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ACS Chemical Biology

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https://www.readbyqxmd.com/read/30240188/discovery-and-functional-characterization-of-a-yeast-sugar-alcohol-phosphatase
#1
Yi-Fan Xu, Wenyun Lu, Jonathan C Chen, Sarah A Johnson, Patrick A Gibney, David G Thomas, Greg Brown, Amanda L May, Shawn R Campagna, Alexander F Yakunin, David Botstein, Joshua D Rabinowitz
Sugar alcohols (polyols) exist widely in nature. While some specific sugar alcohol phosphatases are known, there is no known phosphatase for some important sugar alcohols (e.g., sorbitol-6-phosphate). Using liquid chromatography-mass spectrometry-based metabolomics, we screened yeast strains with putative phosphatases of unknown function deleted. We show that the yeast gene YNL010W, which has close homologues in all fungi species and some plants, encodes a sugar alcohol phosphatase. We term this enzyme, which hydrolyzes sorbitol-6-phosphate, ribitol-5-phosphate, and (D)-glycerol-3-phosphate, polyol phosphatase 1 or PYP1...
September 21, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30239186/type-ii-kinase-inhibitors-targeting-cys-gatekeeper-kinases-display-orthogonality-with-wild-type-and-ala-gly-gatekeeper-kinases
#2
Cory A Ocasio, Alexander A Warkentin, Patrick J McIntyre, Krister J Barkovich, Clare Vesely, John Spencer, Kevan M Shokat, Richard Bayliss
Analog-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogs of pyrazolopyrimidine-based Src kinase inhibitors (e.g. PP1). This 'bump-hole' method has been utilized for at least 85 of ~520 kinases, but many kinases are intolerant to this approach. To expand the scope of AS-kinase technology, we designed type II kinase inhibitors, ASDO2/6 (Analog-Sensitive 'DFG-Out' kinase inhibitors-2/6), that target the 'DFG-out' conformation of cysteine (Cys)-gatekeeper kinases with submicromolar potency...
September 21, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30216041/systematic-evaluation-of-soluble-protein-expression-using-a-fluorescent-unnatural-amino-acid-reveals-no-reliable-predictors-of-tolerability
#3
Zachary M Hostetler, John J Ferrie, Marc R Bornstein, Itthipol Sungwienwong, E James Petersson, Rahul M Kohli
Improvements in genetic code expansion have made preparing proteins with diverse functional groups almost routine. Nonetheless, unnatural amino acids (Uaas) pose theoretical burdens on protein solubility, and determinants of position-specific tolerability to Uaas remain underexplored. To broadly examine associations, we systematically assessed the effect of substituting the fluorescent Uaa, acridonylalanine, at more than 50 chemically, evolutionarily, and structurally diverse residues in two bacterial proteins: LexA and RecA...
September 20, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30204411/aggregation-of-vibrio-cholerae-by-cationic-polymers-enhances-quorum-sensing-but-overrides-biofilm-dissipation-in-response-to-autoinduction
#4
Nicolas Perez-Soto, Oliver Creese, Francisco Fernandez-Trillo, Anne-Marie Krachler
Vibrio cholerae is a Gram-negative bacterium found in aquatic environments and a human pathogen of global significance. Its transition between host-associated and environmental lifestyles involves the tight regulation of niche-specific phenotypes such as motility, biofilm formation, and virulence. V. cholerae's transition from the host to environmental dispersal usually involves suppression of virulence and dispersion of biofilm communities. In contrast to this naturally occurring transition, bacterial aggregation by cationic polymers triggers a unique response, which is to suppress virulence gene expression while also triggering biofilm formation by V...
September 20, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30107111/structure-activity-relationship-of-flavin-analogues-that-target-the-flavin-mononucleotide-riboswitch
#5
Quentin Vicens, Estefanía Mondragón, Francis E Reyes, Philip Coish, Paul Aristoff, Judd Berman, Harpreet Kaur, Kevin W Kells, Phil Wickens, Jeffery Wilson, Robert C Gadwood, Heinrich J Schostarez, Robert K Suto, Kenneth F Blount, Robert T Batey
The flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative, 5FDQD, that protects mice against diarrhea-causing Clostridium difficile bacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis, and purification of derivatives; (3) in vitro testing for productive binding using two chemical probing methods; (4) in vitro transcription termination assays; and (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates...
September 20, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30230814/metabolic-labeling-of-pseudaminic-acid-containing-glycans-on-bacterial-surfaces
#6
Gloria Andolina, Ruohan Wei, Han Liu, Qing Zhang, Xuemei Yang, Huiluo Cao, Sheng Chen, Aixin Yan, Xiang David Li, Xuechen Li
The rise in antibiotic resistant bacteria is causing worldwide concerns. The urgent need for new antibacterial drugs calls for new thinking and strategies to explore novel, narrow-spectrum and pathogen-specific antibacterial targets. Legionaminic acid (Leg) and pseudaminic acid (Pse) are nonulosonic acid carbohydrates with structural similarity to eukaryotic sialic acid, and are distributed in numerous pathogenic Gram-negative bacteria as components of cell surface-associated glycans. They are involved in the host interaction, pathogenicity, anti-phage defense mechanism and immune escape mechanism...
September 19, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30216042/chemical-instability-and-promiscuity-of-arylmethylidenepyrazolinone-based-mdmx-inhibitors
#7
Jakub Stefaniak, Andrew M Lewis, Daniel Conole, Sébastien R G Galan, Carole J R Bataille, Graham M Wynne, M Paola Castaldi, Thomas Lundbäck, Angela J Russell, Kilian V M Huber
Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity...
September 19, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30226743/a-cyclic-peptide-inhibitor-of-the-inos-spsb-protein-protein-interaction-as-a-potential-anti-infective-agent
#8
Maiada M Sadek, Nicholas Barlow, Eleanor W W Leung, Billy J Williams-Noonan, Beow Keat Yap, Fairolniza Mohd Shariff, Tom T Caradoc-Davies, Sandra E Nicholson, David K Chalmers, Philip E Thompson, Ruby H P Law, Raymond S Norton
SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction...
September 18, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30226371/a-non-heme-feii-2-oxoglutarate-dependent-oxygenase-catalyzes-a-double-bond-migration-within-a-dimethylallyl-moiety-accompanied-by-hydroxylation
#9
Huomiao Ran, Viola Wohlgemuth, Xiulan Xie, Shu-Ming Li
Prenylation of cyclodipeptides contributes largely to the structure diversification and biological activity. The prenylated products can be further metabolized by modifications like hydroxyla-tion with cytochrome P450 enzymes or non-heme FeII/2-oxoglutarate-dependent oxygenases. Herein, we cloned and overexpressed NFIA_045530 from Neosartorya fischeri, which shares high sequence similarity with the non-heme FeII/2-oxoglutarate-dependent oxygenase FtmOx1Af from Aspergillus fumigatus on the amino acid level. FtmOx1Af is a member of the biosynthetic enzymes for fumitremorgin-type mycotoxins and catalyzes the conversion of fu-mitremorgin B to verruculogen by insertion of an oxygen molecule into the two prenyl moieties...
September 18, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30200762/modulating-pcaf-gcn5-immune-cell-function-through-a-protac-approach
#10
Zuni I Bassi, Martin C Fillmore, Afjal H Miah, Trevor D Chapman, Claire Maller, Emma J Roberts, Lauren C Davis, Darcy E Lewis, Nicholas W Galwey, Kirsty E Waddington, Valentino Parravicini, Abigail L Macmillan-Jones, Celine Gongora, Philip G Humphreys, Ian Churcher, Rab K Prinjha, David F Tough
P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells...
September 18, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30183259/rapid-discovery-of-glycocins-through-pathway-refactoring-in-escherichia-coli
#11
Hengqian Ren, Subhanip Biswas, Sherri Ho, Wilfred A van der Donk, Huimin Zhao
Glycocins (glycosylated bacteriocins) are a family of ribosomally synthesized and post-translationally modified peptides with antimicrobial activities against pathogens of interest, including methicillin-resistant Staphylococcus aureus, representing a promising source of new antibiotics. Glycocins are still largely underexplored, and thus far, only six glycocins are known. Here, we used genome mining to identify 50 putative glycocin biosynthetic gene clusters and then chose six of them with distinct features for further investigation...
September 18, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30183254/in-situ-drug-delivery-to-breast-cancer-associated-extracellular-matrix
#12
Jodie M Fleming, Susan T Yeyeodu, Ashley McLaughlin, Darren Schuman, Darlene K Taylor
The extracellular matrix (ECM) contributes to tumor progression through changes induced by tumor and stromal cell signals that promote increased ECM density and stiffness. The increase in ECM stiffness is known to promote tumor cell invasion into surrounding tissues and metastasis. In addition, this scar-like ECM creates a protective barrier around the tumor that reduces the effectiveness of innate and synthetic antitumor agents. Herein, clinically approved breast cancer therapies as well as novel experimental approaches that target the ECM are discussed, including in situ hydrogel drug delivery systems, an emerging technology the delivers toxic chemotherapeutics, gene-silencing microRNAs, and tumor suppressing immune cells directly inside the tumor...
September 18, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30183250/activation-of-the-nlrp3-inflammasome-by-hyaboron-a-new-asymmetric-boron-containing-macrodiolide-from-the-myxobacterium-hyalangium-minutum
#13
Frank Surup, Dhruv Chauhan, Jutta Niggemann, Eva Bartok, Jennifer Herrmann, Matthias Keck, Wiebke Zander, Marc Stadler, Veit Hornung, Rolf Müller
A Natural Compound Library containing myxobacterial secondary metabolites was screened in murine macrophages for novel activators of IL-1β maturation and secretion. The most potent of three hits in total was a so far undescribed metabolite, which was identified from the myxobacterium Hyalangium minutum strain Hym3. While the planar structure of 1 was elucidated by high resolution mass spectrometry and NMR data yielding an asymmetric boron containing a macrodiolide core structure, its relative stereochemistry of all 20 stereocenters of the 42-membered ring was assigned by rotating frame Overhause effect spectroscopy correlations, 1 H,1 H, and 1 H,13 C coupling constants, and by comparison of 13 C chemical shifts to those of the structurally related metabolites tartrolon B-D...
September 17, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30184433/synthesis-and-evaluation-of-a-mitochondria-targeting-poly-adp-ribose-polymerase-1-inhibitor
#14
Tanja Krainz, Andrew M Lamade, Lina Du, Taber S Maskrey, Michael J Calderon, Simon C Watkins, Michael W Epperly, Joel S Greenberger, Hülya Bayır, Peter Wipf, Robert S B Clark
The poly(ADP-ribose) polymerase (PARP) family of enzymes plays a crucial role in cellular and molecular processes including DNA damage detection and repair and transcription; indeed, PARP inhibitors are under clinical evaluation as chemotherapeutic adjuncts given their capacity to impede genomic DNA repair in tumor cells. Conversely, overactivation of PARP can lead to NAD+ depletion, mitochondrial energy failure, and cell death. Since PARP activation facilitates genomic but impedes mitochondrial DNA repair, nonselective PARP inhibitors are likely to have opposing effects in these cellular compartments...
September 14, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30157624/embryonic-stem-cell-engineering-with-a-glycomimetic-fgf2-bmp4-co-receptor-drives-mesodermal-differentiation-in-a-three-dimensional-culture
#15
Matthew R Naticchia, Logan K Laubach, Ember M Tota, Taryn M Lucas, Mia L Huang, Kamil Godula
Cell surface glycans, such as heparan sulfate (HS), are increasingly identified as co-regulators of growth factor signaling in early embryonic development; therefore, chemical tailoring of HS activity within the cellular glycocalyx of stem cells offers an opportunity to control their differentiation. The growth factors FGF2 and BMP4 are involved in mediating the exit of murine embryonic stem cells (mESCs) from their pluripotent state and their differentiation toward mesodermal cell types, respectively. Here, we report a method for remodeling the glycocalyx of mutant Ext1-/- mESCs with defective biosynthesis of HS to drive their mesodermal differentiation in an embryoid body culture...
September 14, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30208272/chemical-proteomics-and-super-resolution-imaging-reveal-that-chloroquine-interacts-with-plasmodium-falciparum-pfmrp1-and-lipids
#16
John G Woodland, Roger Hunter, Peter J Smith, Timothy J Egan
It is well established that chloroquine, a quinoline antimalarial, inhibits hemozoin formation in the malaria parasite. Counterintuitively, this archetypal antimalarial is also used in the treatment of diseases in which hemozoin biocrystallization does not play a role. Hence, we decided to investigate whether chloroquine possesses binding targets other than Fe(III) protoporphyrin IX in blood stage Plasmodium falciparum parasites and whether these are related to sites of accumulation within the parasite other than the digestive vacuole...
September 12, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30204409/molecular-basis-for-autocatalytic-backbone-n-methylation-in-ripp-natural-product-biosynthesis
#17
Chayanid Ongpipattanakul, Satish K Nair
N-Methylation of nucleic acids, proteins and peptides is a chemical modification with significant impact on biological regulation. Despite the simplicity of the structural change, N-methylation can influence diverse functions including epigenetics, protein complex formation, and microtubule stability. While there are limited examples of N-methylation of the α-amino group of bacterial and eukaryotic proteins, there are no examples of catalysts that carry out the post-translation methylation of backbone amides in proteins or peptides...
September 11, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30192509/unbiased-mass-spectrometry-elucidation-of-the-targets-and-mechanisms-of-activity-based-probes-a-case-study-involving-sulfonyl-fluorides
#18
Thomas E J Chavas, Matthew J Fuchter, Peter A DiMaggio
The elucidation of protein/drug interactions remains a major challenge in drug discovery. Liquid chromatography tandem mass spectrometry has emerged as a tremendously powerful technology for this endeavor, but its full potential has yet to be realised owing in part to unresolved challenges in data analysis. Herein, we demonstrate how tandem mass spectrometry can comprehensively map small molecule/peptide adducts when combined with unconstrained sequencing. Using a published sulfonyl fluoride activity-based probe as a model system, this method enabled the discovery of several unreported sites of interaction with its target proteins...
September 7, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30141626/a-chemical-biology-approach-to-model-pontocerebellar-hypoplasia-type-1b-pch1b
#19
Liberty François-Moutal, Shahriyar Jahanbakhsh, Andrew D L Nelson, Debashish Ray, David D Scott, Matthew R Hennefarth, Aubin Moutal, Samantha Perez-Miller, Andrew J Ambrose, Ahmed Al-Shamari, Philippe Coursodon, Bessie Meechoovet, Rebecca Reiman, Eric Lyons, Mark Beilstein, Eli Chapman, Quaid D Morris, Kendall Van Keuren-Jensen, Timothy R Hughes, Rajesh Khanna, Carla Koehler, Joanna Jen, Vijay Gokhale, May Khanna
Mutations of EXOSC3 have been linked to the rare neurological disorder known as Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative RNA-binding structural cap proteins that guide RNA into the RNA exosome, the cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 for long and short G-rich RNA sequences. Although several PCH1B-causing mutations in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they exhibited lower binding affinity to G-rich RNA as demonstrated by MST...
September 6, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30111097/cell-specific-chemical-delivery-using-a-selective-nitroreductase-nitroaryl-pair
#20
Todd D Gruber, Chithra Krishnamurthy, Jonathan B Grimm, Michael R Tadross, Laura M Wysocki, Zev J Gartner, Luke D Lavis
The utility of small molecules to probe or perturb biological systems is limited by the lack of cell-specificity. "Masking" the activity of small molecules using a general chemical modification and "unmasking" it only within target cells overcomes this limitation. To this end, we have developed a selective enzyme-substrate pair consisting of engineered variants of E. coli nitroreductase (NTR) and a 2-nitro- N-methylimidazolyl (NM) masking group. To discover and optimize this NTR-NM system, we synthesized a series of fluorogenic substrates containing different nitroaromatic masking groups, confirmed their stability in cells, and identified the best substrate for NTR...
August 29, 2018: ACS Chemical Biology
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