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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28426198/unified-biosynthetic-origin-of-the-benzodipyrrole-subunits-in-cc-1065
#1
Sheng Wu, Xiao-Hong Jian, Hua Yuan, Wen-Bing Jin, Yue Yin, Ling-Yun Wang, Juan Zhao, Gong-Li Tang
CC-1065 is the first characterized member of a family of naturally occurring antibiotics including yatakemycin and duocarmycins with exceptionally potent anti-tumor activity. CC-1065 contains three benzodipyrroles (1a-, 1b- and 1c-) of which 1a-subunit is remarkable by being composed of a cyclopropane ring, and the mechanism for the biological formation of benzodipyrrole rings remains elusive. Previously, biosynthetic studies of CC-1065 were limited to radioactively labelled precursor feeding experiments, which showed that tyrosine (Tyr) and serine (Ser) were incorporated into the two benzodipyrrole (1b- and 1c-) subunits via the same mode but that this was different from the key cyclopropabenzodipyrrole (1a-) subunit with N1-C2-C3 derived from Ser...
April 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28426192/profiling-cellular-substrates-of-lysine-acetyltransferases-gcn5-and-p300-with-orthogonal-labeling-and-click-chemistry
#2
Zhen Han, Chau-Wen Chou, Xiangkun Yang, Michael G Bartlett, Y George Zheng
p300 and GCN5 are two representative histone/lysine acetyltransferase (HAT/KAT) enzymes in mammalian cells. It was recently reported that they possess multiple acyltransferase activities including acetylation, propionylation, and butyrylation of the -amino group of lysine residues of histones and non-histone protein substrates. Although thousands of acetylated substrates and acetylation sites have been identified by mass spectrometry-based proteomic screening, our knowledge about protein acylation, especially the causative connection between individual KAT members and their substrates remain limited...
April 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28388047/new-acridine-thiourea-gold-i-anticancer-agents-targeting-the-nucleus-and-inhibiting-vasculogenic-mimicry
#3
Sergio A Pérez, Concepción de Haro, Consuelo Vicente, Antonio Donaire, Ana Zamora, Juraj Zajac, Hana Kostrhunova, Viktor Brabec, Delia Bautista, José Ruiz
Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro...
April 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28388044/disclosing-the-interaction-of-carbonic-anhydrase-ix-with-cullin-associated-nedd8-dissociated-protein-1-by-molecular-modeling-and-integrated-binding-measurements
#4
Martina Buonanno, Emma Langella, Nicola Zambrano, Mariangela Succoio, Emanuele Sasso, Vincenzo Alterio, Anna Di Fiore, Annamaria Sandomenico, Claudiu T Supuran, Andrea Scaloni, Simona Maria Monti, Giuseppina De Simone
Human Carbonic Anhydrase (hCA) IX is a membrane-associated member of the CA enzyme family, involved in solid tumor acidification. This enzyme is a marker of tumor hypoxia and a prognostic factor for several human cancers. In a recent paper, we showed that CA IX interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1), a nuclear protein involved in gene transcription and assembly of SCF ubiquitin ligase complexes. A functional role for this interaction was also identified, since lower CA IX levels were observed in cells with decreased CAND1 expression via shRNA-mediated interference...
April 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28418649/nature-s-selection-of-geranyl-group-as-a-trna-modification-the-effects-of-chain-length-on-base-pairing-specificity
#5
Phensinee Haruehanroengra, Sweta Vangaveti, Srivathsan V Ranganathan, Rui Wang, Alan Chen, Jia Sheng
The recently discovered geranyl modification on the 2-thio position of wobble U34 residues in tRNA(Glu), tRNA(Lys), and tRNA(Gln) in several bacteria has been found to enhance the U:G pairing specificity and reduce the frameshifting error during translation. It is a fundamentally interesting question why nature chose a C10 terpene group in tRNA systems. In this study, we explore the significance of the terpene length on base-paring stability and specificity using a series of 2-thiouridine analogues containing different lengths of carbon chains, namely, methyl- (C1), dimethylallyl- (C5), and farnesyl-modified (C15) 2-thiothymidines in a DNA duplex...
April 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28418235/discovery-of-the-showdomycin-gene-cluster-from-streptomyces-showdoensis-atcc-15227-yields-insight-into-the-biosynthetic-logic-of-c-nucleoside-antibiotics
#6
Kaisa Palmu, Petja Rosenqvist, Keshav Thapa, Yulia Ilina, Vilja Siitonen, Bikash Baral, Janne Mäkinen, Georgi Belogurov, Pasi Virta, Jarmo Niemi, Mikko Metsä-Ketelä
Nucleoside antibiotics are a large class of pharmaceutically relevant chemical entities, which exhibit a broad spectrum of biological activities. Most nucleosides belong to the canonical N-nucleoside family, where the heterocyclic unit is connected to the carbohydrate through a carbon-nitrogen bond. However, atypical C-nucleosides have been isolated from Streptomyces bacteria over 50 years ago, but the molecular basis for formation of these metabolites has been unknown. Here we have sequenced the genome of S...
April 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28414448/substrate-profiling-and-high-resolution-co-complex-crystal-structure-of-a-secreted-c11-protease-conserved-across-commensal-bacteria
#7
Emily J Roncase, Clara Moon, Sandip Chatterjee, Gonzalo E González-Páez, Charles S Craik, Anthony J O'Donoghue, Dennis W Wolan
Cysteine proteases are among the most abundant hydrolytic enzymes produced by bacteria, and this diverse family of proteins have significant biological roles in bacterial viability and environmental interactions. Members of the clostripain-like (C11) family of cysteine proteases from distal gut commensal strains have recently been shown to mediate immune responses by inducing neutrophil phagocytosis and activating bacterial pathogenic toxins. Development of substrates, inhibitors, and probes that target C11 proteases from enteric bacteria will help to establish the role of these proteins at the interface of the host and microbiome in health and disease...
April 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28414420/systematic-synthesis-and-binding-study-of-hiv-v3-glycopeptides-reveal-the-fine-epitopes-of-several-broadly-neutralizing-antibodies
#8
Jared Orwenyo, Hui Cai, John Giddens, Mohammed N Amin, Christian Toonstra, Lai-Xi Wang
A class of new glycan-reactive broadly neutralizing antibodies represented by PGT121, 10-1074 and PGT128 has recently been discovered that target specific N-glycans and peptide region around the V3 domain. However, the glycan specificity and fine epitopes of these bNAbs remain to be further defined. We report here a systematic chemoenzymatic synthesis of homogeneous V3 glycopeptides derived from HIV-1 JR-FL strain carrying defined N-glycans at N332, N301 and N295 sites. Antibody binding studies revealed that both the nature and site of glycosylation in the context of the V3 domain were critical for high-affinity binding...
April 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28414209/polypharmacological-in-silico-bioactivity-profiling-and-experimental-validation-uncovers-sedative-hypnotic-effects-of-approved-and-experimental-drugs-in-rat
#9
Georgios Drakakis, Keith A Wafford, Suzanne C Brewerton, Michael J Bodkin, David A Evans, Andreas Bender
In this work, we describe the computational ('in silico') mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side-effects for 491 compounds tested in rat, we defined an 'optimal' (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases, corresponding to 75%), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles...
April 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28406289/phylogenomic-analysis-of-the-microviridin-biosynthetic-pathway-coupled-with-targeted-chemoenzymatic-synthesis-yields-potent-protease-inhibitors
#10
Muhammad N Ahmed, Emmanuel Reyna González, Bianca Schmid, Vincent Wiebach, Roderich Suessmuth, Elke Dittmann, David P Fewer
Natural products and their semi-synthetic derivatives are an important source of drugs for the pharmaceutical industry. Bacteria are prolific producers of natural products and encode a vast diversity of natural product biosynthetic gene clusters. However, much of this diversity is inaccessible to natural product discovery. Here we use a combination of phylogenomic analysis of the microviridin biosynthetic pathway and chemo-enzymatic synthesis of bioinformatically predicted microviridins to yield new protease inhibitors...
April 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28402100/structural-studies-revealed-active-site-distortions-of-human-furin-by-a-small-molecule-inhibitor
#11
Sven O Dahms, Guan-Sheng Jiao, Manuel E Than
Proprotein Convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of several pathologies including cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Here we present the first experimental complex of furin with a non substrate-like small molecule inhibitor, and the X-ray structure of the enzyme complexed to the small molecule inhibitor 1 at 1.9 Å resolution. Two molecules of inhibitor 1 were found to interact with furin...
April 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28355059/membrane-oxidation-in-cell-delivery-and-cell-killing-applications
#12
Ting-Yi Wang, M Daben J Libardo, Alfredo M Angeles-Boza, Jean-Philippe Pellois
Cell delivery or cell killing processes often involve the crossing or disruption of cellular membranes. We review how, by modifying the composition and properties of membranes, membrane oxidation can be exploited to enhance the delivery of macromolecular cargoes into live human cells. We also describe how membrane oxidation can be utilized to achieve efficient killing of bacteria by antimicrobial peptides. Finally, we present recent evidence highlighting how membrane oxidation is intimately engaged in natural biological processes such as antigen delivery in dendritic cells and in the killing of bacteria by antimicrobial peptides...
April 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28345875/reactive-oxygen-species-synergize-to-potently-and-selectively-induce-cancer-cell-death
#13
Hyang Yeon Lee, Elizabeth I Parkinson, Carlotta Granchi, Ilaria Paterni, Dipak Panigrahy, Pankaj Seth, Filippo Minutolo, Paul J Hergenrother
A distinctive feature of cancer cells is their elevated levels of reactive oxygen species (ROS), a trait that can cause cancer cells to be more sensitive to ROS-inducing agents than normal cells. ROS take several forms, each with different reactivity and downstream consequence. Here we show that simultaneous generation of superoxide and hydrogen peroxide within cancer cells results in significant synergy, potently and selectively causing cancer cell death. In these experiments superoxide is generated using the NAD(P)H quinone oxidoreductase 1 (NQO1) substrate deoxynyboquinone (DNQ), and hydrogen peroxide is generated using the lactate dehydrogenase A (LDH-A) inhibitor NHI-Glc-2...
April 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28368100/halogen-%C3%AF-interactions-in-the-cytochrome-p450-active-site-structural-insights-into-human-cyp2b6-substrate-selectivity
#14
Manish B Shah, Jingbao Liu, Qinghai Zhang, C David Stout, James R Halpert
Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2...
April 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28379691/polypharmacology-approaches-against-the-pseudomonas-aeruginosa-mvfr-regulon-and-their-application-in-blocking-virulence-and-antibiotic-tolerance
#15
Damien Maura, Steffen L Drees, Arunava Bandyopadhaya, Tomoe Kitao, Michele Negri, Melissa Starkey, Biliana Lesic, Sylvain Milot, Eric Deziel, Robert Zahler, Mike Pucci, Antonio Felici, Susanne Fetzner, Francois Lepine, Laurence G Rahme
Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less selective resistance to treatment compared to antibiotics. Capitalizing on our non-ligand based benzamide - benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity...
April 5, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28379676/the-root-growth-regulating-brevicompanine-natural-products-modulate-the-plant-circadian-clock
#16
Amaury de Montaigu, Julian Oeljeklaus, Jan H Krahn, Mohamed N S Suliman, Vivek Halder, Elisa de Ansorena, Sabrina Nickel, Markus Schlicht, Ondrej Plihal, Karolina Kubiasova, Lenka Radova, Barbara Kracher, Reka Toth, Farnusch Kaschani, George Coupland, Erich Kombrink, Markus Kaiser
Plant growth regulating properties of brevicompanines (Brvs), natural products of the fungus Penicillium brevicompactum, have been known for several years, but further investigations into the molecular mechanism of their bioactivity have not been performed. Following chemical synthesis of brevicompanine derivatives, we studied their activity in the model plant Arabidopsis by a combination of plant growth assays, transcriptional profiling and numerous additional bioassays. These studies demonstrated that brevicompanines cause transcriptional misregulation of core components of the circadian clock, whereas other biological read-outs were not affected...
April 5, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28375604/structure-directed-and-tailored-diversity-synthetic-antibody-libraries-yield-novel-anti-egfr-antagonists
#17
Shane Miersch, Bharathikumar Vellalore Maruthachalam, C Ronald Geyer, Sachdev S Sidhu
We tested whether grafting an interaction domain into the hypervariable loop of a combinatorial antibody library could promote targeting to a specific epitope. Formation of the epidermal growth factor receptor (EGFR) signaling heterodimer involves extensive contacts mediated by a "dimerization loop." We grafted the dimerization loop into the third hypervariable loop of a synthetic antigen-binding fragment (Fab) library and diversified other loops using a tailored diversity strategy. This structure-directed Fab library and a naı̈ve synthetic Fab library were used to select Fabs against EGFR...
April 4, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28368102/the-molecular-mechanisms-underlying-the-hijack-of-host-proteins-by-the-1918-spanish-influenza-virus
#18
Qingliang Shen, Danyun Zeng, Baoyu Zhao, Veer S Bhatt, Pingwei Li, Jae-Hyun Cho
The 1918 Spanish influenza A virus (IAV) caused one of the most serious pandemics in history. The nonstructural protein 1 (NS1) of the 1918 IAV hijacks the interaction between human CrkII and JNK1. Little is, however, known about its molecular mechanism. Here, we performed X-ray crystallography, NMR relaxation dispersion experiment, and fluorescence spectroscopy to determine the structural, kinetic, and thermodynamic mechanisms underlying the hijacking of CrkII by 1918 IAV NS1. We observed that the interaction between a proline-rich motif in NS1 and the N-terminal SH3 domain of CrkII displays strikingly rapid kinetics and exceptionally high affinity with 100-fold faster kon and 3,300-fold lower Kd compared to those for the CrkII-JNK1 interaction...
April 3, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28333442/photoaffinity-ligand-for-the-inhalational-anesthetic-sevoflurane-allows-mechanistic-insight-into-potassium-channel-modulation
#19
Kellie A Woll, Wesley Peng, Qiansheng Liang, Lianteng Zhi, Jack A Jacobs, Lina Maciunas, Natarajan Bhanu, Benjamin A Garcia, Manuel Covarrubias, Patrick J Loll, William P Dailey, Roderic G Eckenhoff
Sevoflurane is a commonly used inhaled general anesthetic. Despite this, its mechanism of action remains largely elusive. Compared to other anesthetics, sevoflurane exhibits distinct functional activity. In particular, sevoflurane is a positive modulator of voltage-gated Shaker-related potassium channels (Kv1.x), which are key regulators of action potentials. Here, we report the synthesis and validation of azisevoflurane, a photoaffinity ligand for the direct identification of sevoflurane binding sites in the Kv1...
April 3, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28323406/affinity-selection-mass-spectrometry-identifies-a-novel-antibacterial-rna-polymerase-inhibitor
#20
Scott S Walker, David Degen, Elliott Nickbarg, Donna Carr, Aileen Soriano, Mihir Mandal, Ronald E Painter, Payal Sheth, Li Xiao, Xinwei Sher, Nicholas Murgolo, Jing Su, David B Olsen, Richard H Ebright, Katherine Young
The growing prevalence of drug resistant bacteria is a significant global threat to human health. The antibacterial drug rifampin, which functions by inhibiting bacterial RNA polymerase (RNAP), is an important part of the antibacterial armamentarium. Here, in order to identify novel inhibitors of bacterial RNAP, we used affinity-selection mass spectrometry to screen a chemical library for compounds that bind to Escherichia coli RNAP. We identified a novel small molecule, MRL-436, that binds to RNAP, inhibits RNAP, and exhibits antibacterial activity...
March 31, 2017: ACS Chemical Biology
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