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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28530797/unexpected-biotransformation-of-the-hdac-inhibitor-vorinostat-yields-aniline-containing-fungal-metabolites
#1
Donovon A Adpressa, Kayla J Stalheim, Philip Jerome Proteau, Sandra Loesgen
The diversity of genetically encoded small molecules produced by filamentous fungi remains largely unexplored, which makes these fungi an attractive source for the discovery of new compounds. However, accessing their full chemical repertoire under common laboratory culture conditions is a challenge. Epigenetic manipulation of gene expression has become a well-established tool for overcoming this obstacle. Here we report that perturbation of the endophytic ascomycete Chalara sp. 6661, producer of the isofusidienol class of antibiotics, with the HDAC inhibitor vorinostat resulted in the production of four new modified xanthones...
May 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28530791/farnesyltransferase-mediated-delivery-of-a-covalent-inhibitor-overcomes-alternative-prenylation-to-mislocalize-k-ras
#2
Christopher J Novotny, Gregory L Hamilton, Frank McCormick, Kevan Shokat
Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition though alternative prenylation by geranylgeranyltransferase...
May 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28525268/rational-design-of-novel-allosteric-dihydrofolate-reductase-inhibitors-showing-antibacterial-effects-on-drug-resistant-e-coli-escape-variants
#3
Bharath Srinivasan, João V Rodrigues, Sam Tonddast-Navaei, Eugene Shakhnovich, Jeffrey Skolnick
In drug-discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug-resistance. On the other hand, conventional drug-discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28525266/gliotoxin-biosynthesis-structure-mechanism-and-metal-promiscuity-of-carboxypeptidase-glij
#4
Antoine Marion, Michael Groll, Daniel H Scharf, Kirstin Scherlach, Manuel Glaser, Holger Sievers, Michael Schuster, Christian Hertweck, Axel A Brakhage, Iris Antes, Eva M Huber
The formation of glutathione (GSH) conjugates, best known from the detoxification of xenobiotics, is a widespread strategy to incorporate sulfur into biomolecules. The biosynthesis of gliotoxin, a virulence factor of the human pathogenic fungus Aspergillus fumigatus, involves attachment of two GSH molecules and their sequential decomposition to yield two reactive thiol groups. The degradation of the GSH moieties requires the activity of the Cys-Gly carboxypeptidase GliJ, for which we describe the X-ray structure here...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28525263/yellow-and-orange-fluorescent-proteins-with-tryptophan-based-chromophores
#5
Nina G Bozhanova, Mikhail S Baranov, Karen S Sarkisyan, Roman Gritсenko, Konstantin V Mineev, Svetlana V Golodukhina, Nadezhda S Baleeva, Konstantin A Lukyanov, Alexander S Mishin
Rapid development of new microscopy techniques exposed the need for genetically encoded fluorescent tags with special properties. Recent works demonstrated the potential of fluorescent proteins with tryptophan-based chromophores. We applied rational design and random mutagenesis to the monomeric red fluorescent protein FusionRed and found two groups of mutants carrying tryptophan-based chromophore: with yellow (535 nm) or orange (565 nm) emission. On the basis of the properties of proteins, a model synthetic chromophore, and a computational modelling we concluded that the presence of a ketone-containing chromophore in different isomeric forms can explain the observed yellow and orange phenotypes...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28485916/hidden-antioxidative-functions-of-reduced-nicotinamide-adenine-dinucleotide-coexisting-with-hemoglobin
#6
Magohei Yamada, Hiromi Sakai
Ferrous oxyhemoglobin (HbO2) in red blood cells (RBCs) invariably and slowly autoxidizes to form ferric methemoglobin (metHb). However, the level of metHb is always maintained below 0.5% by intracellular metHb reduction of enzymatic systems with coenzymes, such as reduced nicotinamide adenine dinucleotide (NADH), and by superoxide dismutase (SOD) and catalase (CAT), which eliminate reactive oxygen species. Unquestionably, NADH cannot reduce metHb without the corresponding enzymatic system. Our study, however, demonstrated that a high concentration of NADH (100-fold of normal level, equimolar to HbO2) retarded autoxidation of HbO2 in a highly purified Hb solution with no enzymatic system...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28467833/heterologous-production-and-yield-improvement-of-epothilones-in-burkholderiales-strain-dsm-7029
#7
Xiaoying Bian, Biao Tang, Yucong Yu, Qiang Tu, Frank Gross, Hailong Wang, Aiying Li, Jun Fu, Yuemao Shen, Yue-Zhong Li, A Francis Stewart, Guoping Zhao, Xiaoming Ding, Rolf Müller, Youming Zhang
The cloning of microbial natural product biosynthetic gene clusters and their heterologous expression in a suitable host have proven to be a feasible approach to improve the yield of valuable natural products and to begin mining cryptic natural products in microorganisms. Myxobacteria are a prolific source of novel bioactive natural products with only limited choices of heterologous hosts that have been exploited. Here, we describe the use of Burkholderiales strain DSM 7029 as a potential heterologous host for the functional expression of myxobacterial secondary metabolites...
May 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28505407/unique-n-phenylacetylation-and-nrps-with-substrate-promiscuity-for-biosynthesis-of-heptapeptide-variants-jbir-78-and-jbir-95
#8
Kunpei Takeda, Kohei Kemmoku, Yasuharu Satoh, Yasushi Ogasawara, Kazuo Shin-Ya, Tohru Dairi
JBIR-78 (1) and JBIR-95 (2), both of which are heptapeptide derivatives isolated from Kibdelosporangium sp. AK-AA56, have the same amino acid sequences except for the second amino acid; phenylacetic acid (Paa)-L-Val-D-Asp (1)/D-cysteic acid (2)-L-Ala-(3S)-3-hydroxy-D-Leu-Gly-D-Ala-L-Phe. Heterologous expression of the biosynthetic gene cluster including genes encoding non-ribosomal peptide synthetases (NRPS) and in vitro assays with recombinant Orf3, L-cysteic acid synthase homolog, suggested the single A-domain in module 2 activates both L-Asp and L-cysteic acid to yield 1 and 2, respectively, although the substrate specificities of the A-domains of NRPSs are usually strict...
May 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28472585/real-time-imaging-of-the-azole-class-of-antifungal-drugs-in-live-candida-cells
#9
Raphael I Benhamou, Maayan Bibi, Kfir B Steinbuch, Hamutal Engel, Maayan Levin, Yael Roichman, Judith Berman, Micha Fridman
Azoles are the most commonly used class of antifungal drugs, yet where they localize within fungal cells and how they are imported remain poorly understood. Azole antifungals target lanosterol 14α-demethylase, a cytochrome P450, encoded by ERG11 in Candida albicans, the most prevalent fungal pathogen. We report the synthesis of fluorescent probes that permit visualization of antifungal azoles within live cells. Probe 1 is a dansyl dye-conjugated azole, and probe 2 is a Cy5-conjugated azole. Docking computations indicated that each of the probes can occupy the active site of the target cytochrome P450...
May 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28493677/the-n6-position-of-adenine-is-a-blind-spot-for-tal-effectors-that-enables-effective-binding-of-methylated-and-fluorophore-labeled-dna
#10
Sarah Flade, Julia Jasper, Mario Giess, Matyas Juhasz, Andreas Dankers, Grzegorz Kubik, Oliver Koch, Elmar Weinhold, Daniel Summerer
Transcription-activator-like effectors (TALEs) are programmable DNA binding proteins widely used for genome targeting. TALEs consist of multiple concatenated repeats, each selectively recognizing one nucleobase via a defined repeat variable diresidue (RVD). Effective use of TALEs requires knowledge about their binding ability to epigenetic and other modified nucleobases occurring in target DNA. However, aside from epigenetic cytosine-5 modifications, the binding ability of TALEs to modified DNA is unknown. We here study the binding of TALEs to the epigenetic nucleobase N6-methyladenine (6mA) found in prokaryotic and eukaryotic genomes...
May 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28489343/rearranged-biosynthetic-gene-cluster-and-synthesis-of-hassallidin-e-in-planktothrix-serta-pcc-8927
#11
Claire Pancrace, Jouni Jokela, Nathalie Sassoon, Christelle Ganneau, Marie Desnos-Ollivier, Matti Wahlsten, Anu Humisto, Alexandra Calteau, Sylvie Bay, David P Fewer, Kaarina Sivonen, Muriel Gugger
Cyanobacteria produce a wide range of natural products with antifungal bioactivity. The cyclic glycosylated lipopeptides of the hassallidin family have potent antifungal activity and display a great degree of chemical diversity. Here we report the discovery of a hassallidin biosynthetic gene cluster from the filamentous cyanobacterium Planktothrix serta PCC 8927. The hassallidin gene cluster showed heavy rearrangement and marks of genomic plasticity. Nucleotide bias, differences in GC content and phylogenetic incongruence suggested the acquisition of the hassallidin biosynthetic gene cluster in Planktothrix serta PCC 8927 by horizontal gene transfer...
May 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28463479/phanerochaete-chrysosporium-multienzyme-catabolic-system-for-in-vivo-modification-of-synthetic-lignin-to-succinic-acid
#12
Chang-Young Hong, Sun-Hwa Ryu, Hanseob Jeong, Sung-Suk Lee, Myungkil Kim, In-Gyu Choi
Whole cells of the basidiomycete fungus Phanerochaete chrysosporium (ATCC 20696) were applied to induce the biomodification of lignin in an in vivo system. Our results indicated that P. chrysosporium has a catabolic system that induces characteristic biomodifications of synthetic lignin through a series of redox reactions, leading not only to the degradation of lignin but also to its polymerization. The reducing agents ascorbic acid and α-tocopherol were used to stabilize the free radicals generated from the ligninolytic process...
May 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28440616/discovery-and-characterization-of-a-eukaryotic-initiation-factor-4a-3-selective-inhibitor-that-suppresses-nonsense-mediated-mrna-decay
#13
Misa Iwatani-Yoshihara, Masahiro Ito, Yoshihiro Ishibashi, Hideyuki Oki, Toshio Tanaka, Daisuke Morishita, Takashi Ito, Hiromichi Kimura, Yasuhiro Imaeda, Samuel Aparicio, Atsushi Nakanishi, Tomohiro Kawamoto
Eukaryotic initiation factor 4A-3 (eIF4A3) is an Asp-Glu-Ala-Asp (DEAD) box-family adenosine triphosphate (ATP)-dependent RNA helicase. Subtypes eIF4A1 and eIF4A2 are required for translation initiation, but eIF4A3 participates in the exon junction complex (EJC) and functions in RNA metabolism including nonsense-mediated RNA decay (NMD). No small molecules for NMD inhibition via selective inhibition of eIF4A3 have been discovered. Here, we identified allosteric eIF4A3 inhibitors from a high-throughput screening campaign...
May 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28485919/stabilization-of-glucocerebrosidase-by-active-site-occupancy
#14
Fredj Ben Bdira, Wouter W Kallemeijn, Saskia V Oussoren, Saskia Scheij, Boris Bleijlevens, Cindy P A A van Roomen, Roelof Ottenhoff, Marielle J F M van Kooten, Marthe T C Walvoort, Martin D Witte, Rolf G Boot, Marcellus Ubbink, Herman S Overkleeft, Johannes M F G Aerts
Glucocerebrosidase (GBA) is a retaining lysosomal β-glucosidase degrading glucosylceramide. Its deficiency results in Gaucher disease (GD). We examined the effects of active site occupancy of GBA on its structural stability. For this we made use of cyclophellitol-derived activity-based probes (ABPs) that bind irreversibly to the catalytic nucleophile E340 and for comparison the potent reversible inhibitor, isofagomine. We demonstrate that cyclophellitol ABPs improve GBA stability in vitro as revealed by thermodynamic measurements (Tm increase by 21 °C) and introduce resistance to tryptic digestion...
May 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28485572/citrullination-methylation-crosstalk-on-histone-h3-regulates-er-target-gene-transcription
#15
Kathleen W Clancy, Anna-Maria Russell, Venkataraman Subramanian, Hannah Nguyen, Yuewei Qian, Robert M Campbell, Paul R Thompson
Posttranslational modifications of histone tails are a key contributor to epigenetic regulation. Histone H3 Arg26 and Lys27 are both modified by multiple enzymes, and their modifications have profound effects on gene expression. Citrullination of H3R26 by PAD2 and methylation of H3K27 by PRC2 have opposing downstream impacts on gene regulation; H3R26 citrullination activates gene expression, and H3K27 methylation represses gene expression. Both of these modifications are drivers of a variety of cancers, and their writer enzymes, PAD2 and EZH2, are the targets of drug therapies...
May 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28481502/efficient-inhibition-of-smnace-by-coordination-complexes-is-abolished-by-s-mansoni-sequestration-of-metal
#16
Hélène Muller-Steffner, Sylvain A Jacques, Isabelle Kuhn, Michael D Schultz, Davide Botta, Paul Osswald, Clarisse Maechling, Frances E Lund, Esther Kellenberger
SmNACE is a NAD catabolizing enzyme expressed on the outer tegument of S. mansoni, a human parasite that is one of the major agents of the neglected tropical disease Schistosomiasis. Recently, we identified aroylhydrazone derivatives capable of inhibiting the recombinant form of the enzyme with variable potency (IC50 ranging from 88 μM to 33 nM). In the present study, we investigated the mechanism of action of the least potent micromolar inhibitor (compound 1) and the most potent nanomolar inhibitor (compound 2) in the series on both the recombinant and native SmNACE enzymes...
May 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28467834/nickel-ii-inhibits-tet-mediated-5-methylcytosine-oxidation-by-high-affinity-displacement-of-the-cofactor-iron-ii
#17
Ruichuan Yin, Jiezhen Mo, Jiayin Dai, Hailin Wang
Ten-eleven translocation (Tet) family proteins are Fe(II)- and 2-oxoglutarate-dependent dioxygenases that regulate the dynamics of DNA methylation by catalyzing the oxidation of DNA 5-methylcytosine (5mC). To exert physiologically important functions, redox-active iron chelated in the catalytic center of Tet proteins directly involves the oxidation of the multiple substrates. To understand the function and interaction network of Tet dioxygenases, it is interesting to obtain high affinity and a specific inhibitor...
May 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28459531/the-folding-pathway-of-the-kix-domain
#18
Francesca Troilo, Daniela Bonetti, Angelo Toto, Lorenzo Visconti, Maurizio Brunori, Sonia Longhi, Stefano Gianni
The KIX domain is an 89-residues globular domain with an important role in mediating protein-protein interactions. The presence of two distinct binding sites in such a small domain makes KIX a suitable candidate to investigate the effect of the potentially divergent demands between folding and function. Here, we report an extensive mutational analysis of the folding pathway of the KIX domain, based on 30 site-directed mutants, which allow us to assess the structures of both the transition and denatured states...
May 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28459525/a-chemical-genetic-approach-to-generate-selective-covalent-inhibitors-of-protein-kinases
#19
Alvin Kung, Marianne Schimpl, Arunika Ekanayake, Ying-Chu Chen, Ross Overman, Chao Zhang
Although a previously developed bump-hole approach has proven powerful in generating specific inhibitors for mapping functions of protein kinases, its application is limited by the intolerance of the large-to-small mutation by certain kinases and the inability to control two kinases separately in the same cells. Herein, we describe the development of an alternative chemical-genetic approach to overcome these limitations. Our approach features the use of an engineered cysteine residue at a particular position as a reactive feature to sensitize a kinase of interest to selective covalent blockade by electrophilic inhibitors and is thus termed the Ele-Cys approach...
May 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28452462/glycan-remodeling-of-human-erythropoietin-epo-through-combined-mammalian-cell-engineering-and-chemoenzymatic-transglycosylation
#20
Qiang Yang, Yanming An, Shilei Zhu, Roushu Zhang, Chun Mun Loke, John F Cipollo, Lai-Xi Wang
The tremendous structural heterogeneity of N-glycosylation of glycoproteins poses a great challenge for deciphering the biological functions of specific glycoforms and for developing protein-based therapeutics. We have previously reported a chemoenzymatic glycan remodeling method for producing homogeneous glycoforms of N-glycoproteins including intact antibodies, which consist of endoglycosidase-catalyzed deglycosylation and novel glycosynthase-catalyzed transglycosylation, but its application to complex glycoproteins carrying multiple N-glycans remains to be examined...
May 5, 2017: ACS Chemical Biology
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