ChemBioChem

Cover image for ChemBioChem

March 2, 2009

Volume 10, Issue 4

Pages 593–771

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Concept
    7. Communications
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    1. Cover Picture: Screening for Cytochrome P450 Reactivity by Harnessing Catalase as Reporter Enzyme (ChemBioChem 4/2009) (page 593)

      Kersten S. Rabe, Mark Spengler, Michael Erkelenz, Joachim Müller, Valerie J. Gandubert, Heiko Hayen and Christof M. Niemeyer

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200990010

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      The cover picture shows a bacterial cytochrome P450 enzyme (CYP152A1, blue protein) screening for new substrates, such as nifidepine (highlighted green). The identification of novel reactivities of P450 enzymes is of major importance for applications in biocatalysis, biosensing and metabolic engineering. In their contribution on p. 751 ff, Niemeyer et al. report a novel assay for the rapid and facile screening of substrate libraries for organic hydroperoxide-mediated P450 reactivity. Peroxide depletion is monitored in a fluorescence microplate assay, by harnessing a previously undescribed reactivity of the enzyme catalase (orange protein structure). The assay thus connects the occurrence of P450 reactivity with a universal read-out, thereby circumventing the need for substrate-specific detection schemes.

  2. Graphical Abstract

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    1. Graphical Abstract: ChemBioChem 4/2009 (pages 595–602)

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200990011

  3. News

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    1. Spotlights on our sister journals: ChemBioChem 4/2009 (pages 604–605)

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200990012

  4. Minireviews

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    1. The Structural Diversity of Acidic Lipopeptide Antibiotics (pages 607–616)

      Matthias Strieker and Mohamed A. Marahiel

      Article first published online: 20 JAN 2009 | DOI: 10.1002/cbic.200800546

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      Resisting resistance: Acidic lipopeptide antibiotics are very effective in fighting multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The structural diversity of these lipopeptides, including daptomycin, which is already in clinical use, is depicted in this review. Engineering approaches to yield novel lipopeptides and tailoring events facilitating structural variety are presented.

    2. Specific Labeling of Peptidoglycan Precursors as a Tool for Bacterial Cell Wall Studies (pages 617–624)

      Vincent van Dam, Nick Olrichs and Eefjan Breukink

      Article first published online: 28 JAN 2009 | DOI: 10.1002/cbic.200800678

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      Wall chart: The predominant component of the bacterial cell wall, peptidoglycan, consists of long alternating stretches of aminosugar subunits interlinked in a large three-dimensional network and is formed from precursors through several cytosolic and membrane-bound steps. The high tolerance of the cell wall synthesis machinery allows for the use of labeled precursor derivatives to study diverse aspects of bacterial cell wall synthesis and interaction with antibiotics.

  5. Concept

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    1. Strategies for the Discovery of New Natural Products by Genome Mining (pages 625–633)

      Malek Zerikly and Gregory L. Challis

      Article first published online: 22 JAN 2009 | DOI: 10.1002/cbic.200800389

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      New drugs from silent gene clusters: Analysis of genome sequence data has identified numerous “cryptic” gene clusters encoding novel natural product biosynthetic assembly lines; this suggests that many new bioactive metabolites remain to be discovered, even in extensively investigated organisms. Several related and complementary strategies for identifying the products of these clusters have emerged recently and revitalized the search for novel bioactive natural products.

  6. Communications

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    1. Photogenerated Quinone Methides as Protein Affinity Labeling Reagents (pages 635–638)

      Jiangsong Jiang, Dexing Zeng and Shuwei Li

      Article first published online: 5 FEB 2009 | DOI: 10.1002/cbic.200800700

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      Highly specific protein labeling: Photogenerated quinine methides (QMs) can act as highly specific light-controllable protein affinity labeling reagents, broadening their applications to the study of protein–ligand and protein–protein interactions. The reactions between QMs and nucleophiles are less heterogeneous than those of other photogenerated active intermediates such as carbenes and nitrenes, making it easier to identify labeled species.

    2. Dispersed Phantom Scatterer Technique Reveals Subtle Differences in Substrate Recognition by Phospholipase D Inactive Mutants (pages 639–644)

      Carlo Morasso, Tommaso Bellini, Daniela Monti, Mattia Bassi, Davide Prosperi and Sergio Riva

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200800718

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      Stretch out: An elastic light-scattering-based method that makes use of phantom nanoparticles as a substrate organizer (see illustration) allowed the quantitative evaluation of the molecular recognition events between a series of inactivated mutants of phospholipase D and lysophosphatidylcholine. The results highlight the remarkable effects on binding capability caused by single amino acid substitutions.

    3. A Peptide Antagonist of the TLR4–MD2 Interaction (pages 645–649)

      Peter F. Slivka, Mitesh Shridhar, Gui-in Lee, Deanne W. Sammond, Mark R. Hutchinson, Alexander J. Martinko, Madison M. Buchanan, Page W. Sholar, Jeffrey J. Kearney, Jacqueline A. Harrison, Linda R. Watkins and Hang Yin

      Article first published online: 30 JAN 2009 | DOI: 10.1002/cbic.200800769

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      Toll-like receptors are an integral part of innate immunity in the central nervous system (CNS); they orchestrate a robust defense in response to both exogenous and endogenous danger signals. Recently, toll-like receptor 4 (TLR4) has emerged as a therapeutic target for the treatment of CNS-related diseases such as sepsis and chronic pain. We herein report a chemical biology approach by using a rationally designed peptide inhibitor to disrupt the TLR4–MD2 association, thereby blocking TLR4 signaling.

    4. Cooperative Effects on Radical Recombination in CYP3A4-Catalyzed Oxidation of the Radical Clock β-Thujone (pages 650–653)

      Yongying Jiang and Paul R. Ortiz de Montellano

      Article first published online: 2 FEB 2009 | DOI: 10.1002/cbic.200800772

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      Tick tock: The timing of the β-thujone radical clock (see scheme) can be specifically altered by an allosteric effector. Progesterone, a well-documented CYP3A4 allosteric effector, was found to increase the yield of the unrearranged, C4-derived product of β-thujone oxidation at the expense of the combined yields of all the rearranged C4-oxidized metabolites. The results demonstrate that the apparent radical recombination rate in the CYP3A4 hydroxylation of β-thujone is accelerated by the progesterone hetereotropic cooperativity.

    5. Differential Regulation of Protein Subdomain Activity with Caged Bivalent Ligands (pages 654–657)

      Günter Mayer, Jens Müller, Timo Mack, Daniel F. Freitag, Thomas Höver, Bernd Pötzsch and Alexander Heckel

      Article first published online: 2 FEB 2009 | DOI: 10.1002/cbic.200800814

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      Subtle change: Spatiotemporal modulation of individual protein subdomains with light as the trigger signal becomes possible by using bivalent aptamers and introducing photolabile “caging groups” to switch individual aptamer modules ON or OFF differentially. To the best of our knowledge, this is the first study to show that it is possible to modulate individual domain activity in aptamers, and thus also domain activity in proteins, with light.

    6. Efficient and Chemoselective Surface Immobilization of Proteins by Using Aniline-Catalyzed Oxime Chemistry (pages 658–662)

      Edith H. M. Lempens, Brett A. Helms, Maarten Merkx and E. W. Meijer

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200900028

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      Site-specific immobilization of peptides and proteins is crucial to ensure their functionality in surface-based assays. We report the use of aniline-catalyzed oxime ligations as a very efficient and broadly applicable method to covalently attach the N terminus of proteins and peptides to a surface functionalized with alkoxy-amine groups.

    7. Structurally Refined β-Lactones as Potent Inhibitors of Devastating Bacterial Virulence Factors (pages 663–666)

      Thomas Böttcher and Stephan A. Sieber

      Article first published online: 10 FEB 2009 | DOI: 10.1002/cbic.200800743

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      Disarmed forces: Inhibition of the central virulence regulator ClpP by structurally refined β-lactones resulted in dramatically reduced production of devastating virulence factors, including pyrogenic toxin superantigens derived from pathogenic multiresistant Staphylococcus aureus strains. Targeting of this virulence regulator could present an attractive strategy for neutralizing the harmful effects of bacterial pathogens, and help the host immune response to eliminate the disarmed bacteria.

    8. Fluorescence Detection of a Protein-Bound 2Fe2S Cluster (pages 667–670)

      Kevin G. Hoff, Rochelle Goodlitt, Rui Li, Christina D. Smolke and Jonathan J. Silberg

      Article first published online: 30 JAN 2009 | DOI: 10.1002/cbic.200800747

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      A fluorescent biosensor is described for 2Fe2S clusters that is composed of green fluorescent protein (GFP) fused to glutaredoxin 2 (Grx2), as illustrated here. 2Fe2S detection is based on the reduction of GFP fluorescence upon the 2Fe2S-induced dimerization of GFP-Grx2. This assay is sufficiently sensitive to detect submicromolar changes in 2Fe2S levels, thus making it suitable for high-throughput measurements of metallocluster degradation and synthesis reactions.

  7. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Concept
    7. Communications
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    1. Mapping the Limits of Substrate Specificity of the Adenylation Domain of TycA (pages 671–682)

      Benoit R. M. Villiers and Florian Hollfelder

      Article first published online: 2 FEB 2009 | DOI: 10.1002/cbic.200800553

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      The limits and potential of substrate promiscuity of the adenylation domain of tyrocidine synthetase 1 were systematically explored. Substrate acceptance is governed by hydrophobic effects (as shown by the correlation of kcat/KM and side-chain log P), shape complementarity and steric exclusion. The quantification of these factors provides ground rules for understanding and possibly evolving substrate specificity in this class of enzymes.

    2. Crystalline Nanorods as Possible Templates for the Synthesis of Amorphous Biosilica during Spicule Formation in Demospongiae (pages 683–689)

      Enrico Mugnaioli, Filipe Natalio, Ute Schloßmacher, Xiaohong Wang, Werner E. G. Müller and Ute Kolb

      Article first published online: 30 JAN 2009 | DOI: 10.1002/cbic.200800623

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      In tandem: High-resolution TEM shows that during the initial stages of demosponge spicule formation, a primordial crystalline structure is formed within the axial filament. The recently developed electron diffraction tomography technique (ADT) reveals that the nanorods have a layered structure that matches smectitic phyllosilicates. These intracellular nanorods have been considered as precursors of mature spicules.

    3. NO Formation by Neuronal NO-Synthase can be Controlled by Ultrafast Electron Injection from a Nanotrigger (pages 690–701)

      Edward Beaumont, Jean-Christophe Lambry, Mireille Blanchard-Desce, Pavel Martasek, Satya P. Panda, Ernst E. H. van Faassen, Jean-Claude Brochon, Eric Deprez and Anny Slama-Schwok

      Article first published online: 16 FEB 2009 | DOI: 10.1002/cbic.200800721

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      Synchronized catalysis in native enzyme: We used a photoactive nanotrigger (NT) to study the initial electron transfer to FAD in native neuronal NOS catalysis. Modeling and fluorescence spectroscopy showed that selective NT binding to NADPH sites is able to override Phe1395 regulation, thus permitting ultrafast injection of electrons into the protein electron pathway. That NT initiation of flavoenzyme catalysis led to the formation of NO is promising for time-resolved X-ray and other cellular applications.

    4. Observing Proteins as Single Molecules Encapsulated in Surface-Tethered Polymeric Nanocontainers (pages 702–709)

      Tobias Rosenkranz, Alexandros Katranidis , Diaa Atta, Ingo Gregor , Jörg Enderlein, Mariusz Grzelakowski, Per Rigler, Wolfgang Meier and Jörg Fitter

      Article first published online: 3 FEB 2009 | DOI: 10.1002/cbic.200800739

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      Protein unfolding inside immobilized polymerosomes: One of the most interesting properties of polymeric vesicles is their remarkable stability against extreme temperatures and osmotic stress, and their longevity even under harsh environmental conditions. We have demonstrated, in an application on protein folding, that surface-tethered polymerosomes are suitable for performing time-resolved single molecule studies with encapsulated proteins, as illustrated here.

    5. “Click Peptide“: pH-Triggered in Situ Production and Aggregation of Monomer Aβ1–42 (pages 710–715)

      Atsuhiko Taniguchi , Youhei Sohma , Yuta Hirayama, Hidehito Mukai, Tooru Kimura, Yoshio Hayashi , Katsumi Matsuzaki and Yoshiaki Kiso

      Article first published online: 16 FEB 2009 | DOI: 10.1002/cbic.200800765

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      Into neutral: We demonstrate the unique features of a pH click peptide based on an O-acyl isopeptide method. Under acidic conditions, the click peptide remains in a monomeric form. Upon increase of the pH to 7.4, the click peptide is quickly able to convert into Aβ1–42 through an O-to-N intramolecular acyl migration. Further study using this pH click peptide would elucidate the pathological role of Aβ1–42 in Alzheimer's disease.

    6. Crystal Structure Analysis and in Silico pKa Calculations Suggest Strong pKa Shifts of Ligands as Driving Force for High-Affinity Binding to TGT (pages 716–727)

      Tina Ritschel, Simone Hoertner, Andreas Heine, François Diederich and Gerhard Klebe

      Article first published online: 6 FEB 2009 | DOI: 10.1002/cbic.200800782

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      Expandedlin-benzoguanines exhibit binding affinities to tRNA-guanine transglycosylase (TGT) in the low-nanomolar range. A significant pKa shift is observed for the inhibitors moving from aqueous solution to protein environment. The protonation of the inhibitor facilitates a charge-assisted hydrogen bond in the protein–ligand complex.

    7. Phosphorothioation of Oligonucleotides Strongly Influences the Inhibition of Bacterial (M.HhaI) and Human (Dnmt1) DNA Methyltransferases (pages 728–734)

      Simon Warncke, Aline Gégout and Thomas Carell

      Article first published online: 16 FEB 2009 | DOI: 10.1002/cbic.200800798

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      Methyltransferase inhibitors: Short double-stranded oligonucleotides that have a hemimethylated target sequence and 5-fluoro-2′-deoxycytidine as a suicide inhibitor as well as their phosphorothioated analogues were tested for their ability to inhibit the bacterial methyltransferase M.HhaI and the human Dnmt1 in vitro.

    8. A Shielding Topology Stabilizes the Early Stage Protein–Mineral Complexes of Fetuin-A and Calcium Phosphate: A Time-Resolved Small-Angle X-ray Study (pages 735–740)

      Christophe N. Rochette, Sabine Rosenfeldt, Alexander Heiss, Theyencheri Narayanan, Matthias Ballauff and Willi Jahnen-Dechent

      Article first published online: 16 FEB 2009 | DOI: 10.1002/cbic.200800719

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      Biomineralization mechanisms: The serum protein α2-HS glycoprotein/fetuin-A is an important inhibitor that prevents pathological mineralization of calcium phosphate in soft tissues and in the extracellular fluid. TR-SAXS and stopped-flow analysis were used to monitor the growth of protein mineral particles nucleating from supersaturated salt solutions in the presence of the protein. It was found that fetuin-A did not influence the formation of mineral nuclei, but did prevent the aggregation of nuclei and thus mineral precipitation.

    9. Discovery of Additional Members of the Tyrosine Aminomutase Enzyme Family and the Mutational Analysis of CmdF (pages 741–750)

      Daniel Krug and Rolf Müller

      Article first published online: 16 FEB 2009 | DOI: 10.1002/cbic.200800748

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      Stereochemical antipoles: The myxobacteria Chondromyces crocatus and Myxococcus fulvus utilize tyrosine aminomutase (TAM) enzymes with opposite stereoselectivity to produce β-Tyr building blocks, which are subsequently incorporated into potent secondary metabolites. The evolution of stereochemical preference within this expanding enzyme family is unexplored. Intriguingly, the mutation of one amino acid in the aminomutase CmdF from C. crocatus influences the enantiomeric excess of (R)-β-Tyr formation (see chromatograms).

    10. Screening for Cytochrome P450 Reactivity by Harnessing Catalase as Reporter Enzyme (pages 751–757)

      Kersten S. Rabe, Mark Spengler, Michael Erkelenz, Joachim Müller, Valerie J. Gandubert, Heiko Hayen and Christof M. Niemeyer

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200800750

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      The big screen: We have devised a high-throughput screening method for organic peroxide-dependent P450 reactivity by taking advantage of a previously undescribed activity of catalase, which was used as reporter enzyme. This two-step assay, followed by liquid chromatography/mass spectrometry analyses, allowed the facile identification of several new substrates for bacterial P450 enzymes.

    11. DNA and RNA-Controlled Switching of Protein Kinase Activity (pages 758–765)

      Lars Röglin, Frank Altenbrunn and Oliver Seitz

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200800771

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      Constrained: The readily programmable nucleic acid mediated recognition is used to constrain a phosphopeptide that was flanked by PNA segments. RNA-based switching allows control over the activity of target enzymes such as the protein kinase Src. It might thus be feasible to transduce changes of the concentration of selected RNA molecules to changes of the activity of signal transduction proteins.

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      Preview: ChemBioChem 5/2009 (page 771)

      Article first published online: 24 FEB 2009 | DOI: 10.1002/cbic.200990013

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