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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28741926/redesigned-spider-peptide-with-improved-antimicrobial-and-anticancer-properties
#1
Sonia Troeira Henriques, Nicole Lawrence, Stephanie Chaousis, Anjaneya S Ravipati, Olivier Cheneval, Aurélie H Benfield, Alysha G Elliott, Angela Maria Kavanagh, Matthew A Cooper, Lai Yue Chan, Yen-Hua Huang, David J Craik
Gomesin, a disulfide-rich antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against melanoma cells. In a recent study, a backbone cyclized analogue of gomesin was shown to be as active but more stable than its native form. In the current study, we were interested in improving the antimicrobial properties of the cyclic gomesin, understanding its selectivity towards melanoma cells and elucidating its antimicrobial and anticancer mode of action...
July 25, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28732158/deleterious-consequences-of-udp-galactopyranose-mutase-inhibition-for-nematodes
#2
Valerie J Winton, Alexander M Justen, Helen Deng, Laura L Kiessling
Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to anti-parasitic agents underscores the need to replenish our anthelmintic arsenal. The non-pathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf)-containing glycans and is needed in nematodes for proper cuticle formation...
July 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28727444/fosfomycin-biosynthesis-via-transient-cytidylylation-of-2-hydroxyethylphosphonate-by-the-bifunctional-fom1-enzyme
#3
Su-Hee Cho, Seung-Young Kim, Takeo Tomita, Taro Shiraishi, Jin-Soo Park, Shusuke Sato, Fumitaka Kudo, Tadashi Eguchi, Nobutaka Funa, Makoto Nishiyama, Tomohisa Kuzuyama
Fosfomycin is a wide-spectrum phosphonate antibiotic that is used clinically to treat cystitis, tympanitis, etc. Its biosynthesis starts with the formation of a carbon-phosphorus bond catalyzed by the phosphoenolpyruvate phosphomutase Fom1. We identified an additional cytidylyltransferase (CyTase) domain at the Fom1 N-terminus in addition to the phosphoenolpyruvate phosphomutase domain at the Fom1 C-terminus. Here, we demonstrate that Fom1 is bifunctional and that the Fom1 CyTase domain catalyzes the cytidylylation of the 2-hydroxyethylphosphonate (HEP) intermediate to produce cytidylyl-HEP...
July 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28723094/structure-activity-relationships-reveal-key-features-of-8-oxoguanine-adenine-mismatch-detection-by-the-muty-dna-glycosylase
#4
Amelia H Manlove, Paige L McKibbin, Emily L Doyle, Chandrima Majumdar, Michelle L Hamm, Sheila S David
Base excision repair glycosylases locate and remove damaged based in DNA with remarkable specificity. The MutY glycosylases, unusual for their excision of undamaged adenines mispaired to the oxidized base 8-oxoguanine (OG), must recognize both bases of the mispair in order to prevent promutagenic activity. Moreover, MutY must effectively find OG:A mismatches within the context of highly abundant and structurally similar T:A base-pairs. Very little is known about the factors that initiate MutY's interaction with the substrate when it first encounters an intrahelical OG:A mispair, or about the order of recognition checkpoints...
July 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28687042/discovery-of-heteroaromatic-sulfones-as-a-new-class-of-biologically-compatible-thiol-selective-reagents
#5
Xiaofei Chen, Hanzhi Wu, Chung-Min Park, Thomas H Poole, Gizem Keceli, Nelmi O Devarie-Baez, Allen W Tsang, W Todd Lowther, Leslie B Poole, S Bruce King, Ming Xian, Cristina M Furdui
The selective reaction of chemical reagents with reduced protein thiols is critical to biological research. This reaction is utilized to prevent cross-linking of cysteine-containing peptides in common proteomics workflows and is applied widely in discovery and targeted redox investigations of the mechanisms underlying physiological and pathological processes. However, known and commonly used thiol blocking reagents like iodoacetamide, N-ethylmaleimide, and others were found to cross-react with oxidized protein sulfenic acids (-SOH) introducing significant errors in studies employing these reagents...
July 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28719185/small-molecule-enhancement-of-20s-proteasome-activity-targets-intrinsically-disordered-proteins
#6
Corey L Jones, Evert Njomen, Benita Sjogren, Thomas S Dexheimer, Jetze J Tepe
The 20S proteasome is the main protease for degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceed proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disor-ders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28719183/streptomyces-virginiae-ppdc-is-a-new-type-of-phenylpyruvate-decarboxylase-composed-of-two-subunits
#7
Xiaoshu Xu, Chao Wang, Jun Chen, Sheng Yang
Streptomyces virginiae phenylpyruvate decarboxylase (PPDC) has not been identified before. Two putative branched-chain α-keto acid dehydrogenase subunit genes bkdC and bkdD from S. virginiae are similar to halves of other PPDC coding sequences. We cloned and characterized them biochemically in this work. The two proteins formed a stable complex attested by pull-down assay, consistent with the finding that their soluble expression was obtained only when they were coexpressed in Escherichia coli. The subunits were redesignated as SvPPDCα and SvPPDCβ, because the SvPPDCα/β complex catalyzed the conversion of phenylpyruvate to phenylacetaldehyde, reflecting the nature of the enzyme...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28718624/covalent-enzyme-inhibition-through-fluorosulfate-modification-of-a-non-catalytic-serine-residue
#8
Olugbeminiyi O Fadeyi, Lise R Hoth, Chulho Choi, Xidong Feng, Ariamala Gopalsamy, Erik C Hett, Robert E Kyne, Ralph P Robinson, Lyn H Jones
Irreversible enzyme inhibitors often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (an acrylamide for example) in the ligand template. Cysteine residues are not always available for site-specific protein labeling and therefore new approaches are needed to expand the toolkit of appropriate electrophiles that target alternative amino acids. We have previously described the rational targeting of tyrosine residues in the active site of a protein (the mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with sulfonyl fluoride electrophiles that additionally enabled the subsequent development of clickable probe technology to measure drug-target occupancy in live cells...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28714670/cross-linking-furan-modified-kisspeptin-10-to-the-kiss-receptor
#9
Willem Vannecke, Christophe Ampe, Marleen Van Troys, Massimiliano Beltramo, Annemieke Madder
Chemical cross-linking is well-established for investigating protein-protein interactions. Traditionally, photo cross-linking is used but is associated with problems of selectivity and UV toxicity in a biological context. We here describe, with live cells and under normal growth conditions, selective cross-linking of a furan-modified peptide ligand to its membrane-presented receptor with zero toxicity, high efficiency, and spatio-specificity. Furan-modified kisspeptin-10 is covalently coupled to its glycosylated membrane receptor, GPR54(KISS1R)...
July 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28708379/chemical-genomics-structure-elucidation-and-in-vivo-studies-of-the-marine-derived-anticlostridial-ecteinamycin
#10
Thomas P Wyche, René F Ramos Alvarenga, Jeff S Piotrowski, Megan N Duster, Simone R Warrack, Gabriel Cornilescu, Travis J De Wolfe, Yanpeng Hou, Doug R Braun, Gregory A Ellis, Scott W Simpkins, Justin Nelson, Chad L Myers, James Steele, Hirotada Mori, Nasia Safdar, John L Markley, Scott Raymond Rajski, Tim S Bugni
A polyether antibiotic, ecteinamycin (1) was isolated from a marine Actinomadura sp., cultivated from the ascidian Ectein-ascidia turbinata. 13C-enrichment, high resolution NMR spectroscopy and molecular modeling enabled elucidation of the structure of 1 which was validated on the basis of comparisons with its recently reported crystal structure. Importantly, ec-teinamycin demonstrated potent activity against the toxigenic strain of Clostridium difficile NAP1/B1/027 (MIC = 59 ng/μL), as well as other toxigenic and non-toxigenic C...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28708377/membrane-association-dictates-ligand-specificity-for-the-innate-immune-receptor-nod2
#11
Amy K Schaefer, James E Melnyk, Michael Baksh, Klare M Lazor, M G Finn, Catherine Leimkuhler Grimes
The human gut must regulate its immune response to resident and pathogenic bacteria, numbering in the trillions. The peptidoglycan component of the bacterial cell wall is a dense and rigid structure that consists of polymeric carbohydrates and highly crosslinked peptides which offers protection from the host and surrounding environment. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a human membrane-associated innate immune receptor found in the gut epithelium and mutated in an estimated 30% of Crohn's disease patients, binds to peptidoglycan fragments and initiates an immune response...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28708375/enzyme-that-makes-you-cry-crystal-structure-of-lachrymatory-factor-synthase-from-allium-cepa
#12
Josie A Silvaroli, Matthew J Pleshinger, Surajit Banerjee, Philip D Kiser, Marcin Golczak
The biochemical pathway that gives onions their savor is part of the chemical warfare against microbes and animals. This defense mechanism involves formation of a volatile lachrymatory factor (LF) ((Z)-propanethial S-oxide) that causes familiar eye irritation associated with onion chopping. LF is produced in a reaction catalyzed by lachrymatory factor synthase (LFS). The principles by which LFS facilitates conversion of a sulfenic acid substrate into LF have been difficult to experimentally examine owing to the inherent substrate reactivity and lability of LF...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28708374/chemical-modification-and-detoxification-of-the-pseudomonas-aeruginosa-toxin-2-heptyl-4-hydroxyquinoline-n-oxide-by-environmental-and-pathogenic-bacteria
#13
Sven Thierbach, Franziska S Birmes, Matthias C Letzel, Ulrich Hennecke, Susanne Fetzner
2-Heptyl-4-hydroxyquinoline N-oxide (HQNO), a major secondary metabolite and virulence factor produced by the opportunistic pathogen Pseudomonas aeruginosa, acts as potent inhibitor of respiratory electron transfer and thereby affects host cells as well as microorganisms. In this study, we demonstrate the previously unknown capability of environmental and pathogenic bacteria to transform and detoxify this compound. Strains of Arthrobacter and Rhodococcus spp. as well as Staphylococcus aureus introduced a hydroxyl group at C-3 of HQNO, whereas Mycobacterium abscessus, M...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28703575/a-novel-family-of-small-molecules-that-enhance-the-intracellular-delivery-and-pharmacological-effectiveness-of-antisense-and-splice-switching-oligonucleotides
#14
Ling Wang, Yamuna Ariyarathna, Xin Ming, Bing Yang, Lindsey I James, Silvia M Kreda, Melissa Porter, William Janzen, Rudolph L Juliano
The pharmacological effectiveness of oligonucleotides has been hampered by their tendency to remain entrapped in endosomes, thus limiting their access to cytosolic or nuclear targets. We have previously reported a group of small molecules that enhance the effects of oligonucleotides by causing their release from endosomes. Here, we describe a second novel family of oligonucleotide enhancing compounds (OECs) that is chemically distinct from the compounds reported previously. We demonstrate that these molecules substantially augment the actions of splice switching oligonucleotides (SSOs) and antisense oligonucleotides (ASOs) in cell culture...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28699733/diversity-of-alkylproline-moieties-in-pyrrolobenzodiazepines-arises-from-postcondensation-modifications-of-a-unified-building-block
#15
Zdenek Kamenik, Stanislav Kadlcik, Radek Gazak, Simon Vobruba, Lucie Palanova, Marek Kuzma, Jiri Janata
Anticancer pyrrolobenzodiazepines (PBDs) are one of several groups of natural products that contain unusual 4-alkyl-l-proline derivatives (APDs) in their structure. APD moieties of PBDs are characterized by high structural diversity achieved through unknown biosynthetic machinery. Based on LC-MS analysis of culture broths, feeding experiments, and protein assays, we show that APDs are not incorporated into PBDs in their final form as was previously hypothesized. Instead, a uniform building block, 4-propylidene-l-proline or 4-ethylidene-l-proline, enters the condensation reaction...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28678467/a-two-photon-photocleavable-linker-for-triggering-light-induced-strand-breaks-in-oligonucleotides
#16
Xenia M M Weyel, Manuela A H Fichte, Alexander Heckel
We synthesized a two-photon-sensitive photocleavable linker based on the 7-diethylaminocoumarin structure and introduced it successfully into DNA strands. First, we demonstrated the inducibility of strand scissions upon irradiation at 365 nm. To verify and visualize the two-photon activity, we used a fluorescence assay based on a DNA strand displacement immobilized in a hydrogel. Additionally, we investigated its use in a new class of DNA decoys that are able to catch and release nuclear factor κB (NF-κB) by using light as an external trigger signal...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28644609/galnac-tyrosine-is-a-ligand-of-plant-lectins-antibodies-and-human-and-murine-macrophage-galactose-type-lectins
#17
Ruslan Gibadullin, David Wayne Farnsworth, Joseph J Barchi, Jeffrey C Gildersleeve
In 2011, a new type of protein O-glycosylation was discovered in which N-acetylgalactosamine is attached to the side chain of tyrosine (GalNAc-Tyr). While present on dozens of proteins, the biological roles of GalNAc-Tyr are unknown. To gain insight into this new type of modification, we synthesized a group of GalNAc-Tyr glycopeptides, constructed microarrays, and evaluated potential recognition of GalNAc-Tyr by a series of glycan-binding proteins. Through a series of >150 microarray experiments, we assessed binding properties of a variety of plant lectins, monoclonal antibodies, and endogenous lectins...
July 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28679043/novel-class-of-potent-and-cellularly-active-inhibitors-devalidates-mth1-as-broad-spectrum-cancer-target
#18
Manuel Ellermann, Ashley Eheim, Fredrik Rahm, Jenny Viklund, Judith Guenther, Martin Andersson, Ulrika Ericsson, Rickard Forsblom, Tobias Ginman, Johan Lindström, Camilla Silvander, Lionel Trésaugues, Anja Giese, Stefanie Bunse, Roland Neuhaus, Jörg Weiske, Maria Quanz, Andrea Glasauer, Katrin Nowak-Reppel, Benjamin Bader, Horst Irlbacher, Hanna Meyer, Nina Queisser, Marcus Bauser, Andrea Haegebarth, Mátyás Gorjánácz
MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published...
July 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28617580/progressive-stereo-locking-psl-a-residual-dipolar-coupling-based-force-field-method-for-determining-the-relative-configuration-of-natural-products-and-other-small-molecules
#19
Gabriel Cornilescu, René F Ramos Alvarenga, Thomas P Wyche, Tim S Bugni, Roberto R Gil, Claudia C Cornilescu, William M Westler, John L Markley, Charles D Schwieters
Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to allow free sampling of both R and S configurations of the stereocenters of interest. The algorithm uses a floating alignment tensor in a simulated annealing protocol to identify the conformations and configurations that best fit experimental RDC and distance restraints (from NOE and J-coupling data)...
July 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28696669/in-vitro-reconstitution-of-oxya-enzymatic-activity-clarifies-late-steps-in-vancomycin-biosynthesis
#20
Clarissa C Forneris, Seyma Ozturk, Marcus I Gibson, Erik J Sorensen, Mohammad R Seyedsayamdost
Studies on the biosynthesis of glycopeptide antibiotics have provided many insights into the strategies that Nature employs to build architecturally strained molecules. A key structural feature of vancomycin, the founding member of this class, is a set of three aromatic crosslinks that are installed via yet unknown mechanisms. Previous reports have identified three cytochrome P450 enzymes involved in this process and demonstrated enzymatic activity for OxyB, which installs the first aromatic crosslink. However, the activities of the remaining two P450 enzymes have not been recapitulated...
July 11, 2017: ACS Chemical Biology
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