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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28233494/discovery-of-an-extended-austinoid-biosynthetic-pathway-in-aspergillus-calidoustus
#1
Vito Valiante, Derek J Mattern, Anja Schueffler, Fabian Horn, Grit Walther, Kirstin Scherlach, Lutz Petzke, Joachim Dickhaut, Reinhard Guthke, Christian Hertweck, Markus Nett, Eckhard Thines, Axel A Brakhage
Filamentous fungi produce a wide range of natural products that are commonly used in various industrial contexts (e.g. pharmaceuticals and insecticides). Meroterpenoids are natural products of interest because of their various biological activities. Among the meroterpenoids, there is a group of insecticidal compounds known as the austinoids. These compounds have also been studied because of their intriguing spiro-lactone ring formation along with various modifications. Here we present an extension of the original austinol/dehydroaustinol biosynthesis pathway from Aspergillus nidulans, in the recently identified filamentous fungus Aspergillus calidoustus...
February 24, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28233492/mitochondrial-cysteine-desulfurase-and-isd11-co-expressed-in-escherichia-coli-yield-complex-containing-acyl-carrier-protein
#2
Kai Cai, Ronnie O Frederick, Marco Tonelli, John L Markley
Mitochondrial cysteine desulfurase is an essential component of the machinery for iron-sulfur cluster biosynthesis. Human cysteine desulfurase that is catalytically active in vitro can be prepared by overexpressing two protein components of this system, ISD11 and NFS1, in Escherichia coli cells. We report that ISD11 and NFS1 form a complex containing the holo-form of E. coli acyl carrier protein (holo-Acp). The stoichiometry of the complex is [Acp]2:[ISD11]2:[NFS1]2. Because acyl carrier protein recently has been found to be an essential component of the iron-sulfur biosynthesis machinery in mitochondria, it appears that E...
February 24, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28229591/ass1-is-a-metabolic-regulator-of-colorectal-cancer-pathogenicity
#3
Leslie A Bateman, Wan-Min Ku, Martin J Heslin, Carlo M Contreras, Christine F Skibola, Daniel K Nomura
Like many cancer types, colorectal cancers have dysregulated metabolism that promotes their pathogenic features. In this study, we used the activity-based protein profiling chemoproteomic platform to profile cysteine-reactive metabolic enzymes that are upregulated in primary human colorectal tumors. We identified argininosuccinate synthase 1 (ASS1) as an upregulated target in primary human colorectal tumors and show that pharmacological inhibition or genetic ablation of ASS1 impairs colorectal cancer colorectal pathogenicity...
February 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28103010/a-fluorescent-hsp90-probe-demonstrates-the-unique-association-between-extracellular-hsp90-and-malignancy-in-vivo
#4
Lauren B Crowe, Philip F Hughes, David A Alcorta, Takuya Osada, Aaron P Smith, Juliane Totzke, David R Loiselle, Isaac D Lutz, Madhusudhana Gargesha, Debasish Roy, Jose Roques, David Darr, H Kim Lyerly, Neil L Spector, Timothy A J Haystead
Extracellular expression of heat shock protein 90 (eHsp90) by tumor cells is correlated with malignancy. Development of small molecule probes that can detect eHsp90 in vivo may therefore have utility in the early detection of malignancy. We synthesized a cell impermeable far-red fluorophore-tagged Hsp90 inhibitor to target eHsp90 in vivo. High resolution confocal and lattice light sheet microscopy show that probe-bound eHsp90 accumulates in punctate structures on the plasma membrane of breast tumor cells and is actively internalized...
February 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28195704/highly-potent-cell-permeable-and-impermeable-nanoluc-luciferase-inhibitors
#5
Joel R Walker, Mary P Hall, Chad A Zimprich, Matthew B Robers, Sarah J Duellman, Thomas Machleidt, Jacquelynn Rodriguez, Wenhui Zhou
Novel engineered NanoLuc (Nluc) luciferase being smaller, brighter, and superior to traditional firefly (Fluc) or Renilla (Rluc) provides a great opportunity for the development of numerous biological, biomedical, clinical, and food and environmental safety applications. This new platform created an urgent need for Nluc inhibitors that could allow selective bioluminescent suppression and multiplexing compatibility with existing luminescence or fluorescence assays. Starting from thienopyrrole carboxylate 1, a hit from a 42 000 PubChem compound library with a low micromolar IC50 against Nluc, we derivatized four different structural fragments to discover a family of potent, single digit nanomolar, cell permeable inhibitors...
February 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28195695/o-glcnacylation-of-%C3%AE-synuclein-at-serine-87-reduces-aggregation-without-affecting-membrane-binding
#6
Yuka E Lewis, Ana Galesic, Paul M Levine, Cesar A De Leon, Natalie Lamiri, Caroline K Brennan, Matthew R Pratt
The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson's disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation...
February 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28165699/eg5-inhibitors-have-contrasting-effects-on-microtubule-stability-and-metaphase-spindle-integrity
#7
Geng-Yuan Chen, You Jung Kang, A Sophia Gayek, Wiphu Youyen, Erkan Tüzel, Ryoma Ohi, William O Hancock
To uncover their contrasting mechanisms, antimitotic drugs that inhibit Eg5 (kinesin-5) were analyzed in mixed-motor gliding assays of kinesin-1 and Eg5 motors in which Eg5 "braking" dominates motility. Loop-5 inhibitors (monastrol, STLC, ispinesib, and filanesib) increased gliding speeds, consistent with inducing a weak-binding state in Eg5, whereas BRD9876 slowed gliding, consistent with locking Eg5 in a rigor state. Biochemical and single-molecule assays demonstrated that BRD9876 acts as an ATP- and ADP-competitive inhibitor with 4 nM KI...
February 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28221753/structure-activity-relationships-of-the-competence-stimulating-peptides-csps-in-streptococcus-pneumoniae-reveal-motifs-critical-for-intra-group-and-cross-group-comd-receptor-activation
#8
Yifang Yang, Bimal Koirala, Lucia A Sanchez, Naiya R Phillips, Sally R Hamry, Yftah Tal-Gan
Streptococcus pneumoniae is a highly recombinogenic human pathogen that utilizes the competence stimulating peptide (CSP)-based quorum sensing (QS) circuitry to acquire antibiotic resistance genes from the environment and initiate its attack on the human host. Modulation of QS in this bacterium, either inhibition or activation, can therefore be used to attenuate S. pneumoniae infectivity and slow down pneumococcal resistance development. In this study we set to determine the molecular mechanism that drives CSP:receptor binding and identify CSP-based QS modulators with distinct activity profiles...
February 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28221017/change-in-heat-capacity-for-enzyme-catalysis-determines-temperature-dependence-of-enzyme-catalyzed-rates
#9
Joanne K Hobbs, Wanting Jiao, Ashley D Easter, Emily J Parker, Louis A Schipper, Vickery L Arcus
No abstract text is available yet for this article.
February 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28191925/mechanistic-debris-generated-by-twister-ribozymes
#10
Ronald R Breaker
Twister RNAs represent a recently discovered class of natural ribozymes that promote rapid cleaving of RNA backbones. Although an abundance of theoretical, biochemical, and structural data exist for several members of the twister class, disagreements about the architecture and mechanism of its active site have emerged. Historically, such storms regarding mechanistic details typically occur soon after each new self-cleaving ribozyme class is reported, but paths forward exist to quickly reach calmer conditions...
February 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28051298/the-activity-of-jmjc-histone-lysine-demethylase-kdm4a-is-highly-sensitive-to-oxygen-concentrations
#11
Rebecca L Hancock, Norma Masson, Kate Dunne, Emily Flashman, Akane Kawamura
The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG)-dependent oxygenases, are related to the cellular oxygen sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that the activity of some KDMs, including the pseudogene-encoded KDM4E, may be sensitive to changing oxygen concentrations...
February 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28211680/two-way-gold-nanoparticle-label-free-sensing-of-specific-sequence-and-small-molecule-targets-using-switchable-concatemers
#12
Longjiao Zhu, Xiangli Shao, Yunbo Luo, Kunlun Huang, Wentao Xu
A two-way colorimetric biosensor based on unmodified gold nanoparticles (GNPs) and a switchable double-stranded DNA (dsDNA) concatemer have been demonstrated. Two hairpin probes (H1&H2) were first designed that provided the fuels to assemble the dsDNA concatemers via hybridization chain reaction (HCR). A functional hairpin (FH) was rationally designed to recognize the target sequences. All the hairpins contained single-stranded DNA (ssDNA) loop and sticky-ends to prevent GNPs from salt-induced aggregation. In the presence of target sequence, the capture probe blocked in the FH recognizes the target to form a duplex DNA, which causes the release of the initiator probe by FH conformational change...
February 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28182402/evolution-and-distribution-of-c7-cyclitol-synthases-in-prokaryotes-and-eukaryotes
#13
Andrew R Osborn, Kelsey M Kean, Khaled M Alseud, Khaled H Almabruk, Shumpei Asamizu, Janet A Lee, P Andrew Karplus, Taifo Mahmud
2-Epi-5-epi-valiolone synthase (EEVS), a C7-sugar phosphate cyclase (SPC) homologous to 3-dehydroquinate synthase (DHQS), was discovered during studies of the biosynthesis of the C7N-aminocyclitol family of natural products. EEVS was originally thought to be present only in certain actinomycetes, but analyses of genome sequences showed that it is broadly distributed in both prokaryotes and eukaryotes, including vertebrates. Another SPC, desmethyl-4-deoxygadusol synthase (DDGS), was later discovered as being involved in the biosynthesis of mycosporine-like amino acid sunscreen compounds...
February 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28205432/fluorescent-hexose-conjugates-establish-stringent-stereochemical-requirement-by-glut5-for-recognition-and-transport-of-monosaccharides
#14
Olivier-Mohamad Soueidan, Thomas W Scully, Jatinder Kaur, Rashmi Panigrahi, Alexandr Belovodskiy, Victor Do, Carson D Matier, M Joanne Lemieux, Frank Wuest, Chris Cheeseman, F G West
The specificity characteristics of transporters can be exploited for the development of novel diagnostic therapeutic probes. The facilitated hexose transporter family (GLUTs) has a distinct set of preferences for monosaccharide substrates, and while some are expressed ubiquitously (e.g., GLUT1), others are quite tissue specific (e.g., GLUT5, which is overexpressed in some breast cancer tissues). While these differences have enabled the development of new molecular probes based upon hexose- and tissue-selective uptake, substrate design for compounds targeting these GLUT transporters has been encumbered by a limited understanding of the molecular interactions at play in hexose binding and transport...
February 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28199080/characterization-of-cyp115-as-a-gibberellin-3-oxidase-indicates-that-certain-rhizobia-can-produce-bioactive-gibberellin-a4
#15
Ryan S Nett, Tiffany Contreras, Reuben J Peters
The gibberellin (GA) phytohormones are produced not only by plants but also by fungi and bacteria. Previous characterization of a cytochrome P450 (CYP)-rich GA biosynthetic operon found in many symbiotic, nitrogen-fixing rhizobia led to the elucidation of bacterial GA biosynthesis and implicated GA9 as the final product. However, GA9 does not exhibit hormonal/biological activity and presumably requires further transformation to elicit an effect in the legume host plant. Some rhizobia that contain the GA operon also possess an additional CYP (CYP115), and here we show that this acts as a GA 3-oxidase to produce bioactive GA4 from GA9...
February 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28165718/modification-of-the-orthosteric-ppar%C3%AE-covalent-antagonist-scaffold-yields-an-improved-dual-site-allosteric-inhibitor
#16
Richard Brust, Hua Lin, Jakob Fuhrmann, Alice Asteian, Theodore M Kamenecka, Douglas J Kojetin
GW9662 and T0070907 are widely used commercially available irreversible antagonists of peroxisome proliferator-activated receptor gamma (PPARγ). These antagonists covalently modify Cys285 located in an orthosteric ligand-binding pocket embedded in the PPARγ ligand-binding domain and are used to block binding of other ligands. However, we recently identified an alternate/allosteric ligand-binding site in the PPARγ LBD to which ligand binding is not inhibited by these orthosteric covalent antagonists. Here, we developed a series of analogs based on the orthosteric covalent antagonist scaffold with the goal of inhibiting both orthosteric and allosteric cellular activation of PPARγ by MRL20, an orthosteric agonist that also binds to an allosteric site...
February 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28198609/an-unusual-flavin-dependent-halogenase-from-the-metagenome-of-the-marine-sponge-theonella-swinhoei-wa
#17
Duncan R M Smith, Agustinus R Robert Uria, Eric J N Helfrich, Daniela Milbredt, Karl-Heinz van-Pee, Joern 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, and with potential as a useful new biocatalytic tool is described...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28186406/substrate-trapping-in-the-siderophore-tailoring-enzyme-pvdq
#18
Kenneth D Clevenger, Romila Mascarenhas, Daniel Catlin, Rui Wu, Neil L Kelleher, Eric J Drake, Andrew M Gulick, Dali Liu, Walter Fast
Siderophore biosynthesis by Pseudomonas aeruginosa enhances virulence and represents an attractive drug target. PvdQ functions in the type-1 pyoverdine biosynthetic pathway by removing a myristoyl anchor from a pyoverdine precursor, allowing eventual release from the periplasm. A circularly permuted version of PvdQ bypasses the self-processing step of this Ntn-hydrolase and retains the activity, selectivity, and structure of wild-type PvdQ, as revealed by a 1.8 Å resolution X-ray crystal structure. A 2.55 Å resolution structure of the inactive S1A/N269D-cpPvdQ mutant in complex with the pyoverdine precursor PVDIq reveals a specific binding pocket for the d-Tyr of this modified peptide substrate...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28186404/inositol-pyrophosphate-specificity-of-the-spx-dependent-polyphosphate-polymerase-vtc
#19
Ruta Gerasimaite, Igor Pavlovic, Samanta Capolicchio, Alexandre Hofer, Andrea Schmidt, Henning J Jessen, Andreas Mayer
The free energy of nucleotide hydrolysis depends on phosphate concentration. Cells regulate cytosolic phosphate levels by orchestrating phosphate acquisition and storage through inositol pyrophosphates (PP-InsP) and SPX domains. Here, we report the synthesis of the novel 5-PPP-InsP5 containing a triphosphate subunit. Using this and a series of synthetic PP-InsP, we examined the ligand specificity of the SPX domain in the PP-InsP-controlled yeast polyphosphate polymerase VTC. SPX decodes the relative positioning of the phosphoric anhydrides, their structure (diphosphate vs triphosphate), and the presence of other phosphates on the inositol ring...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28186401/chemoproteomic-screening-of-covalent-ligands-reveals-uba5-as-a-novel-pancreatic-cancer-target
#20
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
February 15, 2017: ACS Chemical Biology
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