3,116 results match your criteria ACS Chemical Biology [Journal]


Discovery and structural characterization of ATP-site ligands for the wild-type and V617F-mutant JAK2 pseudokinase domain.

ACS Chem Biol 2019 Feb 14. Epub 2019 Feb 14.

The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Read More

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http://dx.doi.org/10.1021/acschembio.8b00722DOI Listing
February 2019

An autoinducer analog reveals an alternative mode of ligand binding for the LasR quorum-sensing receptor.

ACS Chem Biol 2019 Feb 14. Epub 2019 Feb 14.

Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. Read More

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http://dx.doi.org/10.1021/acschembio.8b00971DOI Listing
February 2019

GLI1-inducible glucuronidation targets a broad spectrum of drugs.

ACS Chem Biol 2019 Feb 14. Epub 2019 Feb 14.

Cancer therapies are plagued by resistance. Previously, we discovered a novel form of cancer drug resistance where the Glioma-associated protein 1 (GLI1) elevates UGT1A glucuronidation enzymes thereby glucuronidating cytarabine and ribavirin leading to resistance in leukemia patients. Here, we demonstrate that GLI1 imparts resistance to ~40 compounds, including FDA-approved drugs with disparate chemotypes (e. Read More

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http://dx.doi.org/10.1021/acschembio.8b01118DOI Listing
February 2019

Mass spectrometry uncovers the role of surfactin as an interspecies recruitment factor.

ACS Chem Biol 2019 Feb 14. Epub 2019 Feb 14.

Microbes use metabolic exchange to sense and respond to their changing environment. Surfactins, produced by Bacillus subtilis are extensively studied for its attributed role in biofilm formation, biosurfactant properties and antimicrobial activity, affecting the surrounding microbial consortia. Using mass spectrometry, we reveal that Paenibacillus dendritiformis, originally isolated with B. Read More

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http://dx.doi.org/10.1021/acschembio.8b01120DOI Listing
February 2019

Salinipeptins: Integrated genomic and chemical approaches reveal unusual D-amino acid-containing ribosomally synthesized and post-translationally modified peptides (RiPPs) from a Great Salt Lake Streptomyces sp.

ACS Chem Biol 2019 Feb 12. Epub 2019 Feb 12.

Analysis of the full genome of an environmentally-unique, halotolerant Streptomyces sp. strain GSL-6C, isolated from the Great Salt Lake, revealed a gene cluster encoding the biosynthesis of the salinipeptins, D-amino acid containing members of the rare linaridin subfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). The sequence organization of the unmodified amino acid residues in salinipeptins A-D (1-4) were suggested by genome annotation, and subsequently their sequence and post-translational modifications were defined using a range of spectroscopic techniques and chemical derivatization approaches. Read More

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http://dx.doi.org/10.1021/acschembio.8b01058DOI Listing
February 2019

Engineering Atypical Tetracycline Formation in Amycolatopsis sulphurea for the Production of Modified Chelocardin Antibiotics.

ACS Chem Biol 2019 Feb 12. Epub 2019 Feb 12.

Department of Microbial Natural Products , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University, Campus E8.1 , 66123 Saarbrücken , Germany.

To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline chelocardin and its potent broad-spectrum derivative 2-carboxamido-2-deacetyl-chelocardin. Heterologous biosynthetic genes were introduced into this chelocardin producer to modify functional groups and generate new derivatives. Read More

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http://dx.doi.org/10.1021/acschembio.8b01125DOI Listing
February 2019
1 Read

Cu-ATCUN Derivatives of Sub5 Exhibit Enhanced Antimicrobial Activity via Multiple Modes of Action.

ACS Chem Biol 2019 Feb 11. Epub 2019 Feb 11.

Antimicrobial peptides (AMP's) are short, amphipathic peptides that are typically cationic in sequence and display broad-spectrum activity against bacteria, fungi, and protists. Herein, we report the effect of appending the amino terminal copper and nickel binding motif (ATCUN) to Sub5. The Cu-ATCUN derivatives show a two to three-fold increase in antimicrobial activity for a variety of microbes, relative to Sub5, with MICs as low as 0. Read More

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http://dx.doi.org/10.1021/acschembio.8b01087DOI Listing
February 2019

Regulatory mechanisms of the mucin-like region on herpes simplex virus during cellular attachment.

ACS Chem Biol 2019 Feb 8. Epub 2019 Feb 8.

Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. Read More

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http://dx.doi.org/10.1021/acschembio.9b00064DOI Listing
February 2019
1 Read

Small molecule SOS1 agonists modulate MAPK and PI3K signaling via independent cellular responses.

ACS Chem Biol 2019 Feb 8. Epub 2019 Feb 8.

Activating mutations in RAS lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00869
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http://dx.doi.org/10.1021/acschembio.8b00869DOI Listing
February 2019
2 Reads

Peptidoglycan metabolite photoaffinity reporters reveal direct binding to intracellular pattern recognition receptors and Arf GTPases.

ACS Chem Biol 2019 Feb 8. Epub 2019 Feb 8.

The peptidoglycan fragments -D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl-dipeptide (MDP) are microbial-specific metabolites that activate intracellular pattern recognition receptors and stimulate immune signaling pathways. While extensive structure-activity studies have demonstrated that these bacterial cell wall metabolites trigger NOD1- and NOD2-dependent signaling, their direct binding to these innate immune receptors or other proteins in mammalian cells has not been established. To characterize these fundamental microbial metabolite-host interactions, we synthesized a series of peptidoglycan metabolite photoaffinity reporters and evaluated their crosslinking to NOD1 and NOD2 in mammalian cells. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b01038
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http://dx.doi.org/10.1021/acschembio.8b01038DOI Listing
February 2019
2 Reads

New Molecular Scaffolds for Fluorescent Voltage Indicators.

ACS Chem Biol 2019 Feb 8. Epub 2019 Feb 8.

The ability to non-invasively monitor membrane potential dynamics in excitable cells like neurons and cardiomyocytes promises to revolutionize our understanding of the physiology and pathology of the brain and heart. Here, we report the design, synthesis, and application of a new class of fluorescent voltage indicators that make use of a fluorene-based molecular wire as a voltage-sensing domain to provide fast and sensitive measurements of membrane potential in both mammalian neurons and human-derived cardiomyocytes. We show that the best of the new probes, fluorene VoltageFluor 2 (fVF 2), readily reports on action potentials in mammalian neurons, detects perturbations to the cardiac action potential waveform in human induced pluripotent stem cell-derived cardiomyocytes, shows a substantial decrease in phototoxicity compared to existing molecular wire-based indicators, and can monitor cardiac action potentials for extended periods of time. Read More

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http://dx.doi.org/10.1021/acschembio.8b00978DOI Listing
February 2019

SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate.

ACS Chem Biol 2019 Feb 5. Epub 2019 Feb 5.

Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target:PROTAC:ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation in vitro using purified proteins. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00092
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http://dx.doi.org/10.1021/acschembio.9b00092DOI Listing
February 2019
1 Read

Abnormal cannabidiol modulates vitamin A metabolism by acting as a competitive inhibitor of CRBP1.

ACS Chem Biol 2019 Feb 5. Epub 2019 Feb 5.

Cellular retinol-binding proteins (CRBPs) facilitate the uptake and intracellular transport of vitamin A. They integrate retinoid metabolism, playing an important role in regulating the synthesis of bioactive vitamin A metabolites. Thus, CRBPs constitute potential pharmacological targets to modulate cellular retinoid status that in turn may have applications in the treatment of certain immunological, metabolic, and ocular disorders. Read More

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http://dx.doi.org/10.1021/acschembio.8b01070DOI Listing
February 2019
1 Read
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Understanding Intramolecular Crosstalk in an Intrinsically Disordered Protein.

ACS Chem Biol 2019 Feb 12. Epub 2019 Feb 12.

Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR , Sapienza Università di Roma , 00185 Rome , Italy.

The interaction between N and XD from the measles virus represents a paradigmatic example of molecular recognition between an intrinsically disordered protein and a folded partner. By binding to XD, a small portion of N (classically denoted as MoRE) undergoes a disorder-to-order transition, populating an α-helical structure, while the reminder of the protein remains disordered. Here, we demonstrate an unexpected crosstalk between such a disordered region and the adjacent molecular recognition element (MoRE). Read More

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http://dx.doi.org/10.1021/acschembio.8b01055DOI Listing
February 2019

Development of a Nitric Oxide-Responsive Labeling Reagent for Proteome Analysis of Live Cells.

ACS Chem Biol 2019 Feb 14. Epub 2019 Feb 14.

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering , Kyoto University , Katsura, Nishikyo-ku, Kyoto 615-8510 , Japan.

Nitric oxide (NO) is a pleiotropic signaling molecule involved in the regulation of diverse physiological and pathophysiological mechanisms in cardiovascular, nervous, and immunological systems. To understand the biological functions of NO in detail, comprehensive characterization of proteins found in high-NO concentration environments is crucial. Herein, we describe the design of NO-responsive protein labeling reagents based on N-alkoxyacyl- o-phenylenediamine as an optimal reactive scaffold. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b01021
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http://dx.doi.org/10.1021/acschembio.8b01021DOI Listing
February 2019
3 Reads

Glycated insulin exacerbates the cytotoxicity of human islet amyloid polypeptides: a vicious cycle in type 2 diabetes.

ACS Chem Biol 2019 Feb 4. Epub 2019 Feb 4.

The aggregation of human islet amyloid polypeptide (hIAPP) is one of the triggering factors of type 2 diabetes mellitus (T2DM). hIAPP is co-synthesized, co-stored and co-secreted with insulin in pancreatic β-cells, and insulin inhibits hIAPP aggregation. In T2DM patients, long-term hyperglycemia causes glycation of near 10% of total insulin. Read More

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http://dx.doi.org/10.1021/acschembio.8b01128DOI Listing
February 2019
1 Read

Gap-Junction-Dependent Labeling of Nascent Proteins in Multicellular Networks.

ACS Chem Biol 2019 Feb 4. Epub 2019 Feb 4.

Intercellular communication via gap junctions is crucial for orchestrating behaviors of multicellular systems. Imaging methods and electrophysiological techniques have been widely used to identify gap junctions and map the gap-junction-connected cell networks. However, analyzing gene expression within a gap-junction network remains challenging. Read More

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http://dx.doi.org/10.1021/acschembio.8b01065DOI Listing
February 2019

Fluorescent retinoic acid analogues as probes for biochemical and intracellular characterization of retinoid signaling pathways.

ACS Chem Biol 2019 Feb 1. Epub 2019 Feb 1.

Retinoids, such as all-trans-retinoic acid (ATRA), are endogenous signalling molecules derived from Vitamin A that influ-ence a variety of cellular processes through mediation of transcription events in the cell nucleus. Due to these wide-ranging and powerful biological activities, retinoids have emerged as therapeutic candidates of enormous potential. However, their use has been limited, to date, due to a lack of understanding of the complex and intricate signaling pathways that they con-trol. Read More

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http://dx.doi.org/10.1021/acschembio.8b00916DOI Listing
February 2019

Toolbox of Diverse Linkers for Navigating the Cellular Efficacy Landscape of Stapled Peptides.

ACS Chem Biol 2019 Feb 7. Epub 2019 Feb 7.

Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , United Kingdom.

Stapled peptides have great potential as modulators of protein-protein interactions (PPIs). However, there is a vast landscape of chemical features that can be varied for any given peptide, and identifying a set of features that maximizes cellular uptake and subsequent target engagement remains a key challenge. Herein, we present a systematic analysis of staple functionality on the peptide bioactivity landscape in cellular assays. Read More

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http://dx.doi.org/10.1021/acschembio.9b00063DOI Listing
February 2019

Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

ACS Chem Biol 2019 Jan 31. Epub 2019 Jan 31.

Department of Chemistry, The Skaggs Institute for Chemical Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.

Clinical investigation of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 resulted in serious adverse neurological events. Structurally unrelated FAAH inhibitors tested in humans have not presented safety concerns, suggesting that BIA 10-2474 has off-target activities. A recent activity-based protein profiling (ABPP) study revealed that BIA 10-2474 and one of its major metabolites inhibit multiple members of the serine hydrolase class to which FAAH belongs. Read More

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http://dx.doi.org/10.1021/acschembio.8b01097DOI Listing
January 2019

Detecting Secretory Proteins by Acoustic Droplet Ejection in Multiplexed High-Throughput Applications.

ACS Chem Biol 2019 Feb 14. Epub 2019 Feb 14.

National Center for Advancing Translational Sciences , National Institutes of Health , Rockville , Maryland 20850 , United States.

Nearly one-third of the encoded proteome is comprised of secretory proteins that enable communication between cells and organ systems, playing a ubiquitous role in human health and disease. High-throughput detection of secreted proteins would enhance efforts to identify therapies for secretion-related diseases. Using the Z mutant of alpha-1 antitrypsin as a human secretory model, we have developed 1536-well high-throughput screening assays that utilize acoustic droplet ejection to transfer nanoliter volumes of sample for protein quantification. Read More

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http://dx.doi.org/10.1021/acschembio.9b00001DOI Listing
February 2019
1 Read

Biosynthesis and Chemical Applications of Thioamides.

ACS Chem Biol 2019 Jan 30. Epub 2019 Jan 30.

Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine , University of Pennsylvania , 3700 Hamilton Walk , Philadelphia , Pennsylvania 19104 , United States.

Thioamidation as a posttranslational modification is exceptionally rare, with only a few reported natural products and exactly one known protein example (methyl-coenzyme M reductase from methane-metabolizing archaea). Recently, there has been significant progress in elucidating the biosynthesis and function of several thioamide-containing natural compounds. Separate developments in the chemical installation of thioamides into peptides and proteins have enabled cell biology and biophysical studies to advance the current understanding of natural thioamides. Read More

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http://dx.doi.org/10.1021/acschembio.8b01022DOI Listing
January 2019

N-Acyl Homoserine Lactone Derived Tetramic Acids Impair Photosynthesis in Phaeodactylum tricornutum.

ACS Chem Biol 2019 Feb 6. Epub 2019 Feb 6.

SynBioC, Department of Green Chemistry and Technology , Ghent University , Coupure Links 653 , B-9000 Ghent , Belgium.

Marine bacteria contribute substantially to nutrient cycling in the oceans and can engage in close interactions with microalgae. Many microalgae harbor characteristic satellite bacteria, many of which participate in N-acyl homoserine lactone (AHL) mediated quorum sensing. In the diffusion-controlled phycosphere, AHLs can reach high local concentrations, with some of them transforming into tetramic acids, compounds with a broad bioactivity. Read More

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http://dx.doi.org/10.1021/acschembio.8b01101DOI Listing
February 2019

Engineering of Chimeric Polyketide Synthases Using SYNZIP Docking Domains.

ACS Chem Biol 2019 Feb 11. Epub 2019 Feb 11.

Institute of Organic Chemistry and Chemical Biology, Buchmann Institute for Molecular Life Sciences , Goethe University Frankfurt , Max-von-Laue-Str. 15 , 60438 Frankfurt am Main , Germany.

Engineering of assembly line polyketide synthases (PKSs) to produce novel bioactive compounds has been a goal for over 20 years. The apparent modularity of PKSs has inspired many engineering attempts in which entire modules or single domains were exchanged. In recent years, it has become evident that certain domain-domain interactions are evolutionarily optimized and, if disrupted, cause a decrease of the overall turnover rate of the chimeric PKS. Read More

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http://dx.doi.org/10.1021/acschembio.8b01060DOI Listing
February 2019

Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System.

ACS Chem Biol 2019 Feb 4. Epub 2019 Feb 4.

State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology , Huazhong Agricultural University , Wuhan 430070 , China.

A nonribosomal peptide synthetase (NRPS) assembly line ( sfa) in Streptomyces thioluteus that directs the formation of the diisonitrile chalkophore SF2768 (1) has been characterized by heterologous expression and directed gene knockouts. Herein, differential metabolic analysis of the heterologous expression strain and the original host led to the isolation of an SF2768 analogue (2, a byproduct of sfa) that possesses N-isovaleryl rather than 3-isocyanobutyryl side chains. The proposed biosynthetic logic of sfa and the structural difference between 1 and 2 suggested substrate promiscuity of the adenylate-forming enzyme SfaB. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00938
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http://dx.doi.org/10.1021/acschembio.8b00938DOI Listing
February 2019
2 Reads

N-Acyl l-Homocysteine Thiolactones Are Potent and Stable Synthetic Modulators of the RhlR Quorum Sensing Receptor in Pseudomonas aeruginosa.

ACS Chem Biol 2019 Feb 1. Epub 2019 Feb 1.

Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.

The RhlR quorum sensing (QS) receptor in the pathogen Pseudomonas aeruginosa plays a prominent role in infection, and both antagonism and agonism of RhlR have been shown to negatively regulate important virulence phenotypes. Non-native lactone ligands are known to modulate RhlR activity, but their utility as chemical probes is relatively limited due to hydrolytic instability. Herein, we report our design and biological evaluation of a suite of hybrid AHL analogs with structures merging (1) features of reported lead RhlR ligands and (2) head groups with improved hydrolytic stabilities. Read More

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http://dx.doi.org/10.1021/acschembio.8b01079DOI Listing
February 2019
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Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization.

ACS Chem Biol 2019 Jan 29. Epub 2019 Jan 29.

Institute for Integrative Genome Biology , University of California Riverside , Riverside , California 92521 , United States.

Pyrabactin resistance 1 (PYR1) and related abscisic acid (ABA) receptors are new targets for manipulating plant drought tolerance. Here, we identify and use PYR1 hypersensitive mutants to define ligand binding hotspots and show that these can guide improvements in agonist potency. One hotspot residue defined, A160, is part of a pocket that is occupied by ABA's C6 methyl or by the toluyl methyl of the synthetic agonist quinabactin (QB). Read More

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http://dx.doi.org/10.1021/acschembio.8b00955DOI Listing
January 2019
1 Read

Metabolic Regulation of the Epitranscriptome.

ACS Chem Biol 2019 Feb 1. Epub 2019 Feb 1.

Chemical Biology Laboratory , National Cancer Institute , Frederick , Maryland 21702 , United States.

An emergent theme in cancer biology is that dysregulated energy metabolism may directly influence oncogenic gene expression. This is due to the fact that many enzymes involved in gene regulation use cofactors derived from primary metabolism, including acetyl-CoA,  S-adenosylmethionine, and 2-ketoglutarate. While this phenomenon was first studied through the prism of histone and DNA modifications (the epigenome), recent work indicates metabolism can also impact gene regulation by disrupting the balance of RNA post-transcriptional modifications (the epitranscriptome). Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00951
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http://dx.doi.org/10.1021/acschembio.8b00951DOI Listing
February 2019
7 Reads

Biosynthetic basis for structural diversity of aminophenylpyrrole-derived alkaloids.

ACS Chem Biol 2019 Jan 16. Epub 2019 Jan 16.

Bacterial aminophenylpyrrole-derived alkaloids (APPAs) represent high value lead compounds. Pyrrolnitrin, which was developed into globally important fungicides, is the only reported APPA produced by Proteobacteria. Recently, various APPAs showing diverse bioactivities were discovered from Bacteroidetes. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00993
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http://dx.doi.org/10.1021/acschembio.8b00993DOI Listing
January 2019
7 Reads

Kinetics of d-Amino Acid Incorporation in Translation.

ACS Chem Biol 2019 Jan 16. Epub 2019 Jan 16.

Department of Cell and Molecular Biology , Uppsala University , Husargatan 3 , Box 596, 751 24 Uppsala , Sweden.

Despite the stereospecificity of translation for l-amino acids (l-AAs) in vivo, synthetic biologists have enabled ribosomal incorporation of d-AAs in vitro toward encoding polypeptides with pharmacologically desirable properties. However, the steps in translation limiting d-AA incorporation need clarification. In this work, we compared d- and l-Phe incorporation in translation by quench-flow kinetics, measuring 250-fold slower incorporation into the dipeptide for the d isomer from a tRNA-based adaptor (tRNA). Read More

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http://dx.doi.org/10.1021/acschembio.8b00952DOI Listing
January 2019
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High Sensitivity of Human Translesion DNA Synthesis Polymerase κ to Variation in O-Carboxymethylguanine Structures.

ACS Chem Biol 2019 Feb 5. Epub 2019 Feb 5.

Department of Health Sciences and Technology , ETH Zürich , Schmelzbergstrasse 9 , 8092 , Zürich , Switzerland.

Carboxymethylation of DNA, including the formation of the DNA adduct O-carboxymethylguanine ( O-CMG), is associated with lifestyle factors, such as diet. It can impede replicative polymerases (Pols) and lead to replication fork stalling, or an alternative means for replication to proceed by translesion DNA synthesis (TLS). TLS requires specialized DNA Pols characterized by open and preformed active sites capable of preferential bypass of alkylated DNA adducts but that have high error rates, leading to mutations. Read More

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http://dx.doi.org/10.1021/acschembio.8b00802DOI Listing
February 2019
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Crystal Structures of Fumarate Hydratases from Leishmania major in a Complex with Inhibitor 2-Thiomalate.

ACS Chem Biol 2019 Jan 24. Epub 2019 Jan 24.

Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , São Paulo 14040-903 , Brazil.

Leishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mechanism of action of the first class-specific FH inhibitor, 2-thiomalate, through X-ray crystallography and inhibition assays. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00972
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http://dx.doi.org/10.1021/acschembio.8b00972DOI Listing
January 2019
5 Reads

Site-Specifically Studying Lysine Acetylation of Aminoacyl-tRNA Synthetases.

ACS Chem Biol 2019 Jan 29. Epub 2019 Jan 29.

Aminoacyl-tRNA synthetases (AARSs) charge their cognate tRNAs with corresponding amino acids, playing key roles in ribosomal protein synthesis. A series of proteomic studies have demonstrated that AARSs have levels of lysine acetylation much higher than those of other proteins in Escherichia coli. To study AARS acetylation, 25 site-specifically acetylated variants of four AARSs were generated by the genetic code expansion strategy. Read More

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http://dx.doi.org/10.1021/acschembio.8b01013DOI Listing
January 2019
2 Reads

Condensation-Incompetent Ketosynthase Inhibits trans-Acyltransferase Activity.

ACS Chem Biol 2019 Jan 29. Epub 2019 Jan 29.

Department of Chemistry and Biochemistry , George Mason University , Fairfax , Virginia 22030 , United States.

Nonelongating modules with condensation-incompetent ketosynthase (KS) are frequently found in many trans-acyltransferase polyketide synthases ( trans-AT PKS). KS catalyzes translocation of carbon chain without decarboxylative condensation. Unlike typical elongating modules where malonylation of acyl carrier protein (ACP) precedes elongation, the malonylation of ACP downstream of KS is assumed to be prevented. Read More

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http://dx.doi.org/10.1021/acschembio.8b01043DOI Listing
January 2019
1 Read

CB-6644 Is a Selective Inhibitor of the RUVBL1/2 Complex with Anticancer Activity.

ACS Chem Biol 2019 Jan 25. Epub 2019 Jan 25.

Cleave Biosciences, Inc. , Burlingame , California 94010 , United States.

RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) that form a complex involved in a variety of cellular processes, including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated with tumor growth and poor prognosis in several cancer types. CB-6644, an allosteric small-molecule inhibitor of the ATPase activity of the RUVBL1/2 complex, interacts specifically with RUVBL1/2 in cancer cells, leading to cell death. Read More

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http://dx.doi.org/10.1021/acschembio.8b00904DOI Listing
January 2019
2 Reads

Tunable Esterase-Triggered Self-Immolative Thiocarbamates Provide Insights into COS Cytotoxicity.

ACS Chem Biol 2019 Jan 14. Epub 2019 Jan 14.

Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors are self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than H2S. Read More

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http://dx.doi.org/10.1021/acschembio.8b00981DOI Listing
January 2019
1 Read

Slt, MltD and MltG of Pseudomonas aeruginosa as Targets of Bulgecin A in Potentiation of -Lactam Antibiotics.

ACS Chem Biol 2019 Jan 8. Epub 2019 Jan 8.

The interplay between the activities of lytic transglycosylases (LTs) and penicillin-binding proteins (PBPs) is critical for the health of bacterial cell wall. Bulgecin A (a natural-product inhibitor of LTs) potentiates the activity of β-lactam antibiotics (inhibitors of PBPs), underscoring this intimate mechanistic interdependence. Bulgecin A in the presence of an appropriate β-lactam causes bulge deformation due to the formation of aberrant peptidoglycan at the division site of the bacterium. Read More

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http://dx.doi.org/10.1021/acschembio.8b01025DOI Listing
January 2019
1 Read

Activity-based protein profiling identifies α-ketoamides as inhibitors for Phospholipase A2 Group XVI.

ACS Chem Biol 2019 Jan 8. Epub 2019 Jan 8.

Phospholipase A2, group XVI (PLA2G16) is a thiol-hydrolase from the HRASLS family that regulates lipolysis in adipose tissue and has been identified as a host factor enabling the cellular entry of picornaviruses. Chemical tools are essential to visualize and control PLA2G16 activity, but have not been reported to date. Here we show that MB064, a fluorescent lipase probe, also labels recombinant and endogenously expressed PLA2G16. Read More

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http://dx.doi.org/10.1021/acschembio.8b00969DOI Listing
January 2019
3 Reads
5.331 Impact Factor

Selective Small-Molecule Targeting of a Triple Helix Encoded by the Long Noncoding RNA, MALAT1.

ACS Chem Biol 2019 Jan 31. Epub 2019 Jan 31.

Basic Research Laboratory, Center for Cancer Research , National Cancer Institute , Frederick , Maryland 21702 , United States.

Metastasis-associated lung adenocarcinoma transcript 1 ( Malat1/ MALAT1, mouse/human), a highly conserved long noncoding (lnc) RNA, has been linked with several physiological processes, including the alternative splicing, nuclear organization, and epigenetic modulation of gene expression. MALAT1 has also been implicated in metastasis and tumor proliferation in multiple cancer types. The 3' terminal stability element for nuclear expression (ENE) assumes a triple-helical configuration that promotes its nuclear accumulation and persistent function. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00807
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http://dx.doi.org/10.1021/acschembio.8b00807DOI Listing
January 2019
5 Reads
5.331 Impact Factor

An Isotope-Coded Photocleavable Probe for Quantitative Profiling of Protein O-GlcNAcylation.

ACS Chem Biol 2019 Jan 8. Epub 2019 Jan 8.

MOE Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences , Zhejiang University , Hangzhou 310058 , China.

O-linked N-acetylglucosamine ( O-GlcNAc) is a ubiquitous post-translational modification of proteins and is essential for cell function. Quantifying the dynamics of O-GlcNAcylation in a proteome-wide level is critical for uncovering cellular mechanisms and functional roles of O-GlcNAcylation in cells. Here, we develop an isotope-coded photocleavable probe for profiling protein O-GlcNAcylation dynamics using quantitative mass spectrometry-based proteomics. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b01052
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http://dx.doi.org/10.1021/acschembio.8b01052DOI Listing
January 2019
5 Reads

NMR Dynamics Study Reveals the Zα Domain of Human ADAR1 Associates with and Dissociates from Z-RNA more slowly than Z-DNA.

ACS Chem Biol 2018 Dec 28. Epub 2018 Dec 28.

Human RNA editing enzyme ADAR1 deaminates adenosine in pre-mRNA to yield inosine. The Zα domain of human ADAR1 (hZαADAR1) binds specifically to left-handed Z-RNA as well as Z-DNA and stabilizes the Z-conformation. To answer the question of how hZαADAR1 can induce both the B-Z transition of DNA and the A-Z transition of RNA, we investigated the structure and dynamics of hZαADAR1 in complex with 6-base-pair Z-DNA or Z-RNA. Read More

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http://dx.doi.org/10.1021/acschembio.8b00914DOI Listing
December 2018
1 Read

Tryptophan Metabolism in Caenorhabditis elegans Links Aggregation Behavior to Nutritional Status.

ACS Chem Biol 2018 Dec 26. Epub 2018 Dec 26.

Department of Chemistry , University of Florida , Gainesville , Florida 32611 , United States.

Caenorhabditis elegans uses aggregation pheromones to communicate its nutritional status and recruit fellow members of its species to food sources. These aggregation pheromones include the IC-ascarosides, ascarosides modified with an indole-3-carbonyl (IC) group on the 4'-position of the ascarylose sugar. Nothing is known about the biosynthesis of the IC modification beyond the fact that it is derived from tryptophan. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00872
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http://dx.doi.org/10.1021/acschembio.8b00872DOI Listing
December 2018
12 Reads

Persistent, Multi-Generational Reduction of Oxysterol-Binding Protein Caused by Compound Treatment Induces Prophylactic Anti-Viral Activity.

ACS Chem Biol 2018 Dec 21. Epub 2018 Dec 21.

Oxysterol-binding protein (OSBP) is a lipid transport and regulatory protein required for the replication of Enterovirus genus viruses, which includes many significant human pathogens. Short-term exposure (i.e. Read More

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http://dx.doi.org/10.1021/acschembio.8b00984DOI Listing
December 2018
3 Reads

A cancer-selective zinc ionophore inspired by the natural product naamidine A.

ACS Chem Biol 2018 Dec 20. Epub 2018 Dec 20.

We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn2+-uptake in transformed cells. ZNA's cancer selectivity was evaluated using metastatic, patient-derived breast cancer cells, established human breast cancer cell lines, and 3-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demonstrated that the compound interacts with zinc through the N2-acyl-2-aminoimidazole core. Read More

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http://dx.doi.org/10.1021/acschembio.8b00977DOI Listing
December 2018
1 Read
5.331 Impact Factor

Covalent modifiers of Botulinum neurotoxin counteract toxin persistence.

ACS Chem Biol 2018 Dec 20. Epub 2018 Dec 20.

Botulinum neurotoxins (BoNTs) are the most potent toxin known to man and a significant threat as a weapon of bioterrorism. BoNTs contain a metalloprotease domain that blocks neurotransmitter release in nerve terminals, resulting in a descending, flaccid paralysis with a 5-10% mortality rate. Existing treatment options cannot access or neutralize toxin following its endocytosis, so there is a clear need to develop novel therapies. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00937
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http://dx.doi.org/10.1021/acschembio.8b00937DOI Listing
December 2018
6 Reads
5.331 Impact Factor

A Unique Biosynthetic Pathway in Bloom-Forming Cyanobacterial Genus Microcystis Jointly Assembles Cytotoxic Aeruginoguanidines and Microguanidines.

ACS Chem Biol 2018 Dec 17. Epub 2018 Dec 17.

The cyanobacterial genus Microcystis is known to produce an elaborate array of structurally unique and biologically active natural products including hazardous cyanotoxins. Cytotoxic aeruginoguanidines represent a yet unexplored family of peptides featuring a trisubstituted benzene unit and farnesylated arginine derivatives. In this study, we aimed at assigning these compounds to a biosynthetic gene cluster by utilizing biosynthetic attributes deduced from public genomes of Microcystis and the sporadic distribution of the metabolite in axenic strains of the Pasteur Culture Collection of Cyanobacteria. Read More

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http://dx.doi.org/10.1021/acschembio.8b00918DOI Listing
December 2018
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Novel methoxymethacrylate natural products uncovered by statistics-based mining of the Myxococcus fulvus secondary metabolome.

ACS Chem Biol 2018 Dec 13. Epub 2018 Dec 13.

This study reports the uncovering of new myxobacterial natural products through comprehensive analysis of the Myxococcus fulvus secondary metabolome. Statistics-based mining of mass spectrometry data paved the way for full structure elucidation of two new secondary metabolites named fulvuthiacene A and B, and investigation of the underlying biosynthetic pathway revealed an evolutionary link between the fulvuthiacene hybrid polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) gene cluster and the related myxothiazol and melithiazol assembly lines. Detailed characterization of the post-PKS modification enzyme cascade responsible for the fulvuthiacenes' terminal β-methoxy-methylacrylate moiety was pursued by heterologous expression of these enzymes in the myxothiazol producer Stigmatella aurantiaca DW4/3-1. Read More

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http://dx.doi.org/10.1021/acschembio.8b00948DOI Listing
December 2018
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Class I methyltransferase VioH catalyzes unusual SAM cyclization leading to 4-methylazetidinecarboxylic acid formation in vioprolide biosynthesis.

Authors:
Fu Yan Rolf Müller

ACS Chem Biol 2018 Dec 12. Epub 2018 Dec 12.

SAM-dependent methyltransferases are intensely studied since they play important roles in the methylation of biomolecules in all domains of life. In this study we describe that the methyltransferase VioH from Cysotobacter violaceus catalyzes a so far unknown cyclization of SAM to azetidine-2-carboxylic acid (AZE), which is proposed to be the precursor of the unusual 4-methylazetidinecarboxylic acid (MAZ) moiety of vioprolides. In vitro biochemical investigations reveal that SAM is converted to AZE in the presence of VioH, while MAZ is generated by coexpression of VioH and the radical SAM enzyme VioG in Myxococcus xanthus or by combination of VioH and the cell lysate of M. Read More

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http://dx.doi.org/10.1021/acschembio.8b00958DOI Listing
December 2018
1 Read