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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28198609/an-unusual-flavin-dependent-halogenase-from-the-metagenome-of-the-marine-sponge-theonella-swinhoei-wa
#1
Duncan R M Smith, Agustinus R Uria, Eric J N Helfrich, Daniela Milbredt, Karl-Heinz van Pée, Jörn Piel, Rebecca J M Goss
Uncultured bacteria from sponges have been demonstrated to be responsible for the generation of many potent, bioactive natural products including halogenated metabolites.1 The identification of gene clusters from the metagenomes of such bacterial communities enables the discovery of enzymes that mediate new and useful chemistries and allows insight to be gained into the biogenesis of potentially pharmacologically important natural products. Here we report a new pathway to the keramamides (krm); the first functional evidence for the existence of a distinct producer in the Theonella swinhoei WA chemotype is revealed, and a key enzyme on the pathway, a unique flavin-dependent halogenase with a broad substrate specificity, with potential as a useful new biocatalytic tool, is described...
March 24, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28333443/systematic-investigation-of-ginkgo-biloba-leaves-for-treating-cardio-cerebrovascular-diseases-in-an-animal-model
#2
Yinfeng Yang, Yan Li, Jinghui Wang, Ke Sun, Weiyang Tao, Zhenzhong Wang, Wei Xiao, Yanqiu Pan, Shuwei Zhang, Yonghua Wang
Globally, cardio-cerebrovascular diseases (CCVDs) account for the leading cause of death, and thus the development of novel strategies for preventing and treating such diseases is in urgent need. Traditional Chinese Medicine (TCM), used for thousands of years in Asia and other regions, have been proven effective in certain disorders. As a medicinal herb for a long time in TCM, Ginkgo Biloba Leaves (GBLs), have been widely used to treat various diseases including CCVDs. However, the underlying molecular mechanisms of medicinal herb in treating these diseases are still unclear...
March 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28333442/photoaffinity-ligand-for-the-inhalational-anesthetic-sevoflurane-allows-mechanistic-insight-into-potassium-channel-modulation
#3
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...
March 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28290654/new-ulvan-degrading-polysaccharide-lyase-family-structure-and-catalytic-mechanism-suggests-convergent-evolution-of-active-site-architecture
#4
ThirumalaiSelvi Ulaganathan, Michal T Boniecki, Elizabeth Foran, Vitaliy Buravenkov, Naama Mizrachi, Ehud Banin, William Helbert, Miroslaw Cygler
Ulvan is a complex sulfated polysaccharide biosynthesized by green seaweed and contains predominantly rhamnose, xylose, and uronic acid sugars. Ulvan-degrading enzymes have only recently been identified and added to the CAZy ( www.cazy.org ) database as family PL24, but neither their structure nor catalytic mechanism(s) are yet known. Several homologous, new ulvan lyases, have been discovered in Pseudoalteromonas sp. strain PLSV, Alteromonas LOR, and Nonlabens ulvanivorans, defining a new family PL25, with the lyase encoded by the gene PLSV_3936 being one of them...
March 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28323406/affinity-selection-mass-spectrometry-identifies-a-novel-antibacterial-rna-polymerase-inhibitor
#5
Scott S Walker, David Degen, Elliott Nickbarg, Donna Carr, Aileen Soriano, Mihir Baran Mandal, Ronald E Painter, Payal R Sheth, Li Xiao, Xinwei Sher, Nicholas Murgolo, Jing Su, David B Olsen, Richard H Ebright, Katherine Young
The growing prevalence of drug-resistant Gram-negative bacteria is a significant global threat to human health. Rifampicin, an RNA polymerase-targeting agent, is an important part of the antibacterial armamentarium; however the emergence of resistance requires that it be used against only certain infections and usually in combination with another antibiotic. While rifampicin has significant clinical limitations, it does show that bacterial RNA polymerase can be an effective target for antibacterial intervention...
March 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28323402/single-particle-observation-of-sv40-vp1-polyanion-induced-assembly-shows-that-substrate-size-and-structure-modulate-capsid-geometry
#6
Chenglei Li, Andrew R Kneller, Stephen C Jacobson, Adam Zlotnick
Simian virus 40 capsid protein (VP1) is a unique system for studying substrate-dependent assembly of a nanoparticle. Here, we investigate a simplest case of this system where twelve VP1 pentamers and a single polyanion, e.g. RNA, form a T=1 particle. To test the roles of polyanion substrate length and structure during assembly, we characterized the assembly products with size exclusion chromatography, transmission electron microscopy, and single-particle resistive-pulse sensing. We found that a 500 nt RNA has the optimal length and structure for assembly of uniform T=1 particles...
March 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28323400/stepwise-loop-insertion-strategy-for-active-site-remodeling-to-generate-novel-enzyme-functions
#7
Md Anarul Hoque, Yong Zhang, Liuqing Chen, Guang-Yu Yang, Mst Afroza Khatun, Hai-Feng Chen, Liu Hao, Yan Feng
The remodeling of active sites to generate novel biocatalysts is an attractive and challenging task. We developed a stepwise loop insertion strategy (StLois), in which randomized residue pairs are inserted into active site loops. The phosphotriesterase-like lactonase from Geobacillus kaustophilus (GkaP-PLL) was used to investigate StLois's potential for changing enzyme function. By inserting 6 residues into active site loop7, the best variant ML7-B6 demonstrated a 16 fold further increase in catalytic efficiency toward ethyl-paraoxon compared with its initial template, that is a 609-fold higher, >107 fold substrate specificity shift relative to that of wild-type lactonase...
March 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28263555/novel-peptides-derived-from-dengue-virus-capsid-protein-translocate-reversibly-the-blood-brain-barrier-through-a-receptor-free-mechanism
#8
Vera Neves, Frederico Aires-da-Silva, Maurício Morais, Lurdes Gano, Elisabete Ribeiro, Antónia Pinto, Sandra Aguiar, Diana Gaspar, Célia Fernandes, João D G Correia, Miguel A R B Castanho
The delivery of therapeutic molecules to the central nervous system is hampered by poor delivery across the blood-brain barrier (BBB). Several strategies have been proposed to enhance transport into the brain, including invasive techniques and receptor-mediated transport (RMT). Both approaches have several drawbacks, such as BBB disruption, receptor saturation, and off-target effects, raising safety issues. Herein, we show that specific domains of Dengue virus type 2 capsid protein (DEN2C) can be used as trans-BBB peptide vectors...
March 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28318229/tracing-effects-of-fluorine-substitutions-on-g-quadruplex-conformational-changes
#9
Jonathan Dickerhoff, Linn Haase, Walter Langel, Klaus Weisz
A human telomere sequence that folds into an intramolecular (3+1)-hybrid G-quadruplex was modified by the incorporation of 2'-fluoro-2'-deoxyriboguanosines ((F)G) into syn positions of its outer tetrad. A circular dichroism and NMR spectral analysis reveals a nearly quantitative switch of the G-tetrad polarity with concerted syn↔anti transitions of all four G residues. These observations follow findings on a (F)G-substituted (3+1)-hybrid quadruplex with a different fold, suggesting a more general propensity of hybrid-type quadruplexes to undergo a tetrad polarity reversal...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28318222/selective-downregulation-of-jak2-and-jak3-by-an-atp-competitive-pan-jak-inhibitor
#10
S Denise Field, Jacob Arkin, Jing Li, Lyn H Jones
PF-956980 has been used previously as a JAK3-selective chemical probe in numerous cell-based experiments. Here, we report that not only is PF-956980 a pan-JAK ATP-competitive inhibitor, but it also causes selective reduction of endogenous JAK2 and JAK3 protein levels in human primary immune cells (in a time-dependent manner), leaving the other JAK family members (JAK1 and TYK2) unchanged. We found that PF-956980 selectively downregulated JAK2 and JAK3 mRNA, corresponding to changes observed at the protein level...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28318221/crystal-structure-of-a-homogeneous-igg-fc-glycoform-with-the-n-glycan-designed-to-maximize-the-antibody-dependent-cellular-cytotoxicity
#11
Chia-Lin Chen, Jen-Chi Hsu, Chin-Wei Lin, Chia-Hung Wang, Ming-Hung Tsai, Chung-Yi Wu, Chi-Huey Wong, Che Ma
N-glycosylation on IgG modulates Fc conformation and effector functions. An IgG-Fc contains a human sialo-complex type (hSCT) glycan of biantennary structure with two α2,6-sialylations and without core-fucosylation is an optimized glycoform developed to enhance the antibody dependent cellular cytotoxicity (ADCC). hSCT modification not only enhances the binding affinity to Fc receptors in the presence of antigen, but also in some cases provides gain-of-function effector activity. We used enzymatic glyco-engineering to prepare an IgG-Fc with homogeneous hSCT attached to each CH2 domain, and solved its crystal structure...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28263557/proteolysis-targeting-chimeras-induced-protein-degradation-as-a-therapeutic-strategy
#12
Philipp Ottis, Craig M Crews
Until recently, the only ways to reduce specific protein signaling were to either knock down the target by RNAi or to interfere with the signaling by inhibiting an enzyme or receptor within the signal transduction cascade. Herein, we review an emerging class of small molecule pharmacological agents, called PROTACs, that present a novel approach to specifically target proteins and their respective signaling pathways. These heterobifunctional molecules utilize endogenous cellular quality control machinery by recruiting it to target proteins in order to induce their degradation...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28263556/a-chemical-probe-strategy-for-interrogating-inhibitor-selectivity-across-the-mek-kinase-family
#13
Kristine K Deibler, Rama K Mishra, Matthew R Clutter, Aleksandar Antanasijevic, Raymond Bergan, Michael Caffrey, Karl A Scheidt
MEK4 is an upstream kinase in MAPK signaling pathways where it phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. Despite a high level of sequence homology in the ATP-binding site, most reported MEK inhibitors are selective for MEK1/2 and display reduced potency toward other MEKs...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28314097/fragment-sized-ethr-inhibitors-exhibit-exceptionally-strong-ethionamide-boosting-effect-in-whole-cell-mycobacterium-tuberculosis-assays
#14
Petar O Nikiforov, Michal Blaszczyk, Sachin Surade, Helena I Boshoff, Andaleeb Sajid, Vincent Delorme, Nathalie Deboosere, Priscille Brodin, Alain R Baulard, Clifton E Barry Rd, Tom L Blundell, Chris Abell
Small molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethionamide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration (MEC) values for the boosting of ethionamide activity in M...
March 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28314095/rational-redesign-of-a-functional-protein-kinase-substrate-interaction
#15
Catherine Chen, Wutigri Nimlamool, Chad J Miller, Hua Jane Lou, Benjamin E Turk
Eukaryotic protein kinases typically phosphorylate substrates in the context of specific sequence motifs, contributing to specificity essential for accurate signal transmission. Protein kinases recognize their target sequences through complementary interactions within the active site cleft. As a step toward the construction of orthogonal kinase signaling systems, we have re-engineered the protein kinase Pim1 to alter its phosphorylation consensus sequence. Residues in the Pim1 catalytic domain interacting directly with a critical arginine residue in the substrate were substituted to produce a kinase mutant that instead accommodates a hydrophobic residue...
March 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28303709/meeting-proceedings-icbs2016-translating-the-power-of-chemical-biology-to-clinical-advances
#16
Yugo Kuriki, Toru Komatsu, Peter D Ycas, Sara K Coulup, Erick J Carlson, William C K Pomerantz
No abstract text is available yet for this article.
March 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28300390/recruitment-and-regulation-of-the-non-ribosomal-peptide-synthetase-modifying-cytochrome-p450-involved-in-nikkomycin-biosynthesis
#17
Courtney E Wise, Thomas M Makris
The beta-hydroxylation of L-histidine is the first step in the biosynthesis of the imidazolone base of the antifungal drug nikkomycin. The cytochrome P450 (NikQ) hydroxylates the amino acid while it is appended via a phosphopantetheine linker to the non-ribosomal peptide synthetase (NRPS) NikP1. The latter enzyme is comprised of an MbtH, and single adenylation and thiolation domains, a minimal composition that allows for detailed binding and kinetics studies using an intact and homogeneous NRPS substrate. Electron paramagnetic resonance studies confirm that a stable complex is formed with NikQ with NikP1 when the amino acid is tethered...
March 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28294600/histo-blood-group-antigen-presentation-is-critical-for-norovirus-vlp-binding-to-glycosphingolipids-in-model-membranes
#18
Waqas Nasir, Martin Frank, Angelika Kunze, Marta Bally, Francisco Parra, Per-Georg Nyholm, Fredrik Höök, Göran Larson
Virus entry depends on biomolecular recognition at the surface of cell membranes. In case of glycolipid receptors, these events are expected to be influenced by how the glycan epitope close to the membrane is presented to the virus. This presentation of membrane associated glycans is more restricted as compared to glycans in solution, particularly because of orientational constraints imposed on the glycolipid through its lateral interactions with other membrane lipids and proteins. We have developed and employed total internal reflection fluorescence microscopy (TIRFM) based binding assay and a scheme for molecular dynamics (MD) membrane simulations to investigate the consequences of various glycan presentation effects...
March 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28294596/the-macrolide-toxin-mycolactone-promotes-bim-dependent-apoptosis-in-buruli-ulcer-through-inhibition-of-mtor
#19
Raphael Bieri, Nicole Scherr, Thérèse Ruf, Jean-Pierre Dangy, Philipp Gersbach, Matthias Gehringer, Karl-Heinz Altmann, Gerd Pluschke
Mycolactone, the macrolide exotoxin produced by Mycobacterium ulcerans, is central to the pathogenesis of the chronic necrotizing skin disease Buruli ulcer (BU). Here we show that mycolactone acts as an inhibitor of the mechanistic Target of Rapamycin (mTOR) signaling pathway by interfering with the assembly of the two distinct mTOR protein complexes mTORC1 and mTORC2, which regulate different cellular processes. Inhibition of the assembly of the rictor containing mTORC2 complex by mycolactone prevents phosphorylation of the serine/threonine protein kinase Akt...
March 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28257177/glycation-of-lysozyme-by-glycolaldehyde-provides-new-mechanistic-insights-in-diabetes-related-protein-aggregation
#20
Laura Mariño, Carlos Andrés Maya-Aguirre, Kris Pauwels, Bartolomé Vilanova, Joaquin Ortega-Castro, Juan Frau, Josefa Donoso, Miquel Adrover
Glycation occurs in vivo as a result of the nonenzymatic reaction of carbohydrates (and/or their autoxidation products) with proteins, DNA, or lipids. Protein glycation causes loss-of-function and, consequently, the development of diabetic-related diseases. Glycation also boosts protein aggregation, which can be directly related with the higher prevalence of aggregating diseases in diabetic people. However, the molecular mechanism connecting glycation with aggregation still remains unclear. Previously we described mechanistically how glycation of hen egg-white lysozyme (HEWL) with ribose induced its aggregation...
March 14, 2017: ACS Chemical Biology
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