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ACS Chemical Biology

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https://www.readbyqxmd.com/read/27930882/a-look-into-the-biochemistry-of-magnetosome-biosynthesis-in-magnetotactic-bacteria
#1
Shiran Barber-Zucker, Raz Zarivach
Magnetosomes are protein-rich membrane organelles that encapsulate magnetite or greigite and whose chain-alignment enables magnetotactic bacteria (MTB) to sense the geomagnetic field. As these bacteria synthesize uniform magnetic particles, their biomineralization mechanism is of great interest among researchers from different fields, from material engineering to medicine. Both magnetosome formation and magnetic particle synthesis are highly controlled processes that can be divided into several crucial steps: membrane invagination from the inner-cell membrane, protein sorting, the magnetosomes' arrangement into chains, iron transport and chemical environment regulation of the magnetosome lumen, magnetic particle nucleation and finally crystal growth, size and morphology control...
December 8, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27809474/elucidating-the-rimosamide-detoxin-natural-product-families-and-their-biosynthesis-using-metabolite-gene-cluster-correlations
#2
Ryan A McClure, Anthony W Goering, Kou-San Ju, Joshua A Baccile, Frank C Schroeder, William W Metcalf, Regan J Thomson, Neil L Kelleher
As microbial genome sequencing becomes more widespread, the capacity of microorganisms to produce an immense number of metabolites has come into better view. Utilizing a metabolite/gene cluster correlation platform, the biosynthetic origins of a new family of natural products, the rimosamides, were discovered. The rimosamides were identified in Streptomyces rimosus and associated to their NRPS/PKS-type gene cluster based upon their high frequency of co-occurrence across 179 strains of actinobacteria. This also led to the discovery of the related detoxin gene cluster...
November 4, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27791349/deciphering-piperidine-formation-in-polyketide-derived-indolizidines-reveals-a-thioester-reduction-transamination-and-unusual-imine-reduction-process
#3
Haidong Peng, Erman Wei, Jiali Wang, Yanan Zhang, Lin Cheng, Hongmin Ma, Zixin Deng, Xudong Qu
Piperidine and indolizidine are two basic units of alkaloids that are frequently observed in natural and synthetic compounds. Their biosynthesis in natural products is highly conserved and mostly derived from the incorporation of lysine cyclization products. Through in vitro reconstitution, we herein identified a novel pathway involving a group of polyketide-derived indolizidines, which comprises the processes of tandem two-electron thioester reduction, transamination, and imine reduction to convert acyl carrier protein (ACP)-tethered polyketide chains into the piperidine moieties of their indolizidine scaffolds...
November 3, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27805363/nitrilase-activatable-noncanonical-amino-acid-precursors-for-cell-selective-metabolic-labeling-of-proteomes
#4
Zefan Li, Yuntao Zhu, Yuting Sun, Ke Qin, Weibing Liu, Wen Zhou, Xing Chen
Cell-selective protein metabolic labeling is of great interest for studying cell-cell communications and tissue homeostasis. We herein describe a nitrilase-activatable noncanonical amino acid tagging (NANCAT) strategy that exploits an exogenous nitrilase to enzymatically convert the nitrile-substituted precursors to their corresponding noncanonical amino acids (ncAAs), l-azidohomoalanine (Aha) or homopropargylglycine (Hpg), in living cells. Only cells expressing the nitrilase can generate Aha or Hpg in cellulo and metabolically incorporate them into the nascent proteins...
November 2, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27805358/temporal-analysis-of-pp2a-phosphatase-activity-during-insulin-stimulation-using-a-direct-activity-probe
#5
Jon R Beck, Tiffany Truong, Cliff I Stains
Protein serine/threonine phosphatases (PSPs) are ubiquitously expressed in mammalian cells. In particular, PP2A accounts for up to 1% of the total protein within cells. Despite clear evidence for the role of PP2A in cellular signaling, there is a lack of information concerning the magnitude and temporal dynamics of PP2A catalytic activity during insulin stimulation. Herein, we describe the development of a direct, fluorescent activity probe capable of reporting on global changes in PP2A enzymatic activity in unfractionated cell lysates...
November 2, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27797473/native-design-of-soluble-aggregation-resistant-bioactive-peptides-chemical-evolution-of-human-glucagon
#6
Piotr A Mroz, Diego Perez-Tilve, Fa Liu, John P Mayer, Richard D DiMarchi
Peptide-based therapeutics commonly suffer from biophysical properties that compromise pharmacology and medicinal use. Structural optimization of the primary sequence is the usual route to address such challenges while trying to maintain as much native character, and avoiding introduction of any foreign element that might evoke an immunological response. Glucagon serves a seminal physiological role in buffering against hypoglycemia, but its low aqueous solubility, chemical instability and propensity to self-aggregate severely complicate its medicinal use...
October 31, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27797468/host-cell-interactions-are-a-significant-barrier-to-the-clinical-utility-of-peptide-antibiotics
#7
Charles G Starr, Jing He, William C Wimley
Despite longstanding promise and many known examples, antimicrobial peptides (AMPs) have failed, thus far, to impact human medicine. Based on the physical chemistry and mechanism of action of AMPs, we hypothesized that host cell interactions could contribute to loss of activity in vivo where host cells are highly concentrated. To test this idea, we characterized AMP activity in the presence of human red blood cells (RBC). Indeed, we show that most of a representative set of natural and synthetic AMPs tested are significantly inhibited by preincubation with host cells, and would be effectively inactive at physiological cell density...
October 31, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27779380/quantitative-chemical-proteomic-profiling-of-ubiquitin-specific-proteases-in-intact-cancer-cells
#8
Jennifer A Ward, Lauren McLellan, Martin Stockley, Karl R Gibson, Gavin A Whitlock, Charlotte Knights, Jeanine A Harrigan, Xavier Jacq, Edward W Tate
Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes and are emerging as pioneering drug targets. Herein, we present a novel probe, Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling identified 12 USPs, including USP4, USP16, and USP33, as inhibitor targets using submicromolar probe concentrations. This represents the first intact cell activity-based profiling of deubiquitinating enzymes...
October 31, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27748579/molecular-mechanism-for-isoform-selective-inhibition-of-acyl-protein-thioesterases-1-and-2-apt1-and-apt2
#9
Sang Joon Won, Dahvid Davda, Kristin J Labby, Sin Ye Hwang, Rachel Pricer, Jaimeen D Majmudar, Kira A Armacost, Laura A Rodriguez, Christina L Rodriguez, Fei San Chong, Kristopher A Torossian, Jasmine Palakurthi, Edward S Hur, Jennifer L Meagher, Charles L Brooks, Jeanne A Stuckey, Brent R Martin
Post-translational S-palmitoylation directs the trafficking and membrane localization of hundreds of cellular proteins, often involving a coordinated palmitoylation cycle that requires both protein acyl transferases (PATs) and acyl protein thioesterases (APTs) to actively redistribute S-palmitoylated proteins toward different cellular membrane compartments. This process is necessary for the trafficking and oncogenic signaling of S-palmitoylated Ras isoforms, and potentially many peripheral membrane proteins...
October 31, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27792307/a-cell-permeable-biscyclooctyne-as-a-novel-probe-for-the-identification-of-protein-sulfenic-acids
#10
David J McGarry, Maria M Shchepinova, Sergio Lillla, Richard C Hartley, Michael F Olson
Reactive oxygen species act as important second messengers in cell signaling and homeostasis through the oxidation of protein thiols. However, the dynamic nature of protein oxidation and the lack of sensitivity of existing molecular probes have hindered our understanding of such reactions; therefore, new tools are required to address these challenges. We designed a bifunctional variant of the strained bicyclo[6.1.0]nonyne (BCN-E-BCN) that enables the tagging of intracellular protein sulfenic acids for biorthogonal copper-free click chemistry...
October 28, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27791347/discovery-of-a-novel-jak3-selective-inhibitor-functional-differentiation-of-jak3-selective-inhibition-over-pan-jak-or-jak1-selective-inhibition
#11
Jean-Baptiste Telliez, Martin E Dowty, Lu Wang, Jason Jussif, Tsung Lin, Li Li, Erick Moy, Paul Balbo, Wei Li, Yajuan Zhao, Kimberly Crouse, Caitlyn Dickinson, Peter Symanowicz, Martin Hegen, Mary Ellen Banker, Fabien Vincent, Ray Unwalla, Sidney Liang, Adam M Gilbert, Matthew F Brown, Matthew Hayward, Justin Montgomery, Xin Yang, Jonathan Bauman, John I Trujillo, Agustin Casimiro-Garcia, Felix F Vajdos, Louis Leung, Kieran F Geoghegan, Amira Quazi, Dejun Xuan, Lyn H Jones, Erik Hett, Katherine Wright, James D Clark, Atli Thorarensen
PF-06651600, a newly discovered potent JAK3-selective inhibitor is highly efficacious at inhibiting γc cytokine signaling which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that couldn't be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in the rat adjuvant-induced arthritis as well as in the mouse experimental autoimmune encephalomyelitis models...
October 28, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27782396/phenyl-glycolipids-with-different-glycosyl-groups-exhibit-marked-differences-in-murine-and-human-inkt-cell-activation
#12
Tai-Na Wu, Kun-Hsien Lin, Ying-Ta Wu, Jing-Rong Huang, Jung-Tung Hung, Jen-Chine Wu, Chien-Yu Chen, Kuo-Ching Chu, Nan-Horng Lin, Alice L Yu, Chi-Huey Wong
Glycosphingolipids (GSLs) bearing the α-galactosyl head group and the acyl chain terminated with a phenyl derivative were found to be more potent than α-galactosyl ceramide (αGalCer) to stimulate both murine and human invariant natural killer T (iNKT) cells and to induce antibody isotope switch to IgG. In this study, we replaced the galactosyl group with glucose (αGlc) and its fluoro-analogs, and found that phenyl GSLs with αGlc (C34-Glc) and its fluoro-analog 6F-C34-Glc were stronger than those with αGal in stimulating human iNKT cells but weaker in mice...
October 26, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27779865/characterization-of-hedgehog-acyltransferase-inhibitors-identifies-a-small-molecule-probe-for-hedgehog-signaling-by-cancer-cells
#13
Ursula R Rodgers, Thomas Lanyon-Hogg, Naoko Masumoto, Markus Ritzefeld, Rosemary Burke, Julian Blagg, Anthony I Magee, Edward W Tate
The Sonic Hedgehog (Shh) signaling pathway plays a critical role during embryonic development and cancer progression. N-terminal palmitoylation of Shh by Hedgehog acyltransferase (Hhat) is essential for efficient signaling, raising interest in Hhat as a novel drug target. A recently identified series of dihydrothienopyridines has been proposed to function via this mode of action; however, the lead compound in this series (RUSKI-43) was subsequently shown to possess cytotoxic activity unrelated to canonical Shh signaling...
October 25, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27779378/what-can-we-learn-from-bioactivity-data-chemoinformatics-tools-and-applications-in-chemical-biology-research
#14
Lina Humbeck, Oliver Koch
The ever increasing bioactivity data that are produced nowadays allow exhaustive data mining and knowledge discovery approaches that change chemical biology research. A wealth of chemoinformatics tools, web services and applications therefore exists that supports a careful evaluation and analysis of experimental data to draw conclusions that can influence the further development of chemical probes and potential lead structures. This review focuses on open-source approaches that can be handled by scientists who are not familiar with computational methods having no expert knowledge in chemoinformatics and modeling...
October 25, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27779377/comprehensive-analysis-of-a-novel-ketoreductase-for-pentangular-polyphenol-biosynthesis
#15
Timothy R Valentic, David R Jackson, Sean F Brady, Shiou-Chuan Sheryl Tsai
Arixanthomycins are pentangular polyphenols (PP) with potent antiproliferative activities that were discovered through the heterologous expression of environmental DNA-derived gene clusters. The biosynthesis of arixanthomycin and other PPs is unusual, because it requires several novel type II polyketide synthase (PKS) enzymes for its complete maturation. Most type II PKSs contain a ketoreductase (KR) that mediates the C7-C12 first ring cyclization and C9-reduction. In contrast, based on previous studies of product analysis and genome mining, the arixanthomycin (ARX) gene cluster like harbors a C11-reducing ketoreductase (ARX 27), a C9-C14 first-ring aromatase/cyclase (ARX 19), and an unprecedented C-17 and C-19 reducing KR (ARX 21)...
October 25, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27749034/immune-response-modulation-of-conjugated-agonists-with-changing-linker-length
#16
Keun Ah Ryu, Katarzyna Slowinska, Troy Moore, Aaron Esser-Kahn
We report immune response modulation with linked Toll-like receptor (TLR) agonists. Conjugating two agonists of synergistic TLRs induce an increase in immune activity compared to equal molarity of soluble agonists. Additionally, varying the distance between the agonists by changing the linker length alters the level of macrophage NF-κB activity as well as primary bone marrow derived dendritic cell IL-6 production. This modulation is effected by the size of the agonists and the pairing of the stimulated TLRs...
October 25, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27775338/ligand-optimization-by-improving-shape-complementarity-at-a-hepatitis-c-virus-rna-target
#17
Brian P Charrette, Mark A Boerneke, Thomas Hermann
Crystal structure analysis revealed key interactions of a 2-amino-benzimidazole viral translation inhibitor that captures an elongated conformation of an RNA switch target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV). Here, we have designed and synthesized quinazoline derivatives with improved shape complementarity at the ligand binding site of the viral RNA target. A spiro-cyclopropyl modification aimed at filling a pocket in the back of the RNA binding site led to a fivefold increase of ligand affinity while a slightly more voluminous dimethyl substitution at the same position did not improve binding...
October 24, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27775325/a-tpx2-proteomimetic-has-enhanced-affinity-for-aurora-a-due-to-hydrocarbon-stapling-of-a-helix
#18
Yana K Rennie, Patrick J McIntyre, Tito Akindele, Richard Bayliss, Andrew G Jamieson
Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly, and is a promising target for anti-cancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker...
October 24, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27768280/chemical-proteomics-and-structural-biology-define-epha2-inhibition-by-clinical-kinase-drugs
#19
Stephanie Heinzlmeir, Denis Kudlinzki, Sridhar Sreeramulu, Susan Klaeger, Santosh Lakshmi Gande, Verena Linhard, Mathias Wilhelm, Huichao Qiao, Dominic Helm, Benjamin Ruprecht, Krishna Saxena, Guillaume Médard, Harald Schwalbe, Bernhard Kuster
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail...
October 21, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27766829/development-of-rare-bacterial-monosaccharide-analogs-for-metabolic-glycan-labeling-in-pathogenic-bacteria
#20
Emily L Clark, Madhu Emmadi, Katharine L Krupp, Ananda R Podilapu, Jennifer D Helble, Suvarn S Kulkarni, Danielle H Dube
Bacterial glycans contain rare, exclusively bacterial monosaccharides that are frequently linked to pathogenesis and essentially absent from human cells. Therefore, bacterial glycans are intriguing molecular targets. However, systematic discovery of bacterial glycoproteins is hampered by the presence of rare deoxy amino sugars, which are refractory to traditional glycan-binding reagents. Thus, the development of chemical tools that label bacterial glycans is a crucial step toward discovering and targeting these biomolecules...
October 21, 2016: ACS Chemical Biology
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