jie Zhou, Haoqiang Ruan, Han Zhao, Shiying Lu, Yue Zhang, Di Li, Xiaoyun Ji, Benfang Helen Ruan
Ebselen modulates target proteins through redox reactions with selenocysteine/cysteine residues, or through binding to the zinc finger domains. However, a recent contradiction in ebselen inhibition of kidney type glutaminase (KGA) stimulated our interest in investigating its inhibition mechanism with glutamate dehydrogenase (GDH), KGA, thioredoxin reductase (TrxR), and glutathione S-transferase. Fluorescein- or biotin-labeled ebselen derivatives were synthesized for mechanistic analyses. Biomolecular interaction analyses showed that only GDH, KGA, and TrxR proteins can bind to the ebselen derivative, and the binding to GDH and KGA could be competed off by glutamine or glutamate...
November 7, 2017: ACS Chemical Biology
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