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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (597 journals)
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CHEMISTRY (597 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 7)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 31)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 17)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 22)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 218)
ACS Photonics     Full-text available via subscription   (Followers: 10)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 48)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 12)
Advances in Chemistry     Open Access   (Followers: 12)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 18)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 40)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 10)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 25)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Full-text available via subscription   (Followers: 12)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 153)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 204)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 26)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 9)
Biochemistry     Full-text available via subscription   (Followers: 278)
Biochemistry Insights     Open Access   (Followers: 5)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 109)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 99)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 67)
Catalysis for Sustainable Energy     Open Access   (Followers: 6)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 7)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 12)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 69)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 165)
Chemical Science     Open Access   (Followers: 21)
Chemical Technology     Open Access   (Followers: 15)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 137)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 17)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 189)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 8)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 23)
Chromatography Research International     Open Access   (Followers: 7)
Clay Minerals     Full-text available via subscription   (Followers: 9)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 8)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 3)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 2)
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 10)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 4)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 48)
Dalton Transactions     Full-text available via subscription   (Followers: 18)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)
Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 19)

        1 2 3 | Last

Journal Cover Chemistry & Biology
  [SJR: 3.282]   [H-I: 143]   [30 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 1074-5521
   Published by Elsevier Homepage  [3031 journals]
  • Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary
           cis-trans Enoyl CoA Isomerase
    • Authors: Sonali Srivastava; Sarika Chaudhary; Lipi Thukral; Ce Shi; Rinkoo D. Gupta; Radhika Gupta; K. Priyadarshan; Archana Vats; Asfarul S. Haque; Rajan Sankaranarayanan; Vivek T. Natarajan; Rakesh Sharma; Courtney C. Aldrich; Rajesh S. Gokhale
      Pages: 1577 - 1587
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Sonali Srivastava, Sarika Chaudhary, Lipi Thukral, Ce Shi, Rinkoo D. Gupta, Radhika Gupta, K. Priyadarshan, Archana Vats, Asfarul S. Haque, Rajan Sankaranarayanan, Vivek T. Natarajan, Rakesh Sharma, Courtney C. Aldrich, Rajesh S. Gokhale
      Mycobacterium tuberculosis (Mtb) can survive in hypoxic necrotic tissue by assimilating energy from host-derived fatty acids. While the expanded repertoire of β-oxidation auxiliary enzymes is considered crucial for Mtb adaptability, delineating their functional relevance has been challenging. Here, we show that the Mtb fatty acid degradation (FadAB) complex cannot selectively break down cis fatty acyl substrates. We demonstrate that the stereoselective binding of fatty acyl substrates in the Mtb FadB pocket is due to the steric hindrance from Phe287 residue. By developing a functional screen, we classify the family of Mtb Ech proteins as monofunctional or bifunctional enzymes, three of which complement the FadAB complex to degrade cis fatty acids. Crystal structure determination of two cis-trans enoyl coenzyme A (CoA) isomerases reveals distinct placement of active-site residue in Ech enzymes. Our studies thus reveal versatility of Mtb lipid-remodeling enzymes and identify an essential role of stand-alone cis-trans enoyl CoA isomerases in mycobacterial biology.
      Graphical abstract image Teaser Mtb can utilize host lipids as one of the energy sources during infection. Srivastava et al. demonstrate that the assimilation of cis fatty acids by Mtb through β-oxidation machinery requires auxiliary 3-cis 2-trans enoyl CoA isomerases.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.009
       
  • Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain
           Inhibitor Highlights Therapeutic Opportunities
    • Authors: Eugene L. Piatnitski Chekler; Jessica A. Pellegrino; Thomas A. Lanz; R. Aldrin Denny; Andrew C. Flick; Jotham Coe; Jonathan Langille; Arindrajit Basak; Shenping Liu; Ingrid A. Stock; Parag Sahasrabudhe; Paul D. Bonin; Kevin Lee; Mathew T. Pletcher; Lyn H. Jones
      Pages: 1588 - 1596
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Eugene L. Piatnitski Chekler, Jessica A. Pellegrino, Thomas A. Lanz, R. Aldrin Denny, Andrew C. Flick, Jotham Coe, Jonathan Langille, Arindrajit Basak, Shenping Liu, Ingrid A. Stock, Parag Sahasrabudhe, Paul D. Bonin, Kevin Lee, Mathew T. Pletcher, Lyn H. Jones
      Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.
      Graphical abstract image Teaser Chekler et al. designed, synthesized, and transcriptionally profiled a selective inhibitor of the bromodomain of CREB binding protein. The inhibitor, called PF-CBP1, modulated key inflammatory genes in macrophages and downregulated RGS4 (a gene linked to Parkinson's disease) in neurons.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.013
       
  • Halophilic Protein Adaptation Results from Synergistic Residue-Ion
           Interactions in the Folded and Unfolded States
    • Authors: Gabriel Ortega; Tammo Diercks; Oscar Millet
      Pages: 1597 - 1607
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Gabriel Ortega, Tammo Diercks, Oscar Millet
      Halophilic organisms thrive in environments with extreme salt concentrations and have adapted by allowing molar quantities of cosolutes, mainly KCl, to accumulate in their cytoplasm. To cope with this high intracellular salinity, halophilic organisms modified the chemical composition of their proteins to enrich their surface with acidic and short polar side chains, while lysines and bulky hydrophobic residues got depleted. We have emulated the evolutionary process of haloadaptation with natural and designed halophilic polypeptides and applied novel nuclear magnetic resonance (NMR) methodology to study the different mechanisms contributing to protein haloadaptation at a per residue level. Our analysis of an extensive set of NMR observables, determined over several proteins, allowed us to disentangle the synergistic contributions of protein haloadaptation: cation exclusion and electrostatic repulsion between negatively charged residues destabilize the denatured state ensemble while cumulative weak cation-protein interactions stabilize the folded conformations.
      Graphical abstract image Teaser We show that the synergy of protein-ion effects in the folded and the unfolded states governs halophilic proteins adaptation to hypersaline media.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.010
       
  • Reciprocal Regulation of ERα and ERβ Stability and Activity by
           Diptoindonesin G
    • Authors: Zibo Zhao; Lu Wang; Taryn James; Youngeun Jung; Ikyon Kim; Renxiang Tan; F. Michael Hoffmann; Wei Xu
      Pages: 1608 - 1621
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Zibo Zhao, Lu Wang, Taryn James, Youngeun Jung, Ikyon Kim, Renxiang Tan, F. Michael Hoffmann, Wei Xu
      ERβ is regarded as a “tumor suppressor” in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.
      Graphical abstract image Teaser We identified a small molecule Diptoindonesin G that reciprocally stabilizes ERβ and destabilizes ERα in breast cancer cells. Dip G represents a new class of selective estrogen receptor modulator (SERMs) that could restore the balance of ERα and ERβ for the treatment of human breast cancer.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.011
       
  • Unraveling the B. pseudomallei Heptokinase WcbL: From Structure to
           Drug Discovery
    • Authors: Mirella Vivoli; Michail N. Isupov; Rebecca Nicholas; Andrew Hill; Andrew E. Scott; Paul Kosma; Joann L. Prior; Nicholas J. Harmer
      Pages: 1622 - 1632
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Mirella Vivoli, Michail N. Isupov, Rebecca Nicholas, Andrew Hill, Andrew E. Scott, Paul Kosma, Joann L. Prior, Nicholas J. Harmer
      Gram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP. We show that dimeric WcbL binds ATP anti-cooperatively in the absence of heptose, and cooperatively in its presence. Modeling of WcbL suggests that heptose binding causes an elegant switch in the hydrogen-bonding network, facilitating the binding of a second ATP molecule. Finally, we screened a library of drug-like fragments, identifying hits that potently inhibit WcbL. Our results provide a novel mechanism for control of substrate binding and emphasize WcbL as an attractive anti-microbial target for Gram-negative bacteria.
      Graphical abstract image Teaser Vivoli et al. present the structure and mechanism of the bacterial sugar kinase WcbL. WcbL demonstrates unusual kinetics: its cooperativity for ATP switches on binding of the sugar substrate. Screening of a fragment library identified a potent inhibitor of WcbL.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.015
       
  • Biosynthesis of Neocarazostatin A Reveals the Sequential Carbazole
           Prenylation and Hydroxylation in the Tailoring Steps
    • Authors: Sheng Huang; Somayah Sameer Elsayed; Meinan Lv; Jioji Tabudravu; Mostafa E. Rateb; Roland Gyampoh; Kwaku Kyeremeh; Rainer Ebel; Marcel Jaspars; Zixin Deng; Yi Yu; Hai Deng
      Pages: 1633 - 1642
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Sheng Huang, Somayah Sameer Elsayed, Meinan Lv, Jioji Tabudravu, Mostafa E. Rateb, Roland Gyampoh, Kwaku Kyeremeh, Rainer Ebel, Marcel Jaspars, Zixin Deng, Yi Yu, Hai Deng
      Neocarazostatin A (NZS) is a bacterial alkaloid with promising bioactivities against free radicals, featuring a tricyclic carbazole nucleus with a prenyl moiety at C-6 of the carbazole ring. Here, we report the discovery and characterization of the biosynthetic pathway of NZS through genome mining and gene inactivation. The in vitro assays characterized two enzymes: NzsA is a P450 hydroxylase and NzsG is a new phytoene-synthase-like prenyltransferase (PTase). This is the first reported native PTase that specifically acts on the carbazole nucleus. Finally, our in vitro reconstituted experiment demonstrated a coupled reaction catalyzed by NzsG and NzsA tailoring the NZS biosynthesis.
      Graphical abstract image Teaser Huang et al. identified the gene cluster directing the biosynthesis of neocarazostatin A, characterized two new enzymes responsible for the late stage of the biosynthesis, and reconstituted in vitro the biotransformation from the biosynthetic intermediate to neocarazostatin A.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.012
       
  • Human ISPD Is a Cytidyltransferase Required for Dystroglycan
           O-Mannosylation
    • Authors: Moniek Riemersma; D. Sean Froese; Walinka van Tol; Udo F. Engelke; Jolanta Kopec; Monique van Scherpenzeel; Angel Ashikov; Tobias Krojer; Frank von Delft; Marco Tessari; Anna Buczkowska; Ewa Swiezewska; Lucas T. Jae; Thijn R. Brummelkamp; Hiroshi Manya; Tamao Endo; Hans van Bokhoven; Wyatt W. Yue; Dirk J. Lefeber
      Pages: 1643 - 1652
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Moniek Riemersma, D. Sean Froese, Walinka van Tol, Udo F. Engelke, Jolanta Kopec, Monique van Scherpenzeel, Angel Ashikov, Tobias Krojer, Frank von Delft, Marco Tessari, Anna Buczkowska, Ewa Swiezewska, Lucas T. Jae, Thijn R. Brummelkamp, Hiroshi Manya, Tamao Endo, Hans van Bokhoven, Wyatt W. Yue, Dirk J. Lefeber
      A unique, unsolved O-mannosyl glycan on α-dystroglycan is essential for its interaction with protein ligands in the extracellular matrix. Defective O-mannosylation leads to a group of muscular dystrophies, called dystroglycanopathies. Mutations in isoprenoid synthase domain containing (ISPD) represent the second most common cause of these disorders, however, its molecular function remains uncharacterized. The human ISPD (hISPD) crystal structure showed a canonical N-terminal cytidyltransferase domain linked to a C-terminal domain that is absent in cytidyltransferase homologs. Functional studies demonstrated cytosolic localization of hISPD, and cytidyltransferase activity toward pentose phosphates, including ribulose 5-phosphate, ribose 5-phosphate, and ribitol 5-phosphate. Identity of the CDP sugars was confirmed by liquid chromatography quadrupole time-of-flight mass spectrometry and two-dimensional nuclear magnetic resonance spectroscopy. Our combined results indicate that hISPD is a cytidyltransferase, suggesting the presence of a novel human nucleotide sugar essential for functional α-dystroglycan O-mannosylation in muscle and brain. Thereby, ISPD deficiency can be added to the growing list of tertiary dystroglycanopathies.
      Graphical abstract image Teaser Guided by X-ray crystallography and biochemical studies in ISPD knockout and overexpressing cell models, we implicated human ISPD in the synthesis of a novel human nucleotide sugar required for dystroglycan O-mannosylation in muscle and brain.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.014
       
  • Synthetic Peptides as cGMP-Independent Activators of cGMP-Dependent
           Protein Kinase Iα
    • Authors: Thomas M. Moon; Nathan R. Tykocki; Jessica L. Sheehe; Brent W. Osborne; Werner Tegge; Joseph E. Brayden; Wolfgang R. Dostmann
      Pages: 1653 - 1661
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Thomas M. Moon, Nathan R. Tykocki, Jessica L. Sheehe, Brent W. Osborne, Werner Tegge, Joseph E. Brayden, Wolfgang R. Dostmann
      PKG is a multifaceted signaling molecule and potential pharmaceutical target due to its role in smooth muscle function. A helix identified in the structure of the regulatory domain of PKG Iα suggests a novel architecture of the holoenzyme. In this study, a set of synthetic peptides (S-tides), derived from this helix, was found to bind to and activate PKG Iα in a cyclic guanosine monophosphate (cGMP)-independent manner. The most potent S-tide derivative (S1.5) increased the open probability of the potassium channel KCa1.1 to levels equivalent to saturating cGMP. Introduction of S1.5 to smooth muscle cells in isolated, endothelium-denuded cerebral arteries through a modified reversible permeabilization procedure inhibited myogenic constriction. In contrast, in endothelium-intact vessels S1.5 had no effect on myogenic tone. This suggests that PKG Iα activation by S1.5 in vascular smooth muscle would be sufficient to inhibit augmented arterial contractility that frequently occurs following endothelial damage associated with cardiovascular disease.
      Graphical abstract image Teaser The control of vascular smooth muscle relaxation and blood flow are tightly linked to the activity of cGMP-dependent protein kinase (PKG). Moon et al. demonstrate the development and assay of a class of novel vasodilators that are selective cGMP-independent PKG Iα activators.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.11.005
       
  • Differential Regulation of Specific Sphingolipids in Colon Cancer Cells
           during Staurosporine-Induced Apoptosis
    • Authors: Virginia del Solar; Darleny Y. Lizardo; Nasi Li; Jerod J. Hurst; Christopher J. Brais; G. Ekin Atilla-Gokcumen
      Pages: 1662 - 1670
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Virginia del Solar, Darleny Y. Lizardo, Nasi Li, Jerod J. Hurst, Christopher J. Brais, G. Ekin Atilla-Gokcumen
      Apoptosis is accompanied by distinct morphological changes at the plasma and organelle membrane level. Involvement of certain lipids in apoptosis has been established; however, we have limited understanding of the specific lipid structures that participate in this process. We used untargeted comparative lipidomics to study the changes in lipid composition during staurosporine-induced apoptosis in HCT-116. Our results revealed that ceramides, dihydroceramides, and sphingomyelins, with defined acyl chains, constitute the majority of changes in the lipidome. Expression levels and activities of enzymes responsible for the biosynthesis of lipids that change suggest that de novo synthesis causes these specific changes. Further analysis of the lipidome during apoptosis in other cancer and non-cancer cell lines suggested that accumulation of ceramides and dihydroceramides is specific to cancer cells. Taken together, our data propose that these molecules are regulated at the lipid-specific level during apoptosis and that this regulation differs between cancer and non-cancer cells.
      Graphical abstract image Teaser del Solar et al. employ comparative lipidomics to analyze the changes in lipid composition during staurosporine-induced apoptosis in cancer and non-cancer cells, and show that specific ceramides and dihydroceramides accumulate in cancer cells but not in non-cancer cells.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.11.004
       
  • DIVERSE System: De Novo Creation of Peptide Tags for Non-enzymatic
           Covalent Labeling by In Vitro Evolution for Protein Imaging Inside Living
           Cells
    • Authors: Takashi Kawakami; Koji Ogawa; Naoki Goshima; Tohru Natsume
      Pages: 1671 - 1679
      Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Author(s): Takashi Kawakami, Koji Ogawa, Naoki Goshima, Tohru Natsume
      Polypeptide-tag/small-molecule pairs for specific cellular protein labeling are useful for visualizing cellular proteins and controlling their activity. Here, we report the development of an in vitro evolution-based (poly)peptide tag identification system named the DIVERSE (Directed In Vitro Evolution of Reactive peptide tags via Sequential Enrichment) system. In this system, an extremely diverse (1014) library of peptide tags, displayed by covalent attachment to their encoding cDNAs, is continuously prepared from the DNA library in a one-pot approach. Using this system, we demonstrated de novo creation of non-enzymatically covalent-labeling peptide tags for a synthetic small-molecule target from a random peptide library. Protein labeling with these tags was applicable to N- and C-terminal fusions, multiple different proteins and fluorophores, and intracellular labeling. The DIVERSE system can be used not only for the de novo creation of polypeptide tags but also sequence optimization of existing polypeptide tags from extremely diverse libraries.
      Graphical abstract image Teaser Kawakami et al. developed an in vitro evolution-based (poly)peptide tag identification system named the DIVERSE (Directed In Vitro Evolution of Reactive peptide tags via Sequential Enrichment) system. Using the DIVERSE system, the authors demonstrated de novo creation of peptide tags for non-enzymatic, covalent protein labeling.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.016
       
  • Geometrically Precise Building Blocks: the Self-Assembly of
           β-Peptides
    • Authors: Romila D. Gopalan; Mark P. Del Borgo; Adam I. Mechler; Patrick Perlmutter; Marie-Isabel Aguilar
      Pages: 1417 - 1423
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Romila D. Gopalan, Mark P. Del Borgo, Adam I. Mechler, Patrick Perlmutter, Marie-Isabel Aguilar
      Peptides comprised entirely of β-amino acids, or β-peptides, have attracted substantial interest over the past 25 years due to their unique structural and chemical characteristics. β-Peptides form well-defined secondary structures that exhibit different geometries compared with their α-peptide counterparts, giving rise to their foldamer classification. β-Peptide foldamers can be functionalized easily and are metabolically stable and, together with the predictable side-chain topography, have led to the design of a growing number of bioactive β-peptides with a range of biological targets. The strategic engineering of chemical and topographic properties has also led to the design of β-peptide mimics of higher-order oligomers. More recently, the ability of these peptides to self-assemble into complex structures of controlled geometries has been exploited in materials applications. The focus of this mini-review is on how the unique structural features of β-peptide assemblies have been exploited in the design of self-assembled proteomimetic bundles and nanomaterials.
      Teaser Peptides comprised entirely of β-amino acids form unique structures that self-assemble to form ion channels, proteomimetic bundles, and DNA mimics. This structural template also allows the tailored design of new nanomaterials with unique physical properties for application in nanotechnology and biomedicine.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.005
       
  • Substrate Flexibility of a Mutated Acyltransferase Domain and Implications
           for Polyketide Biosynthesis
    • Authors: Kenny Bravo-Rodriguez; Stephan Klopries; Kyra R.M. Koopmans; Uschi Sundermann; Samir Yahiaoui; Julia Arens; Susanna Kushnir; Frank Schulz; Elsa Sanchez-Garcia
      Pages: 1425 - 1430
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Kenny Bravo-Rodriguez, Stephan Klopries, Kyra R.M. Koopmans, Uschi Sundermann, Samir Yahiaoui, Julia Arens, Susanna Kushnir, Frank Schulz, Elsa Sanchez-Garcia
      Polyketides are natural products frequently used for the treatment of various diseases, but their structural complexity hinders efficient derivatization. In this context, we recently introduced enzyme-directed mutasynthesis to incorporate non-native extender units into the biosynthesis of erythromycin. Modeling and mutagenesis studies led to the discovery of a variant of an acyltransferase domain in the erythromycin polyketide synthase capable of accepting a propargylated substrate. Here, we extend molecular rationalization of enzyme-substrate interactions through modeling, to investigate the incorporation of substrates with different degrees of saturation of the malonic acid side chain. This allowed the engineered biosynthesis of new erythromycin derivatives and the introduction of additional mutations into the AT domain for a further shift of the enzyme's substrate scope. Our approach yields non-native polyketide structures with functional groups that will simplify future derivatization approaches, and provides a blueprint for the engineering of AT domains to achieve efficient polyketide synthase diversification.
      Graphical abstract image Teaser Molecular modeling of polyketide synthase domains can yield insights into the structure and function of these giant and complex enzymes. Based on modeling, mutations are devised that shift the substrate scope of an acyltransferase domain of a polyketide synthase toward the incorporation of artificial building blocks into the biosynthesis of the important antibiotic erythromycin to generate new derivatives.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.02.008
       
  • Bioorthogonal Labeling of Ghrelin Receptor to Facilitate Studies of
           Ligand-Dependent Conformational Dynamics
    • Authors: Minyoung Park; Bjørn B. Sivertsen; Sylvia Els-Heindl; Thomas Huber; Birgitte Holst; Annette G. Beck-Sickinger; Thue W. Schwartz; Thomas P. Sakmar
      Pages: 1431 - 1436
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Minyoung Park, Bjørn B. Sivertsen, Sylvia Els-Heindl, Thomas Huber, Birgitte Holst, Annette G. Beck-Sickinger, Thue W. Schwartz, Thomas P. Sakmar
      Ghrelin receptor (GhrR) is a promising drug target because of its central role in energy homeostasis. GhrR, known for high constitutive activity, is thought to display multi-state conformations during activation and signaling. We used genetically encoded unnatural amino acids and bioorthogonal labeling reactions to engineer multiple fluorescent donor-acceptor pairs to probe ligand-directed structural changes in GhrR. We demonstrate how conformational dynamics of a G-protein-coupled receptor can be measured in reconstituted systems.
      Graphical abstract image Teaser Understanding ligand-induced conformations and consequences in ghrelin receptor signaling might assist in drug design. Park et al. use bioorthogonally labeled ghrelin receptors and show that RET-based approaches can reveal distinctive ligand-induced RET signals that are sensitive to inter- and intramolecular conformational changes.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.014
       
  • An L-RNA Aptamer that Binds and Inhibits RNase
    • Authors: Charles Olea; Joachim Weidmann; Philip E. Dawson; Gerald F. Joyce
      Pages: 1437 - 1441
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Charles Olea, Joachim Weidmann, Philip E. Dawson, Gerald F. Joyce
      L-RNA aptamers were developed that bind to barnase RNase and thereby inhibit the function of the enzyme. These aptamers were obtained by first carrying out in vitro selection of D-RNAs that bind to the full-length synthetic D-enantiomer of barnase, then reversing the mirror and preparing L-RNAs of identical sequence that similarly bind to natural L-barnase. The resulting L-aptamers bind L-barnase with an affinity of ∼100 nM and function as competitive inhibitors of enzyme cleavage of D-RNA substrates. L-RNA aptamers are resistant to degradation by ribonucleases, thus enabling them to function in biological samples, most notably for applications in molecular diagnostics and therapeutics. In addition to the irony of using RNA to inhibit RNase, L-RNA aptamers such as those described here could be used to measure the concentration or inhibit the function of RNase in the laboratory or in biological systems.
      Graphical abstract image Teaser Olea et al. select mirror-image RNA molecules, composed of the non-natural L-isomer, for their ability to bind and inhibit RNase, an enzyme that rapidly degrades natural RNA. This was accomplished by selecting natural RNAs that bind the full-length, non-natural isomer of RNase then reversing the mirror to enable L-RNA to protect its natural counterpart.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.017
       
  • Combinatorial Screening Identifies Novel Promiscuous Matrix
           Metalloproteinase Activities that Lead to Inhibition of the Therapeutic
           Target IL-13
    • Authors: Carole Urbach; Nathaniel C. Gordon; Ian Strickland; David Lowne; Cathy Joberty-Candotti; Richard May; Athula Herath; DirkJan Hijnen; Judith L. Thijs; Carla A. Bruijnzeel-Koomen; Ralph R. Minter; Florian Hollfelder; Lutz Jermutus
      Pages: 1442 - 1452
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Carole Urbach, Nathaniel C. Gordon, Ian Strickland, David Lowne, Cathy Joberty-Candotti, Richard May, Athula Herath, DirkJan Hijnen, Judith L. Thijs, Carla A. Bruijnzeel-Koomen, Ralph R. Minter, Florian Hollfelder, Lutz Jermutus
      The practical realization of disease modulation by catalytic degradation of a therapeutic target protein suffers from the difficulty to identify candidate proteases, or to engineer their specificity. We identified 23 measurable, specific, and new protease activities using combinatorial screening of 27 human proteases against 24 therapeutic protein targets. We investigate the cleavage of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-13 by matrix metalloproteinases (MMPs) and serine proteases, and demonstrate that cleavage of IL-13 leads to potent inhibition of its biological activity in vitro. MMP-8 degraded human IL-13 most efficiently in vitro and ex vivo in human IL-13 transgenic mouse bronchoalveolar lavage. Hence, MMP-8 is a therapeutic protease lead against IL-13 for inflammatory conditions whereby reported genetic and genomics data suggest an involvement of MMP-8. This work describes the first exploitation of human enzyme promiscuity for therapeutic applications, and reveals both starting points for protease-based therapies and potential new regulatory networks in inflammatory disease.
      Teaser Proteases with therapeutically relevant activities are generally unknown and cannot be tailor-made. Urbach et al. explore the substrate promiscuity of natural proteases to successfully identify starting scaffolds for novel biological therapies.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.013
       
  • Probing the Substrate Specificity and Protein-Protein Interactions of the
           E. coli Fatty Acid Dehydratase, FabA
    • Authors: Kara Finzel; Chi Nguyen; David R. Jackson; Aarushi Gupta; Shiou-Chuan Tsai; Michael D. Burkart
      Pages: 1453 - 1460
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Kara Finzel, Chi Nguyen, David R. Jackson, Aarushi Gupta, Shiou-Chuan Tsai, Michael D. Burkart
      Microbial fatty acid biosynthetic enzymes are important targets for areas as diverse as antibiotic development to biofuel production. Elucidating the molecular basis of chain length control during fatty acid biosynthesis is crucial for the understanding of regulatory processes of this fundamental metabolic pathway. In Escherichia coli, the acyl carrier protein (AcpP) plays a central role by sequestering and shuttling the growing acyl chain between fatty acid biosynthetic enzymes. FabA, a β-hydroxyacyl-AcpP dehydratase, is an important enzyme in controlling fatty acid chain length and saturation levels. FabA-AcpP interactions are transient in nature and thus difficult to visualize. In this study, four mechanistic crosslinking probes mimicking varying acyl chain lengths were synthesized to systematically probe for modified chain length specificity of 14 FabA mutants. These studies provide evidence for the AcpP-interacting “positive patch,” FabA mutations that alter substrate specificity, and the roles that the FabA “gating residues” play in chain length control.
      Graphical abstract image Teaser Finzel et al. utilized synthetic probes and FabA mutations to detect modified fatty acid dehydratase (FabA)-substrate and FabA-acyl carrier protein (AcpP) interactions. Altering FabA led to the first gain-of-function activity for shorter chain length fatty acid substrates.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.009
       
  • Development of a Clickable Probe for Profiling of Protein
           Glutathionylation in the Central Cellular Metabolism of E. coli and
           Drosophila
    • Authors: Shan Feng; Yuling Chen; Fan Yang; Lei Zhang; Yiyi Gong; Gulishana Adilijiang; Yan Gao; Haiteng Deng
      Pages: 1461 - 1469
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Shan Feng, Yuling Chen, Fan Yang, Lei Zhang, Yiyi Gong, Gulishana Adilijiang, Yan Gao, Haiteng Deng
      Protein glutathionylation is an important post-translational modification that regulates many cellular processes, including energy metabolism, signal transduction, and protein homeostasis. Global profiling of glutathionylated proteins (denoted as glutathionylome) is crucial for understanding redox-regulated signal transduction. Here, we developed a novel method based on click reaction and proteomics to enrich and identify the glutathionylated peptides in Escherichia coli and Drosophila lysates, in which 937 and 1,930 potential glutathionylated peptides were identified, respectively. Bioinformatics analysis showed that the cysteine residue next to negatively charged amino acid residues has a higher frequency of glutathionylation. Importantly, we found that most proteins associated with metabolic pathways were glutathionylated and that the glutathionylation sites of metabolic enzymes were highly conserved among different species. Our results indicate that the glutathione analog is a useful tool to characterize protein glutathionylation, and glutathionylation of metabolic enzymes, which play important roles in regulating cellular metabolism, is conserved.
      Graphical abstract image Teaser Protein glutathionylation plays a crucial role in various cellular processes. Feng et al. describe a novel method based on click reaction to profile glutathionylated proteins and sites in E. coli and Drosophila. The selectivity and conservatism of glutathionylation are characterized.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.012
       
  • Visualization of Compartmentalized Kinase Activity Dynamics Using
           Adaptable BimKARs
    • Authors: Charlene Depry; Sohum Mehta; Ruojing Li; Jin Zhang
      Pages: 1470 - 1479
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Charlene Depry, Sohum Mehta, Ruojing Li, Jin Zhang
      The ability to monitor kinase activity dynamics in live cells greatly aids the study of how signaling events are spatiotemporally regulated. Here, we report on the adaptability of bimolecular kinase activity reporters (bimKARs) as molecular tools to enhance the real-time visualization of kinase activity. We demonstrate that the bimKAR design is truly versatile and can be used to monitor a variety of kinases, including JNK, ERK, and AMPK. Furthermore, bimKARs can have significantly enhanced dynamic ranges over their unimolecular counterparts, allowing the elucidation of previously undetectable kinase activity dynamics. Using these newly designed bimKARs, we investigate the regulation of AMPK by protein kinase A (PKA) in the plasma membrane, and demonstrate that PKA can both negatively and positively regulate AMPK activity in the same cell.
      Graphical abstract image Teaser Depry et al. demonstrate the versatility of FRET-based bimolecular kinase activity reporters (bimKARs) as tools for improving the visualization of signaling dynamics in living cells, and reveal that PKA acts simultaneously as both a positive and negative regulator of AMPK signaling at the plasma membrane.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.004
       
  • Biochemical Studies of Mycobacterial Fatty Acid Methyltransferase: A
           Catalyst for the Enzymatic Production of Biodiesel
    • Authors: Nektaria Petronikolou; Satish K. Nair
      Pages: 1480 - 1490
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Nektaria Petronikolou, Satish K. Nair
      Transesterification of fatty acids yields the essential component of biodiesel, but current processes are cost-prohibitive and generate waste. Recent efforts make use of biocatalysts that are effective in diverting products from primary metabolism to yield fatty acid methyl esters in bacteria. These biotransformations require the fatty acid O-methyltransferase (FAMT) from Mycobacterium marinum (MmFAMT). Although this activity was first reported in the literature in 1970, the FAMTs have yet to be biochemically characterized. Here, we describe several crystal structures of MmFAMT, which highlight an unexpected structural conservation with methyltransferases that are involved in plant natural product metabolism. The determinants for ligand recognition are analyzed by kinetic analysis of structure-based active-site variants. These studies reveal how an architectural fold employed in plant natural product biosynthesis is used in bacterial fatty acid O-methylation.
      Graphical abstract image Teaser Mycobacterial fatty acid methyltransferases are employed as biocatalysts for the production of biodiesel. Petronikolou and Nair describe structural and biochemical characterization of a mycobacterial fatty acid methyltransferase, reveal an unexpected homology to enzymes involved in plant primary metabolism, and provide insights into substrate preference.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.011
       
  • Small-Molecule Disruption of RAD52 Rings as a Mechanism for Precision
           Medicine in BRCA-Deficient Cancers
    • Authors: Gurushankar Chandramouly; Shane McDevitt; Katherine Sullivan; Tatiana Kent; Antonio Luz; J. Fraser Glickman; Mark Andrake; Tomasz Skorski; Richard T. Pomerantz
      Pages: 1491 - 1504
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Gurushankar Chandramouly, Shane McDevitt, Katherine Sullivan, Tatiana Kent, Antonio Luz, J. Fraser Glickman, Mark Andrake, Tomasz Skorski, Richard T. Pomerantz
      Suppression of RAD52 causes synthetic lethality in BRCA-deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-DL-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-Dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA-deficient cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small-molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA-deficient cancers.
      Graphical abstract image Teaser Chandramouly et al. show that the small molecule 6-hydroxy-DL-dopa prevents RAD52 from binding to single-strand DNA by disrupting oligomeric ring structures of the protein, and selectively kills BRCA-deficient cell lines and leukemia patient cells by allosterically inactivating RAD52.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.003
       
  • Engineering Duplex RNAs for Challenging Targets: Recognition of
           GGGGCC/CCCCGG Repeats at the ALS/FTD C9orf72 Locus
    • Authors: Jiaxin Hu; Jing Liu; Liande Li; Keith T. Gagnon; David R. Corey
      Pages: 1505 - 1511
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Jiaxin Hu, Jing Liu, Liande Li, Keith T. Gagnon, David R. Corey
      A GGGGCC expansion within an intronic region of the C9orf72 gene forms RNA foci that are associated with one-third of familial amyotrophic lateral sclerosis and one-quarter of frontotemporal dementia. The C9orf72 locus also expresses an antisense transcript with a CCCCGG expansion that forms foci and may contribute to disease. Synthetic agents that bind these hexanucleotide repeats and block foci would be leads for therapeutic discovery. We have engineered duplex RNAs to enable them to recognize difficult C/G targets. Recognition inhibits foci formed by both GGGGCC and CCCCGG RNA. Our findings show that a single duplex RNA can be used to recognize both disease-related C9orf72 transcripts. More broadly, we extend RNAi to previously inaccessible C/G sequences and provide another example of target recognition in human cells by nuclear RNAi.
      Graphical abstract image Teaser A GGGGCC hexanucleotide expansion within the C9orf72 gene can cause familial amyotrophic lateral sclerosis and frontotemporal dementia. Hu et al. have engineered duplex RNAs to enable them to recognize difficult C/G targets and inhibit potential disease-causing foci formed by both GGGGCC and CCCCGG RNA.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.016
       
  • Combining Suppression of Stemness with Lineage-Specific Induction Leads to
           Conversion of Pluripotent Cells into Functional Neurons
    • Authors: Debasish Halder; Gyeong-Eon Chang; Debojyoti De; Eunji Cheong; Kyeong Kyu Kim; Injae Shin
      Pages: 1512 - 1520
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Debasish Halder, Gyeong-Eon Chang, Debojyoti De, Eunji Cheong, Kyeong Kyu Kim, Injae Shin
      Sox2 is a key player in the maintenance of pluripotency and stemness, and thus inhibition of its function would abrogate the stemness of pluripotent cells and induce differentiation into several types of cells. Herein we describe a strategy that relies on a combination of Sox2 inhibition with lineage-specific induction to promote efficient and selective differentiation of pluripotent P19 cells into neurons. When P19 cells transduced with Skp protein, an inhibitor of Sox2, are incubated with a neurogenesis inducer, the cells are selectively converted into neurons that generate depolarization-induced sodium currents and action potentials. This finding indicates that the differentiated neurons are electrophysiologically active. Signaling pathway studies lead us to conclude that a combination of Skp with the neurogenesis inducer enhances neurogenesis in P19 cells by activating Wnt and Notch pathways. The present differentiation protocol could be valuable to selectively generate functionally active neurons from pluripotent cells.
      Graphical abstract image Teaser Halder et al. demonstrated that a combination of Sox2 inhibition with lineage-specific induction led to efficient and selective differentiation of pluripotent P19 cells into neurons. Differentiated neuronal cells exhibited voltage-dependent inward and outward sodium currents and depolarization-induced action potentials.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.008
       
  • Host-Microbe Protein Interactions during Bacterial Infection
    • Authors: Devin K. Schweppe; Christopher Harding; Juan D. Chavez; Xia Wu; Elizabeth Ramage; Pradeep K. Singh; Colin Manoil; James E. Bruce
      Pages: 1521 - 1530
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Devin K. Schweppe, Christopher Harding, Juan D. Chavez, Xia Wu, Elizabeth Ramage, Pradeep K. Singh, Colin Manoil, James E. Bruce
      Interspecies protein-protein interactions are essential mediators of infection. While bacterial proteins required for host cell invasion and infection can be identified through bacterial mutant library screens, information about host target proteins and interspecies complex structures has been more difficult to acquire. Using an unbiased chemical crosslinking/mass spectrometry approach, we identified interspecies protein-protein interactions in human lung epithelial cells infected with Acinetobacter baumannii. These efforts resulted in identification of 3,076 crosslinked peptide pairs and 46 interspecies protein-protein interactions. Most notably, the key A. baumannii virulence factor, OmpA, was identified as crosslinked to host proteins involved in desmosomes, specialized structures that mediate host cell-to-cell adhesion. Co-immunoprecipitation and transposon mutant experiments were used to verify these interactions and demonstrate relevance for host cell invasion and acute murine lung infection. These results shed new light on A. baumannii-host protein interactions and their structural features, and the presented approach is generally applicable to other systems.
      Graphical abstract image Teaser Pathogenic bacteria exploit host resources through difficult-to-determine interactions between bacterial and host proteins. Schweppe et al. identified interspecies protein interactions during Acinetobacter baumannii infection of lung epithelia by protein crosslinking and mass spectrometry. Host protein targets for bacterial virulence factors were revealed, and crosslinked sites provide structural information for interspecies interactions during infection.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.015
       
  • Optogenetic Inhibitor of the Transcription Factor CREB
    • Authors: Ahmed M. Ali; Jakeb M. Reis; Yan Xia; Asim J. Rashid; Valentina Mercaldo; Brandon J. Walters; Katherine E. Brechun; Vitali Borisenko; Sheena A. Josselyn; John Karanicolas; G. Andrew Woolley
      Pages: 1531 - 1539
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Ahmed M. Ali, Jakeb M. Reis, Yan Xia, Asim J. Rashid, Valentina Mercaldo, Brandon J. Walters, Katherine E. Brechun, Vitali Borisenko, Sheena A. Josselyn, John Karanicolas, G. Andrew Woolley
      Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN-CREB, a blue-light-controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light-driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events.
      Graphical abstract image Teaser Ali et al. use protein engineering to create opto-DN-CREB, a blue-light-controlled specific inhibitor of the transcription factor CREB.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.018
       
  • Molecular Basis of Spectral Diversity in Near-Infrared Phytochrome-Based
           Fluorescent Proteins
    • Authors: Daria M. Shcherbakova; Mikhail Baloban; Sergei Pletnev; Vladimir N. Malashkevich; Hui Xiao; Zbigniew Dauter; Vladislav V. Verkhusha
      Pages: 1540 - 1551
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Daria M. Shcherbakova, Mikhail Baloban, Sergei Pletnev, Vladimir N. Malashkevich, Hui Xiao, Zbigniew Dauter, Vladislav V. Verkhusha
      Near-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes (BphPs) are the probes of choice for deep-tissue imaging. Detection of several processes requires spectrally distinct NIR FPs. We developed an NIR FP, BphP1-FP, which has the most blue-shifted spectra and the highest fluorescence quantum yield among BphP-derived FPs. We found that these properties result from the binding of the biliverdin chromophore to a cysteine residue in the GAF domain, unlike natural BphPs and other BphP-based FPs. To elucidate the molecular basis of the spectral shift, we applied biochemical, structural and mass spectrometry analyses and revealed the formation of unique chromophore species. Mutagenesis of NIR FPs of different origins indicated that the mechanism of the spectral shift is general and can be used to design multicolor NIR FPs from other BphPs. We applied pairs of spectrally distinct point cysteine mutants to multicolor cell labeling and demonstrated that they perform well in model deep-tissue imaging.
      Graphical abstract image Teaser We show that the biliverdin chromophore can bind to cysteine in the GAF domain of bacterial phytochromes and derived near-infrared fluorescent proteins, resulting in their blue shift and high quantum yield. This opens up the way to develop spectrally distinct near-infrared fluorescent proteins for multicolor imaging.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.007
       
  • Profiling of Free Fatty Acids Using Stable Isotope Tagging Uncovers a Role
           for Saturated Fatty Acids in Neuroexocytosis
    • Authors: Vinod K. Narayana; Vanesa M. Tomatis; Tong Wang; David Kvaskoff; Frederic A. Meunier
      Pages: 1552 - 1561
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Vinod K. Narayana, Vanesa M. Tomatis, Tong Wang, David Kvaskoff, Frederic A. Meunier
      The phospholipase-catalyzed release of free fatty acids (FFAs) from phospholipids is implicated in many critical biological processes such as neurotransmission, inflammation, and cancer. However, determining the individual change in FFAs generated during these processes has remained challenging due to the limitations of current methods, and has hampered our understanding of these key mediators. Here, we developed an “iTRAQ”-like method for profiling FFAs by stable isotope tagging (FFAST), based on the differential labeling of the carboxyl group and designed to resolve analytical variance, through a multiplexed assay in cells and subcellular fractions. With nanomolar sensitivity, this method revealed a spectrum of saturated FFAs elicited during stimulation of exocytosis that was identical in neurons and neurosecretory cells. Purified secretory vesicles also generated these FFAs when challenged with cytosol. Our multiplex method will be invaluable to assess the range of FFAs generated in other physiological and pathological settings.
      Graphical abstract image Teaser Narayana et al. developed a free fatty acid stable isotope tagging (FFAST) method that enables multiplexed quantification of endogenous free fatty acids with nanomolar sensitivity. Here, they uncover an unexpected variety of change in free fatty acids generated during neuroexocytosis in neurons and chromaffin cells.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.010
       
  • Quantitative Lipoproteomics in Clostridium difficile Reveals a Role for
           Lipoproteins in Sporulation
    • Authors: Thomas M. Charlton; Andrea Kovacs-Simon; Stephen L. Michell; Neil F. Fairweather; Edward W. Tate
      Pages: 1562 - 1573
      Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Author(s): Thomas M. Charlton, Andrea Kovacs-Simon, Stephen L. Michell, Neil F. Fairweather, Edward W. Tate
      Bacterial lipoproteins are surface exposed, anchored to the membrane by S-diacylglyceryl modification of the N-terminal cysteine thiol. They play important roles in many essential cellular processes and in bacterial pathogenesis. For example, Clostridium difficile is a Gram-positive anaerobe that causes severe gastrointestinal disease; however, its lipoproteome remains poorly characterized. Here we describe the application of metabolic tagging with alkyne-tagged lipid analogs, in combination with quantitative proteomics, to profile protein lipidation across diverse C. difficile strains and on inactivation of specific components of the lipoprotein biogenesis pathway. These studies provide the first comprehensive map of the C. difficile lipoproteome, demonstrate the existence of two active lipoprotein signal peptidases, and provide insights into lipoprotein function, implicating the lipoproteome in transmission of this pathogen.
      Graphical abstract image Teaser Bacterial lipoproteins are S-diacylglyceryl modified, surface anchored proteins, which play important roles at the host-pathogen interface. We use metabolic tagging, combined with inactivation of lipoprotein biosynthesis, to profile the Clostridium difficile lipoproteome, revealing a role for lipoproteins in transmission of this pathogen.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.10.006
       
  • XBP1s Links the Unfolded Protein Response to the Molecular Architecture of
           Mature N-Glycans
    • Authors: Mahender B. Dewal; Andrew S. DiChiara; Aristotelis Antonopoulos; Rebecca J. Taylor; Chyleigh J. Harmon; Stuart M. Haslam; Anne Dell; Matthew D. Shoulders
      Pages: 1301 - 1312
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): Mahender B. Dewal, Andrew S. DiChiara, Aristotelis Antonopoulos, Rebecca J. Taylor, Chyleigh J. Harmon, Stuart M. Haslam, Anne Dell, Matthew D. Shoulders
      The molecular architecture of the mature N-glycome is dynamic, with consequences for both normal and pathologic processes. Elucidating cellular mechanisms that modulate the N-linked glycome is, therefore, crucial. The unfolded protein response (UPR) is classically responsible for maintaining proteostasis in the secretory pathway by defining levels of chaperones and quality control proteins. Here, we employ chemical biology methods for UPR regulation to show that stress-independent activation of the UPR’s XBP1s transcription factor also induces a panel of N-glycan maturation-related enzymes. The downstream consequence is a distinctive shift toward specific hybrid and complex N-glycans on N-glycoproteins produced from XBP1s-activated cells, which we characterize by mass spectrometry. Pulse-chase studies attribute this shift specifically to altered N-glycan processing, rather than to changes in degradation or secretion rates. Our findings implicate XBP1s in a new role for N-glycoprotein biosynthesis, unveiling an important link between intracellular stress responses and the molecular architecture of extracellular N-glycoproteins.
      Graphical abstract image Teaser The molecular architecture of the N-glycome is regulated by poorly defined mechanisms. Dewal et al. now demonstrate that the unfolded protein response plays a critical role in N-glycan maturation, unveiling a functional link between intracellular proteostasis and extracellular N-glycoprotein structures.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.006
       
  • Characterization of the Biosynthetic Gene Cluster for Benzoxazole
           Antibiotics A33853 Reveals Unusual Assembly Logic
    • Authors: Meinan Lv; Junfeng Zhao; Zixin Deng; Yi Yu
      Pages: 1313 - 1324
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): Meinan Lv, Junfeng Zhao, Zixin Deng, Yi Yu
      A33853, which shows excellent bioactivity against Leishmania, is a benzoxazole-family compound formed from two moieties of 3-hydroxyanthranilic acid and one 3-hydroxypicolinic acid. In this study, we have identified the gene cluster responsible for the biosynthesis of A33853 in Streptomyces sp. NRRL12068 through genome mining and heterologous expression. Bioinformatics analysis and functional characterization of the orfs contained in the gene cluster revealed that the biosynthesis of A33853 is directed by a group of unusual enzymes. In particular, BomK, annotated as a ketosynthase, was found to catalyze the amide bond formation between 3-hydroxypicolinic and 3-hydroxyanthranilic acid during the assembly of A33853. BomJ, a putative ATP-dependent coenzyme A ligase, and BomN, a putative amidohydrolase, were further proposed to be involved in the benzoxazole formation in A33853 according to gene deletion experiments. Finally, we have successfully utilized mutasynthesis to generate two analogs of A33853, which were reported previously to possess excellent anti-leishmanial activity.
      Graphical abstract image Teaser Lv et al. unveil the pathway that directs the biosynthesis of the promising anti-leishmanial drug lead A33853, characterize a group of unusual enzymes responsible for the skeleton assembly of A33853, and generate two analogs of A33853 via mutasynthesis.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.005
       
  • Three Redundant Synthetases Secure Redox-Active Pigment Production in the
           Basidiomycete Paxillus involutus
    • Authors: Jana Braesel; Sebastian Götze; Firoz Shah; Daniel Heine; James Tauber; Christian Hertweck; Anders Tunlid; Pierre Stallforth; Dirk Hoffmeister
      Pages: 1325 - 1334
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): Jana Braesel, Sebastian Götze, Firoz Shah, Daniel Heine, James Tauber, Christian Hertweck, Anders Tunlid, Pierre Stallforth, Dirk Hoffmeister
      The symbiotic fungus Paxillus involutus serves a critical role in maintaining forest ecosystems, which are carbon sinks of global importance. P. involutus produces involutin and other 2,5-diarylcyclopentenone pigments that presumably assist in the oxidative degradation of lignocellulose via Fenton chemistry. Their precise biosynthetic pathways, however, remain obscure. Using a combination of biochemical, genetic, and transcriptomic analyses, in addition to stable-isotope labeling with synthetic precursors, we show that atromentin is the key intermediate. Atromentin is made by tridomain synthetases of high similarity: InvA1, InvA2, and InvA5. An inactive atromentin synthetase, InvA3, gained activity after a domain swap that replaced its native thioesterase domain with that of InvA5. The found degree of multiplex biosynthetic capacity is unprecedented with fungi, and highlights the great importance of the metabolite for the producer.
      Graphical abstract image Teaser Diarylcyclopentenones, produced by the symbiotic fungus Paxillus involutus, are redox-active metabolites involved in carbon cycling as they serve Fenton-based decomposition of lignocellulose in forest ecosystems. Braesel et al. show that the fungus uses three enzymes in parallel to secure the key step in diarylcyclopentenone biosynthesis.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.08.016
       
  • Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and
           Growth in Trypanosoma brucei
    • Authors: David J. Leaver; Presheet Patkar; Ujjal K. Singha; Matthew B. Miller; Brad A. Haubrich; Minu Chaudhuri; W. David Nes
      Pages: 1374 - 1383
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): David J. Leaver, Presheet Patkar, Ujjal K. Singha, Matthew B. Miller, Brad A. Haubrich, Minu Chaudhuri, W. David Nes
      Trypanosoma brucei, the causal agent for sleeping sickness, depends on ergosterol for growth. Here, we describe the effects of a mechanism-based inhibitor, 26-fluorolanosterol (26FL), which converts in vivo to a fluorinated substrate of the sterol C24-methyltransferase essential for sterol methylation and function of ergosterol, and missing from the human host. 26FL showed potent inhibition of ergosterol biosynthesis and growth of procyclic and bloodstream forms while having no effect on cholesterol biosynthesis or growth of human epithelial kidney cells. During exposure of cloned TbSMT to 26-fluorocholesta-5,7,24-trienol, the enzyme is gradually killed as a consequence of the covalent binding of the intermediate C25 cation to the active site (k cat/k inact = 0.26 min−1/0.24 min−1; partition ratio of 1.08), whereas 26FL is non-productively bound. These results demonstrate that poisoning of ergosterol biosynthesis by a 26-fluorinated Δ24-sterol is a promising strategy for developing a new treatment for trypanosomiasis.
      Graphical abstract image Teaser Leaver et al. used fluorinated steroids as suicide inhibitors of sterol C24 methyltransferase to inhibit ergosterol biosynthesis and growth of Trypanosoma brucei. This study demonstrates the potential of treating neglected tropical diseases with fluorinated analogs of a crucial enzyme in protozoan parasites absent from the human host.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.08.017
       
  • Engineered Domain Swapping as an On/Off Switch for Protein Function
    • Authors: Jeung-Hoi Ha; Joshua M. Karchin; Nancy Walker-Kopp; Carlos A. Castañeda; Stewart N. Loh
      Pages: 1384 - 1393
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): Jeung-Hoi Ha, Joshua M. Karchin, Nancy Walker-Kopp, Carlos A. Castañeda, Stewart N. Loh
      Domain swapping occurs when identical proteins exchange segments in reciprocal fashion. Natural swapping mechanisms remain poorly understood, and engineered swapping has the potential for creating self-assembling biomaterials that encode for emergent functions. We demonstrate that induced swapping can be used to regulate the function of a target protein. Swapping is triggered by inserting a “lever” protein (ubiquitin) into one of four loops of the ribose binding protein (RBP) target. The lever splits the target, forcing RBP to refold in trans to generate swapped oligomers. Identical RBP-ubiquitin fusions form homo-swapped complexes with the ubiquitin domain acting as the hinge. Surprisingly, some pairs of non-identical fusions swap more efficiently with each other than they do with themselves. Nuclear magnetic resonance experiments reveal that the hinge of these hetero-swapped complexes maps to a region of RBP distant from both ubiquitins. This design is expected to be applicable to other proteins to convert them into functional switches.
      Graphical abstract image Teaser Prevalent in nature yet poorly understood, domain swapping provides protein engineers with a heretofore unrecognized tool to manipulate protein structure, function, and self-assembly. Ha et al. introduce swapping into a target protein in a rational way, and show that by doing so the activity of that protein can be switched on and off.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.007
       
  • Mapping Proteome-Wide Targets of Environmental Chemicals Using
           Reactivity-Based Chemoproteomic Platforms
    • Authors: Daniel Medina-Cleghorn; Leslie A. Bateman; Breanna Ford; Ann Heslin; Karl J. Fisher; Esha D. Dalvie; Daniel K. Nomura
      Pages: 1394 - 1405
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): Daniel Medina-Cleghorn, Leslie A. Bateman, Breanna Ford, Ann Heslin, Karl J. Fisher, Esha D. Dalvie, Daniel K. Nomura
      We are exposed to a growing number of chemicals in our environment, most of which have not been characterized in terms of their toxicological potential or mechanisms. Here, we employ a chemoproteomic platform to map the cysteine reactivity of environmental chemicals using reactivity-based probes to mine for hyper-reactive hotspots across the proteome. We show that environmental contaminants such as monomethylarsonous acid and widely used pesticides such as chlorothalonil and chloropicrin possess common reactivity with a distinct set of proteins. Many of these proteins are involved in key metabolic processes, suggesting that these targets may be particularly sensitive to environmental electrophiles. We show that the widely used fungicide chlorothalonil specifically inhibits several metabolic enzymes involved in fatty acid metabolism and energetics, leading to dysregulated lipid metabolism in mice. Our results underscore the utility of using reactivity-based chemoproteomic platforms to uncover novel mechanistic insights into the toxicity of environmental chemicals.
      Teaser Medina-Cleghorn et al. employ a chemoproteomic platform to map the direct protein targets of several environmental chemicals, and show that these chemicals possess common reactivity with enzymes involved in lipid metabolism.

      PubDate: 2016-04-05T13:16:28Z
      DOI: 10.1016/j.chembiol.2015.09.008
       
  • In This Issue
    • Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12


      PubDate: 2016-04-05T13:16:28Z
       
  • Vitamin C as Cancer Destroyer, Investigating Sulfhydration, and the
           Variability in CFTR Interactome
    • Abstract: Publication date: 17 December 2015
      Source:Chemistry & Biology, Volume 22, Issue 12
      Each month, Chemistry & Biology Select highlights a selection of research reports from the recent literature. These highlights are a snapshot of interesting research done across the field of chemical biology. Our December 2015 selection includes an insight into how vitamin C destroys cancer cells, a new method that makes possible the investigatation of sulfhydration, and the mapping of the CFTR interactome and how it depends on the environmental conditions and differs between wild-type and disease-causing mutant.

      PubDate: 2016-04-05T13:16:28Z
       
  • In This Issue
    • Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11


      PubDate: 2016-04-05T13:16:28Z
       
  • Dissecting How Mtb Makes Its Wall, Buffering Endosomal pH, and Discovery
           of Ribocil
    • Abstract: Publication date: 19 November 2015
      Source:Chemistry & Biology, Volume 22, Issue 11
      Each month, Chemistry & Biology Select highlights a selection of research reports from the recent literature. These highlights are a snapshot of interesting research done across the field of chemical biology. Our November 2015 selection includes an insight into non-overlapping biosynthetic pathways that lead to formation of Mycobacterium tuberculosis peptidoglycan, a new method to not only measure but also buffer the endosomal pH using nanoparticles, and a demonstration that non-coding RNAs can be a target for antibiotic discovery.

      PubDate: 2016-04-05T13:16:28Z
       
  • In This Issue
    • Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10


      PubDate: 2016-04-05T13:16:28Z
       
  • Nuclear Pore Complex: From Structural View to Chemical Tools
    • Authors: Wong
      Abstract: Publication date: 22 October 2015
      Source:Chemistry & Biology, Volume 22, Issue 10
      Author(s): Richard W. Wong
      Nuclear pore complexes (NPCs) are the macromolecular turnstiles between the cytoplasm and the nucleus that control the trafficking of proteins, RNAs and viruses. The giant NPC structures are extremely complex. Here, I highlight several recent findings on NPC architectures, and briefly discuss how chemical biologists might use this information to design synthetic devices and improve strategies for nuclear drug delivery.

      PubDate: 2016-04-05T13:16:28Z
       
 
 
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