Design and Application of In Vivo FRET Biosensors to Identify Protein Prenylation and Nanoclustering Inhibitors

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Highlights? Cellular FRET biosensors for Ras, Rho, and Rab membrane anchorage were developed ? We provide evidence for Rab protein nanoclustering on cellular membranes ? Two FRET biosensors were demonstrated to be suitable for high-throughput screening ? Macrotetrolides were identified as nanoclustering and MAPK signaling disruptors     

Hsp104 Drives “Protein-Only” Positive Selection of Sup35 Prion Strains Encoding Strong [PSI+]

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Highlights? Hsp104 disrupts intermolecular contacts of different synthetic NM prion strains ? Hsp104 selectively amplifies NM prions that confer strong [PSI⁺] phenotypes ? Hsp104 selectively eliminates NM prions that confer weak [PSI⁺] phenotypes ? Hsp104 drives strain selection events that favor prions encoding strong [PSI⁺]     

Deglycosylation as a Mechanism of Inducible Antibiotic Resistance Revealed Using a Global Relational Tree for One-Component Regulators

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Highlights? Phylogenomics can be used to predict cognate ligands for TetR-family regulators ? KijR (SCO7719) regulates kijX (SCO7720) in response to the antibiotic kijanimicin ? kijX encodes a kijanimicin-resistance determinant ? KijX is a glycosyl hydrolase and inactivates kijanimicin through deglycosylation     

Validation of the Proteasome as a Therapeutic Target in Plasmodium Using an Epoxyketone Inhibitor with Parasite-Specific Toxicity

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Highlights? Purification of Plasmodium proteasomes and labeling with an activity-based probe ? Identification of an epoxyketone-based inhibitor with parasite-specific toxicity ? Demonstration that Plasmodium is sensitive to partial inhibition of its proteasome ? Determination of key parameters for selective parasite killing with proteasome inhibitors     

A Bacterial Source for Mollusk Pyrone Polyketides

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Highlights? Symbiotic bacteria synthesize compounds found in mollusks ? Physically defended mollusks provide a source for bioactive metabolite discovery ? A type of pyrone polyketide pathway described ? Nocardiopsis strains may be widespread, casually associated symbionts of inveterbrates     

Fragment Screening at Adenosine-A3 Receptors in Living Cells Using a Fluorescence-Based Binding Assay

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Highlights? Fluorescence-based competition binding assay for adenosine-A₁ and -A₃ receptors ? Fragment screen using receptors in the native membrane environment in living cells ? Lead compound identification and optimization from a commercial fragment library     

Recycling of Informational Units Leads to Selection of Replicators in a Prebiotic Soup

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Highlights? Recycling of genetic material is important for the origins of life ? Simulation studies show recycling leads to the selection of genotypes from a pool ? Recycling can lead to the sudden emergence of a high-fitness RNA genotype ? Experimental studies with the Azoarcus ribozyme show fragment recycling     

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Potent Immunoresolvents

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Highlights? RvD3 accumulates in late inflammation resolution ? Aspirin triggers biosynthesis of RvD3 17R-epimer (AT-RvD3) that is proresolving ? Complete stereochemistry of RvD3 and AT-RvD3 are established ? RvD3 and AT-RvD3 govern leukocyte functions and local inflammatory responses     

Characterization of a Silent Azaphilone Gene Cluster from Aspergillus niger ATCC 1015 Reveals a Hydroxylation-Mediated Pyran-Ring Formation

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Highlights? Discovery of an azaphilone pathway in Aspergillus niger ? Six azaphilone compounds were isolated and characterized ? The biosynthesis involves convergent actions of an HR-PKS and an NR-PKS ? Hydroxylation by a monooxygenase promotes pyran-ring formation     

Fluorescent Saxitoxins for Live Cell Imaging of Single Voltage-Gated Sodium Ion Channels beyond the Optical Diffraction Limit

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Highlights? Fluorescent saxitoxins synthesized as imaging agents for sodium ion channels (Na_Vs) ? Electrophysiology and confocal imaging establish potency and selectivity of Na_V probes ? Single-molecule and super-resolution imaging reveal subdiffraction Na_V distributions ? Dynamic motions of Na_Vs measured in specific membrane regions in live cells     

Cloning,Heterologous Expression,and Characterization of the Gene Cluster Required for Gougerotin Biosynthesis

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Highlights? The complete gougerotin biosynthetic gene cluster is cloned ? Heterologous production of gougerotin is accomplished in S. coelicolor M1146 ? Biosynthetic pathway is proposed based on bioinformatics, genetic, and chemical analyses ? Preliminary data support an uncommon enzymatic reaction for peptide bond formation     

Elucidation of Piericidin A1 biosynthetic locus revealed a thioesterase-dependent mechanism of α-pyridone ring formation

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Highlights? Genome scanning revealed a pathway for α-pyridone antibiotics in bacteria ? Gene replacements verified pieA, C, D are involved in piericidin A1 biosynthesis ? In vitro characterization showed that PieA-TE mediates polyketide hydrolysis ? Biosynthesis of α-pyridone via hydrolysis followed by amidation and cyclization     

A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

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Highlights? S1P₁ antagonists were designed and optimized ? NIBR-0213 is a highly potent and selective S1P₁ antagonist ? NIBR-0213 induces long lasting reduction of lymphocyte counts in blood ? NIBR-0213 has comparable efficacy to fingolimod (FTY720) in a mouse EAE model     

Chemical perturbation of secondary metabolism demonstrates important links to primary metabolism

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Highlights? A chemical screen recapitulates all genetic phenotypes in S. coelicolor ? 19 compounds remodel secondary metabolism in Streptomyces coelicolor ? Partial inhibition of fatty acid synthesis remodels secondary metabolite production     

Insights into a Divergent Phenazine Biosynthetic Pathway Governed by a Plasmid-Born Esmeraldin Gene Cluster

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Highlights? Esm gene cluster resides on a highly unstable giant plasmid ? EsmA1 and A2 work together to promote the formation of phenazine-1,6-dicarboxylic acid ? Polyketide synthase enzymes EsmB1–B5 catalyze the unique methyl transfer ? Atypical polyketide synthase enzymes EsmD1–D3 catalyze the esterification.     

Characterization of a Fungal Thioesterase Having Claisen Cyclase and Deacetylase Activities in Melanin Biosynthesis

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Highlights? Revised C. lagenarium Pks1 coding sequence enabling in vitro analysis ? Clarified third fungal route to dihydroxynaphthalene melanin ? Revealed thioesterase-catalyzed tandem Claisen cyclization and deacetylation ? Lid swap chimera illuminate features necessary for C-C bond making and breaking     

Biosynthesis of the Respiratory Toxin Bongkrekic Acid in the Pathogenic Bacterium Burkholderia gladioli

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Highlights? Molecular basis for the biosynthesis of a fatal food toxin revealed ? Functional genetics by λ Red recombination in the pathogen Burkholderia gladioli ? Stereochemistry of modular bongkrekic acid PKS decoded ? β-Branching and six-electron methyl oxidation lead to tricarboxylic fatty acid     

Discovery of an Iron-Regulated Citrate Synthase in Staphylococcus aureus

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Highlights? Staphylococcus aureus SbnG is discovered to be an iron-regulated citrate synthase ? SbnG provides citrate for synthesis of the citrate siderophore staphyloferrin B ? Staphyloferrin B can be synthesized in vitro using purified enzymes ? SbnG inhibitors identified     

Identification of JadG as the B Ring Opening Oxygenase Catalyzing the Oxidative C-C Bond Cleavage Reaction in Jadomycin Biosynthesis

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Highlights? JadG catalyzes the oxidative C-C bond B ring cleavage of dehydrorabelomycin ? JadG needs FMNH₂ or FADH₂ as cofactors ? JadY is a flavin reductase that could supply FMNH₂ or FADH₂ for JadG     

A Competitive Stapled Peptide Screen Identifies a Selective Small Molecule that Overcomes MCL-1-Dependent Leukemia Cell Survival

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Highlights? A stapled peptide-based screen identified a selective molecular inhibitor of MCL-1 ? MIM1 targets a subregion of the BH3-binding pocket of antiapoptotic MCL-1 ? In contrast to ABT-737, MIM1 binds and functionally neutralizes MCL-1 but not BCL-X_L ? MIM1 exhibits MCL-1-dependent antileukemia activity and synergizes with ABT-737