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Nature Chemical Biology

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https://www.readbyqxmd.com/read/28719589/an-excited-state-underlies-gene-regulation-of-a-transcriptional-riboswitch
#1
Bo Zhao, Sharon L Guffy, Benfeard Williams, Qi Zhang
Riboswitches control gene expression through ligand-dependent structural rearrangements of the sensing aptamer domain. However, we found that the Bacillus cereus fluoride riboswitch aptamer adopts identical tertiary structures in solution with and without ligand. Using chemical-exchange saturation transfer (CEST) NMR spectroscopy, we revealed that the structured ligand-free aptamer transiently accesses a low-populated (∼1%) and short-lived (∼3 ms) excited conformational state that unravels a conserved 'linchpin' base pair to signal transcription termination...
July 17, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28719588/structures-of-carboxylic-acid-reductase-reveal-domain-dynamics-underlying-catalysis
#2
Deepankar Gahloth, Mark S Dunstan, Daniela Quaglia, Evaldas Klumbys, Michael P Lockhart-Cairns, Andrew M Hill, Sasha R Derrington, Nigel S Scrutton, Nicholas J Turner, David Leys
Carboxylic acid reductase (CAR) catalyzes the ATP- and NADPH-dependent reduction of carboxylic acids to the corresponding aldehydes. The enzyme is related to the nonribosomal peptide synthetases, consisting of an adenylation domain fused via a peptidyl carrier protein (PCP) to a reductase termination domain. Crystal structures of the CAR adenylation-PCP didomain demonstrate that large-scale domain motions occur between the adenylation and thiolation states. Crystal structures of the PCP-reductase didomain reveal that phosphopantetheine binding alters the orientation of a key Asp, resulting in a productive orientation of the bound nicotinamide...
July 17, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28692069/the-structure-of-vanadium-nitrogenase-reveals-an-unusual-bridging-ligand
#3
Daniel Sippel, Oliver Einsle
Nitrogenases catalyze the reduction of dinitrogen (N2) gas to ammonium at a complex heterometallic cofactor. This most commonly occurs at the FeMo cofactor (FeMoco), a [Mo-7Fe-9S-C] cluster whose exact reactivity and substrate-binding mode remain unknown. Alternative nitrogenases replace molybdenum with either vanadium or iron and differ in reactivity, most prominently in the ability of vanadium nitrogenase to reduce CO to hydrocarbons. Here we report the 1.35-Å structure of vanadium nitrogenase from Azotobacter vinelandii...
July 10, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28692068/allosteric-sensitization-of-proapoptotic-bax
#4
Jonathan R Pritz, Franziska Wachter, Susan Lee, James Luccarelli, Thomas E Wales, Daniel T Cohen, Paul Coote, Gregory J Heffron, John R Engen, Walter Massefski, Loren D Walensky
BCL-2-associated X protein (BAX) is a critical apoptotic regulator that can be transformed from a cytosolic monomer into a lethal mitochondrial oligomer, yet drug strategies to modulate it are underdeveloped due to longstanding difficulties in conducting screens on this aggregation-prone protein. Here, we overcame prior challenges and performed an NMR-based fragment screen of full-length human BAX. We identified a compound that sensitizes BAX activation by binding to a pocket formed by the junction of the α3-α4 and α5-α6 hairpins...
July 10, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671683/a-molecular-rheostat-maintains-atp-levels-to-drive-a-synthetic-biochemistry-system
#5
Paul H Opgenorth, Tyler P Korman, Liviu Iancu, James U Bowie
Synthetic biochemistry seeks to engineer complex metabolic pathways for chemical conversions outside the constraints of the cell. Establishment of effective and flexible cell-free systems requires the development of simple systems to replace the intricate regulatory mechanisms that exist in cells for maintaining high-energy cofactor balance. Here we describe a simple rheostat that regulates ATP levels by controlling the flow down either an ATP-generating or non-ATP-generating pathway according to the free-phosphate concentration...
July 3, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671682/a-small-molecule-allosteric-inhibitor-of-mycobacterium-tuberculosis-tryptophan-synthase
#6
Samantha Wellington, Partha P Nag, Karolina Michalska, Stephen E Johnston, Robert P Jedrzejczak, Virendar K Kaushik, Anne E Clatworthy, Noman Siddiqi, Patrick McCarren, Besnik Bajrami, Natalia I Maltseva, Senya Combs, Stewart L Fisher, Andrzej Joachimiak, Stuart L Schreiber, Deborah T Hung
New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromolecular synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme...
July 3, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671681/extracellular-vesicles-are-independent-metabolic-units-with-asparaginase-activity
#7
Nunzio Iraci, Edoardo Gaude, Tommaso Leonardi, Ana S H Costa, Chiara Cossetti, Luca Peruzzotti-Jametti, Joshua D Bernstock, Harpreet K Saini, Maurizio Gelati, Angelo Luigi Vescovi, Carlos Bastos, Nuno Faria, Luigi G Occhipinti, Anton J Enright, Christian Frezza, Stefano Pluchino
Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC)-derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1)...
July 3, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671684/a-new-strategy-for-aromatic-ring-alkylation-in-cylindrocyclophane-biosynthesis
#8
Hitomi Nakamura, Erica E Schultz, Emily P Balskus
Alkylation of aromatic rings with alkyl halides is an important transformation in organic synthesis, yet an enzymatic equivalent is unknown. Here, we report that cylindrocyclophane biosynthesis in Cylindrospermum licheniforme ATCC 29412 involves chlorination of an unactivated carbon center by a novel halogenase, followed by a previously uncharacterized enzymatic dimerization reaction featuring sequential, stereospecific alkylations of resorcinol aromatic rings. Discovery of the enzymatic machinery underlying this unique biosynthetic carbon-carbon bond formation has implications for biocatalysis and metabolic engineering...
June 26, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671680/monitoring-thioredoxin-redox-with-a-genetically-encoded-red-fluorescent-biosensor
#9
Yichong Fan, Merna Makar, Michael X Wang, Hui-Wang Ai
Thioredoxin (Trx) is one of the two major thiol antioxidants, playing essential roles in redox homeostasis and signaling. Despite its importance, there is a lack of methods for monitoring Trx redox dynamics in live cells, hindering a better understanding of physiological and pathological roles of the Trx redox system. In this work, we developed the first genetically encoded fluorescent biosensor for Trx redox by engineering a redox relay between the active-site cysteines of human Trx1 and rxRFP1, a redox-sensitive red fluorescent protein...
June 26, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671679/2-deoxyadenosine-5-diphosphoribose-is-an-endogenous-trpm2-superagonist
#10
Ralf Fliegert, Andreas Bauche, Adriana-Michelle Wolf Pérez, Joanna M Watt, Monika D Rozewitz, Riekje Winzer, Mareike Janus, Feng Gu, Annette Rosche, Angelika Harneit, Marianne Flato, Christelle Moreau, Tanja Kirchberger, Valerie Wolters, Barry V L Potter, Andreas H Guse
Transient receptor potential melastatin 2 (TRPM2) is a ligand-gated Ca(2+)-permeable nonselective cation channel. Whereas physiological stimuli, such as chemotactic agents, evoke controlled Ca(2+) signals via TRPM2, pathophysiological stimuli such as reactive oxygen species and genotoxic stress result in prolonged TRPM2-mediated Ca(2+) entry and, consequently, apoptosis. To date, adenosine 5'-diphosphoribose (ADPR) has been assumed to be the main agonist for TRPM2. Here we show that 2'-deoxy-ADPR was a significantly better TRPM2 agonist, inducing 10...
June 26, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28671678/molecular-basis-of-the-evolution-of-alternative-tyrosine-biosynthetic-routes-in-plants
#11
Craig A Schenck, Cynthia K Holland, Matthew R Schneider, Yusen Men, Soon Goo Lee, Joseph M Jez, Hiroshi A Maeda
L-Tyrosine (Tyr) is essential for protein synthesis and is a precursor of numerous specialized metabolites crucial for plant and human health. Tyr can be synthesized via two alternative routes by different key regulatory TyrA family enzymes, prephenate dehydrogenase (PDH, also known as TyrAp) or arogenate dehydrogenase (ADH, also known as TyrAa), representing a unique divergence of primary metabolic pathways. The molecular foundation underlying the evolution of these alternative Tyr pathways is currently unknown...
June 26, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28628097/cpf1-proteins-excise-crispr-rnas-from-mrna-transcripts-in-mammalian-cells
#12
Guocai Zhong, Haimin Wang, Yujun Li, Mai H Tran, Michael Farzan
Cpf1 is a CRISPR effector protein that has greater specificity than Streptococcus pyogenes Cas9 (SpCas9) in genome-editing applications. Here we show that Lachnospiraceae bacterium (Lb) and Acidaminococus sp. (As) Cpf1 orthologs have RNase activities that can excise multiple CRISPR RNAs (crRNAs) from a single RNA polymerase II-driven RNA transcript expressed in mammalian cells. This property simplifies modification of multiple genomic targets and can be used to increase the efficiency of Cpf1-mediated editing...
June 19, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28628096/nucleation-and-growth-of-a-bacterial-functional-amyloid-at-single-fiber-resolution
#13
Mike Sleutel, Imke Van den Broeck, Nani Van Gerven, Cécile Feuillie, Wim Jonckheere, Claire Valotteau, Yves F Dufrêne, Han Remaut
Curli are functional amyloids produced by proteobacteria like Escherichia coli as part of the extracellular matrix that holds cells together into biofilms. The molecular events that occur during curli nucleation and fiber extension remain largely unknown. Combining observations from curli amyloidogenesis in bulk solutions with real-time in situ nanoscopic imaging at the single-fiber level, we show that curli display polar growth, and we detect two kinetic regimes of fiber elongation. Single fibers exhibit stop-and-go dynamics characterized by bursts of steady-state growth alternated with periods of stagnation...
June 19, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28628095/a-scaffold-protein-that-chaperones-a-cysteine-sulfenic-acid-in-h2o2-signaling
#14
Antoine Bersweiler, Benoît D'Autréaux, Hortense Mazon, Alexandre Kriznik, Gemma Belli, Agnès Delaunay-Moisan, Michel B Toledano, Sophie Rahuel-Clermont
In Saccharomyces cerevisiae, Yap1 regulates an H2O2-inducible transcriptional response that controls cellular H2O2 homeostasis. H2O2 activates Yap1 by oxidation through the intermediary of the thiol peroxidase Orp1. Upon reacting with H2O2, Orp1 catalytic cysteine oxidizes to a sulfenic acid, which then engages into either an intermolecular disulfide with Yap1, leading to Yap1 activation, or an intramolecular disulfide that commits the enzyme into its peroxidatic cycle. How the first of these two competing reactions, which is kinetically unfavorable, occurs was previously unknown...
June 19, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28628094/a-water-soluble-dsbb-variant-that-catalyzes-disulfide-bond-formation-in-vivo
#15
Dario Mizrachi, Michael-Paul Robinson, Guoping Ren, Na Ke, Mehmet Berkmen, Matthew P DeLisa
Escherichia coli DsbB is a transmembrane enzyme that catalyzes the reoxidation of the periplasmic oxidase DsbA by ubiquinone. Here, we sought to convert membrane-bound DsbB into a water-soluble biocatalyst by leveraging a previously described method for in vivo solubilization of integral membrane proteins (IMPs). When solubilized DsbB variants were coexpressed with an export-defective copy of DsbA in the cytoplasm of wild-type E. coli cells, artificial oxidation pathways were created that efficiently catalyzed de novo disulfide-bond formation in a range of substrate proteins, in a manner dependent on both DsbA and quinone...
June 19, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28628093/a-heme-dependent-enzyme-forms-the-nitrogen-nitrogen-bond-in-piperazate
#16
Yi-Ling Du, Hai-Yan He, Melanie A Higgins, Katherine S Ryan
Molecules containing a nitrogen-nitrogen (N-N) linkage have a variety of structures and biological activities; however, no enzyme has yet been demonstrated to catalyze N-N bond formation in an organic molecule. Here we report that the heme-dependent enzyme KtzT from Kutzneria sp. 744 catalyzes N-N bond formation in the biosynthesis of piperazate, a building block for nonribosomal peptides.
June 19, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28604697/site-specific-incorporation-of-phosphotyrosine-using-an-expanded-genetic-code
#17
Christian Hoppmann, Allison Wong, Bing Yang, Shuwei Li, Tony Hunter, Kevan M Shokat, Lei Wang
Access to phosphoproteins with stoichiometric and site-specific phosphorylation status is key to understanding the role of protein phosphorylation. Here we report an efficient method to generate pure, active phosphotyrosine-containing proteins by genetically encoding a stable phosphotyrosine analog that is convertible to native phosphotyrosine. We demonstrate its general compatibility with proteins of various sizes, phosphotyrosine sites and functions, and reveal a possible role of tyrosine phosphorylation in negative regulation of ubiquitination...
June 12, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28604696/a-front-face-sni-synthase-engineered-from-a-retaining-double-sn2-hydrolase
#18
Javier Iglesias-Fernández, Susan M Hancock, Seung Seo Lee, Maola Khan, Jo Kirkpatrick, Neil J Oldham, Katherine McAuley, Anthony Fordham-Skelton, Carme Rovira, Benjamin G Davis
SNi-like mechanisms, which involve front-face leaving group departure and nucleophile approach, have been observed experimentally and computationally in chemical and enzymatic substitution at α-glycosyl electrophiles. Since SNi-like, SN1 and SN2 substitution pathways can be energetically comparable, engineered switching could be feasible. Here, engineering of Sulfolobus solfataricus β-glycosidase, which originally catalyzed double SN2 substitution, changed its mode to SNi-like. Destruction of the first SN2 nucleophile through E387Y mutation created a β-stereoselective catalyst for glycoside synthesis from activated substrates, despite lacking a nucleophile...
June 12, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28604695/a-scalable-platform-to-identify-fungal-secondary-metabolites-and-their-gene-clusters
#19
Kenneth D Clevenger, Jin Woo Bok, Rosa Ye, Galen P Miley, Maria H Verdan, Thomas Velk, Cynthia Chen, KaHoua Yang, Matthew T Robey, Peng Gao, Matthew Lamprecht, Paul M Thomas, Md Nurul Islam, Jonathan M Palmer, Chengcang C Wu, Nancy P Keller, Neil L Kelleher
The genomes of filamentous fungi contain up to 90 biosynthetic gene clusters (BGCs) encoding diverse secondary metabolites-an enormous reservoir of untapped chemical potential. However, the recalcitrant genetics, cryptic expression, and unculturability of these fungi prevent scientists from systematically exploiting these gene clusters and harvesting their products. As heterologous expression of fungal BGCs is largely limited to the expression of single or partial clusters, we established a scalable process for the expression of large numbers of full-length gene clusters, called FAC-MS...
June 12, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28604694/a-mutant-o-glcnacase-enriches-drosophila-developmental-regulators
#20
Nithya Selvan, Ritchie Williamson, Daniel Mariappa, David G Campbell, Robert Gourlay, Andrew T Ferenbach, Tonia Aristotelous, Iva Hopkins-Navratilova, Matthias Trost, Daan M F van Aalten
Protein O-GlcNAcylation is a reversible post-translational modification of serines and threonines on nucleocytoplasmic proteins. It is cycled by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (O-GlcNAcase or OGA). Genetic approaches in model organisms have revealed that protein O-GlcNAcylation is essential for early embryogenesis. The Drosophila melanogaster gene supersex combs (sxc), which encodes OGT, is a polycomb gene, whose null mutants display homeotic transformations and die at the pharate adult stage...
June 12, 2017: Nature Chemical Biology
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