ChemBioChem

Cover image for Vol. 9 Issue 16

November 3, 2008

Volume 9, Issue 16

Pages 2549–2754

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
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    1. Cover Picture: Identification of Pharmacological Chaperones for Gaucher Disease and Characterization of Their Effects on β-Glucocerebrosidase by Hydrogen/Deuterium Exchange Mass Spectrometry (ChemBioChem 16/2008) (page 2549)

      Michael B. Tropak, Gregory J. Kornhaber, Brigitte A. Rigat, Gustavo H. Maegawa, Justin D. Buttner, Jan E. Blanchard, Cecilia Murphy, Steven J. Tuske, Stephen J. Coales, Yoshitomo Hamuro, Eric D. Brown and Don J. Mahuran

      Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200890061

      Thumbnail image of graphical abstract

      The cover picture shows the regions (shades of blue) on human lysosomal glucocerebrosidase (green) that undergo a significant reduction in hydrogen–deuterium exchange (denoted by loss of blurriness) upon binding a 2,4-diamino-5-substituted quinazoline (MWP; red). MWP was identified in a high-throughput screen of the Maybridge library of 50 000 small molecule drug-like compounds (grey structures) for inhibitors. The confocal images immediately below the 3D structures of the enzyme are patient fibrobroblasts homozygous for the common N370S Gaucher disease type I allele, stained with an antibody against glucocerebrosidase (green); these show increased levels of the enzyme in MWP treated (+MWP) cells in comparison with untreated control (−MWP) cells. This study has identified pharmacological chaperones (PC) that are not based on the structure of the glycolipid substrate of the enzyme. These new compounds increase the repertoire of chemical frameworks available for the construction of efficient PCs for the treatment of Gaucher disease. For more details, see the article by M. B. Tropak, D. J. Mahuran et al. on p. 2650 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
    11. Preview
  3. Corrigendum

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
    11. Preview
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      Prediction of the Candida antarctica Lipase A Protein Structure by Comparative Modeling and Site-Directed Mutagenesis (page 2559)

      Alex Kasrayan, Marco Bocola, Anders G. Sandström, Gaston Lavén and Jan-E. Bäckvall

      Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200890063

      This article corrects:
  4. News

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
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  5. Minireview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
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    8. Communications
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    10. Book Review
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    1. Synchronization of the Fungal and the Plant Circadian Clock by Light (pages 2565–2573)

      László Kozma-Bognár and Krisztina Káldi

      Version of Record online: 10 OCT 2008 | DOI: 10.1002/cbic.200800385

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      Right on time: Circadian clocks are endogenous time keeping devices that provide temporal control of physiology in accordance with predicted daily changes in the environment. In this review, knowledge about light absorption/transduction and light-induced modifications of oscillator components in Neurospora crassa and Arabidopsis thaliana is summarized. These systems provide a basis for understanding the molecular mechanisms of entrainment in fungal and plant circadian systems.

  6. Highlight

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
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    1. A Bacterial Small Molecule Undermining Immune Response Signaling (pages 2575–2577)

      M. Lienhard Schmitz and Laureano de la Vega

      Version of Record online: 30 SEP 2008 | DOI: 10.1002/cbic.200800562

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      Bacterial small molecules.Pseudomonas aeruginosa is known to produce N-(3-oxo-dodecanoyl) homoserine lactone (C12), a small molecule involved in several bacterial functions such as sensing bacterial crowding in biofilms. In a recent Science paper by Kravchenko and co-workers, it was found that this small molecule also inhibits NF-κB-dependent gene expression, which allows the bacterium to attenuate the host innate immune system and establish a local persistent infection.

  7. Communications

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
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    8. Communications
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    10. Book Review
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    1. Engineering Cytochrome P450 Enzymes for Improved Activity towards Biomimetic 1,4-NADH Cofactors (pages 2579–2582)

      Jessica D. Ryan, Richard H. Fish and Douglas S. Clark

      Version of Record online: 24 SEP 2008 | DOI: 10.1002/cbic.200800246

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      Compromising expensive taste:N-Benzyl-1,4-dihydronicotinamide is a NADH biomimic that is a cost-efficient alternative to NAD(P)H, but wild-type P450 BM-3 oxidation reactions are not supported by this NADH analogue. However, the activity of W1064S/R966D P450 BM-3 (see picture) with the biomimic is comparable to that with NADPH. The activity of P450cam with the analogue was also improved by site-directed mutagenesis.

    2. Ligand Binding to Tandem G Quadruplexes from Human Telomeric DNA (pages 2583–2587)

      Li-Ping Bai, Masaki Hagihara, Zhi-Hong Jiang and Kazuhiko Nakatani

      Version of Record online: 15 OCT 2008 | DOI: 10.1002/cbic.200800256

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      The beads-on-a-string structure of telomeric overhang, as illustrated here, was confirmed by studying the binding behaviours of the G-quadruplex binders sanguinarine and TMPyP4 to long human telomeric sequences by using a DNA polymerase stop assay. Additionally, a novel mode of ligand binding to long telomeric sequences was further suggested, in which ligands favourably bind between tandem G quadruplexes leading to a cooperative stacking interaction.

    3. A Novel Conformationally Constrained Parallel G Quadruplex (pages 2588–2591)

      Pierre Murat, Delphine Cressend, Nicolas Spinelli, Angéline Van der Heyden, Pierre Labbé, Pascal Dumy and Eric Defrancq

      Version of Record online: 26 SEP 2008 | DOI: 10.1002/cbic.200800457

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      Conducting a G quartet. We have devised a peptidic scaffold as a topological template that directs the intramolecular assembly of covalently attached oligonucleotides into stable G quadruplexes that are exclusively constrained in a parallel-stranded conformation. Using this scaffold together with SPR we have analyzed the molecular interactions of ligands for a single conformation of G quadruplex.

    4. SPOT Synthesis of Peptide Arrays on Self-Assembled Monolayers and their Evaluation as Enzyme Substrates (pages 2592–2596)

      Nicolas Laurent, Rose Haddoub, Josef Voglmeir, Stephen C. C. Wong, Simon J. Gaskell and Sabine L. Flitsch

      Version of Record online: 26 SEP 2008 | DOI: 10.1002/cbic.200800481

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      Sweet SPOT: An efficient SPOT peptide synthesis methodology on self-assembled monolayer-coated gold surfaces was developed. Arrays of peptides and glycopeptides were subsequently used to evaluate substrate specificity of proteases and glycosyltransferases. The efficiency of all reactions could be easily monitored directly on-chip by using MALDI-ToF MS.

    5. The Entropy Balance of Nostocyclopeptide Macrocyclization Analysed by NMR Spectroscopy (pages 2597–2601)

      Sebastian Enck, Florian Kopp, Mohamed A. Marahiel and Armin Geyer

      Version of Record online: 26 SEP 2008 | DOI: 10.1002/cbic.200800314

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      Overcoming the problem of irreversibility: In spite of their relevance in biology and synthetic chemistry, biomolecular macrocyclizations still lack quantitative experimental description. The establishment of an imino peptide ring-chain equilibrium allows the determination of the entropy balance involved in macrocyclization. By comparing the backbone dynamics and cyclization behaviour of the modified nostocyclopeptides we can characterise the role of preorientation in the cyclization process.

    6. Amyloid Fibrillar Meshwork Formation of Iron-Induced Oligomeric Species of Aβ40 with Phthalocyanine Tetrasulfonate and Its Toxic Consequences (pages 2602–2605)

      Jae-Woo Park, Jung Sun Ahn, Jung-Ho Lee, Ghibom Bhak, Seunho Jung and Seung R. Paik

      Version of Record online: 18 SEP 2008 | DOI: 10.1002/cbic.200800343

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      Brain detoxification: Phthalocyanine tetrasulfonate (PcTS) transforms iron-induced oligomeric species of Aβ40 into amyloid fibrillar meshworks; this coincidentally eliminates redox-active metal ions and oligomeric species, both of which are toxic candidates.

    7. Inhibition of Mycobacterium tuberculosis Pantothenate Synthetase by Analogues of the Reaction Intermediate (pages 2606–2611)

      Alessio Ciulli, Duncan E. Scott, Michiyo Ando, Fernando Reyes, S. Adrian Saldanha, Kellie L. Tuck, Dimitri Y. Chirgadze, Tom L. Blundell and Chris Abell

      Version of Record online: 26 SEP 2008 | DOI: 10.1002/cbic.200800437

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      Get stuck in: Pantothenate synthetase is an attractive target for the development of novel small-molecule drugs against Mycobacterium tuberculosis. Three related sulfamoyl adenylate inhibitors were designed to closely mimic the structure of the reaction intermediate, pantoyl adenylate. The most potent inhibitor exhibited dissociation and inhibition constants of about 100 nM. The structural elucidation of the compounds bound to the enzyme will aid development of subsequent inhibitors.

    8. Molecular Basis for β-Glucosidase Inhibition by Ring-Modified Calystegine Analogues (pages 2612–2618)

      Matilde Aguilar, Tracey M. Gloster, M. Isabel García-Moreno, Carmen Ortiz Mellet, Gideon J. Davies, Amadeu Llebaria, Josefina Casas, Meritxell Egido-Gabás and José M. García Fernandez

      Version of Record online: 2 OCT 2008 | DOI: 10.1002/cbic.200800451

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      Neutral calystegine B2analogues, such as the 1-deoxy-6-oxa-N-(N′-octyl)thiocarbamoyl derivative, proved to be more potent β-glucosidase inhibitors than the natural alkaloid. Structural studies of the complex with a clan GH-A β-glucosidase from Thermotoga maritima showed a binding mode markedly different from that of the parent compound.

    9. Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs (pages 2619–2622)

      Hannes Kopitz, Aleksandra Živković, Joachim W. Engels and Holger Gohlke

      Version of Record online: 30 SEP 2008 | DOI: 10.1002/cbic.200800461

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      A congeneric series of self-paired fluorine-substituted benzene nucleobases in a designed RNA environment shows a steady increase in stability with respect to the degree of fluorination. Computational free energy component analyses reveal surprisingly different microscopic origins for the observed stability increments and demonstrate an intricate influence of the environment on the molecular-recognition properties of organic fluorine.

    10. Oligosaccharide-Mediated Nuclear Transport of Nanoparticles (pages 2623–2627)

      Kenichi Niikura, Shota Sekiguchi, Takashi Nishio, Tomoya Masuda, Hidetaka Akita, Yasutaka Matsuo, Kentaro Kogure, Hideyoshi Harashima and Kuniharu Ijiro

      Version of Record online: 26 SEP 2008 | DOI: 10.1002/cbic.200800464

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      Door openers. We investigated the efficiency of oligo-α-glucopyranosides to mediate the nuclear import of nanoparticles into digitonin-permeabilized HeLa cells. It was found that maltotriose-displaying quantum dots (QDs) were specifically transported into the nucleus, whereas monosaccharide-displaying QDs did not.

    11. Microfluidic Lithography to Create Dynamic Gradient SAM Surfaces for Spatio-temporal Control of Directed Cell Migration (pages 2628–2632)

      Brian M. Lamb, Nathan P. Westcott and Muhammad N. Yousaf

      Version of Record online: 26 SEP 2008 | DOI: 10.1002/cbic.200800473

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      We have developed a new strategy—microfluidic lithography (μFL)—to generate patterns and gradients of electroactive SAMs that can subsequently react chemoselectively to immobilize ligands. These electroactive SAMs can be dynamically controlled in the presence of cells to promote directional cell migration. We show that fibroblasts migrate towards the higher density regions of a biospecific cell adhesive peptide gradient. The gradients can be quantitatively characterized with both electrochemistry and scanning electron microscopy, and are straightforward to generate and highly reproducible.

  8. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
    11. Preview
    1. A Mitochondriotropic Derivative of Quercetin: A Strategy to Increase the Effectiveness of Polyphenols (pages 2633–2642)

      Andrea Mattarei, Lucia Biasutto, Ester Marotta, Umberto De Marchi, Nicola Sassi, Spiridione Garbisa, Mario Zoratti and Cristina Paradisi

      Version of Record online: 6 OCT 2008 | DOI: 10.1002/cbic.200800162

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      Storming the powerhouse: A permanent cation has been linked to the natural polyphenol quercetin. The new derivative accumulates inside cells and concentrates in mitochondria (as shown in the figure), where the anti- or pro-oxidant properties of the polyphenol are most needed to intervene in processes of physiological and pathological interest.

    2. Isofagomine Induced Stabilization of Glucocerebrosidase (pages 2643–2649)

      Gregory J. Kornhaber, Michael B. Tropak, Gustavo H. Maegawa, Steven J. Tuske, Stephen J. Coales, Don J. Mahuran and Yoshitomo Hamuro

      Version of Record online: 17 OCT 2008 | DOI: 10.1002/cbic.200800249

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      Propagated stability: Analysis of protein dynamics and global probes of stability demonstrate global and local stabilization of β-glucocerebrosidase following complex formation with isofagomine (IFG). IFG-binding strongly rigidified active site regions (blue), which led to a moderate stabilization of adjoining regions (cyan).

    3. Identification of Pharmacological Chaperones for Gaucher Disease and Characterization of Their Effects on β-Glucocerebrosidase by Hydrogen/Deuterium Exchange Mass Spectrometry (pages 2650–2662)

      Michael B. Tropak, Gregory J. Kornhaber, Brigitte A. Rigat, Gustavo H. Maegawa, Justin D. Buttner, Jan E. Blanchard, Cecilia Murphy, Steven J. Tuske, Stephen J. Coales, Yoshitomo Hamuro, Eric D. Brown and Don J. Mahuran

      Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200800304

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      High-throughput screening has identified two novel inhibitors (1 and 2) of GCase (green) that act as pharmacological chaperones to increase activity and colocalization (yellow) of the enzyme with a lysosomal marker (red) relative to untreated Gaucher disease type I patient fibroblasts. H/D exchange MS of GCase in the presence of the ligands showed that subsets of loops (coloured) are rigidified upon binding relative to apo GCase (blurred).

    4. 3- Instead of 4-Helix Formation in a De Novo Designed Protein in Solution Revealed by Small-Angle X-ray Scattering (pages 2663–2672)

      Rasmus Høiberg-Nielsen, A. Pernille Tofteng Shelton, Kasper K. Sørensen, Manfred Roessle, Dimitri I. Svergun, Peter W. Thulstrup, Knud J. Jensen and Lise Arleth

      Version of Record online: 10 OCT 2008 | DOI: 10.1002/cbic.200800263

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      Three not four. In contrast to previous reports, a comprehensive SAXS study of de novo designed carboproteins has revealed that they take on an unexpected 3+1-helix folding topology in solution. The envelopes of the carboproteins are composed of a compact globular section and a thinner tail-like part and they have an inner cavity. These structural data will help in understanding how template assembly affects folding and in de novo protein engineering.

    5. Reconstitution and Anchoring of Cytoskeleton inside Giant Unilamellar Vesicles (pages 2673–2681)

      Dennis Merkle, Nicoletta Kahya and Petra Schwille

      Version of Record online: 1 OCT 2008 | DOI: 10.1002/cbic.200800340

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      An artificial anchor? A critical step in achieving artificial cell replication would be to construct and encapsulate machinery that constrict and divide a cell-like compartment. By extracting integral membrane proteins and lipids from porcine brain, we grew giant unilamellar vesicles (GUVs) that encapsulate polymerised actin and spectrin/ankyrin. In the presence of spectrin/ankyrin, the actin filaments formed tight bundles that often localized and immobilized to the interior walls of the GUVs.

    6. Imaging Target mRNA and siRNA-Mediated Gene Silencing In Vivo with Ribozyme-Based Reporters (pages 2682–2691)

      Min-Kyung So , Gayatri Gowrishankar , Sumitaka Hasegawa, June-Key Chung and Jianghong Rao

      Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200800370

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      mRNA is the target. Genetically encoded RNA reporters were designed to image target mRNA in vivo by combining trans-splicing ribozymes and gene reporters. Mutant p53 mRNA expression was visualized with this reporter system in single living cells and in living animals. It was further applied to image the silencing effect of siRNA on target gene expression in vivo through monitoring the mRNA expression level of the target.

    7. New Peptolides from the Cyanobacterium Nostoc insulare as Selective and Potent Inhibitors of Human Leukocyte Elastase (pages 2692–2703)

      Christian Mehner, Daniela Müller, Stefan Kehraus, Stephanie Hautmann, Michael Gütschow and Gabriele M. König

      Version of Record online: 16 OCT 2008 | DOI: 10.1002/cbic.200800415

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      Combinatorial chemistry in cyanobacteria.Nostoc insulare has the biosynthetic capability to produce an impressive library of nonribosomal peptides. Molecular biological investigations and bioactivity studies led to the isolation of potent and selective inhibitors of the enzyme human leukocyte elastase (HLE).

    8. CAY10499, a Novel Monoglyceride Lipase Inhibitor Evidenced by an Expeditious MGL Assay (pages 2704–2710)

      Giulio G. Muccioli, Geoffray Labar and Didier M. Lambert

      Version of Record online: 15 OCT 2008 | DOI: 10.1002/cbic.200800428

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      Novel and irreversible. We have developed a 96-well-format assay that uses a non-radiolabeled substrate, 4-nitrophenylacetate, to assess monoglyceride lipase (MGL) activity. IC50 values of known MGL inhibitors obtained by using this new substrate were found to be similar to those measured previously using a radiolabeled substrate. Additionally, in a screen for new MGL inhibitors, we identified CAY10499, a novel nanomolar MGL inhibitor that acts through an unprecedented mechanism of action.

    9. A Type I/Type III Polyketide Synthase Hybrid Biosynthetic Pathway for the Structurally Unique ansa Compound Kendomycin (pages 2711–2721)

      Silke C. Wenzel, Helge B. Bode, Irene Kochems and Rolf Müller

      Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200800456

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      Mixed PKS: The biosynthetic gene cluster for the polyketide kendomycin was identified in Streptomyces violaceoruber. A combination of type I and type III polyketide synthases is shown to be involved in the formation of the carbocyclic ansa antibiotic.

    10. Inhibition of Dicing of Guanosine-Rich shRNAs by Quadruplex-Binding Compounds (pages 2722–2729)

      Anja Henn, Astrid Joachimi, Diana P. N. Gonçalves, David Monchaud, Marie-Paule Teulade-Fichou, Jeremy K. M. Sanders and Jörg S. Hartig

      Version of Record online: 16 OCT 2008 | DOI: 10.1002/cbic.200800271

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      No dice! Short hairpin RNAs can trigger RNA interference, which results in potent but specific inhibition of gene expression. With the goal of gaining enhanced control over the knockdown effect, we augmented shRNAs with G-rich sequences to address the dicer-mediated processing by using quadruplex-selective compounds.

    11. Plasmodium Telomeric Sequences: Structure, Stability and Quadruplex Targeting by Small Compounds (pages 2730–2739)

      Anne De Cian, Philippe Grellier, Elisabeth Mouray, Delphine Depoix, Hélène Bertrand, David Monchaud, Marie-Paule Teulade-Fichou, Jean-Louis Mergny and Patrizia Alberti

      Version of Record online: 16 OCT 2008 | DOI: 10.1002/cbic.200800330

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      Attractive targets: The telomeres of the human parasite P. falciparum are composed of a degenerate motif (GGGTTYA, Y=T or C) different from the human one (GGGTTA). We demonstrate the presence of a G-overhang at P. falciparum telomeres and show that Plasmodium degenerate telomeric sequences fold into stable G-quadruplexes. A variety of ligands known to bind to the human telomeric G-quadruplex also stabilize Plasmodium telomeric G-quadruplexes.

    12. A Polylinker Approach to Reductive Loop Swaps in Modular Polyketide Synthases (pages 2740–2749)

      Laurenz Kellenberger, Ian S. Galloway, Guido Sauter, Günter Böhm, Ulf Hanefeld, Jesús Cortés, James Staunton and Peter F. Leadlay

      Version of Record online: 20 OCT 2008 | DOI: 10.1002/cbic.200800332

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      Synthetic biology of polyketides: The level of oxidation and the configuration of the products of a modular polyketide synthase are dictated by the complement of “optional” enzymatic activities (ketoreductase, dehydratase, enoylreductase) in a given extension module. Using alternative restriction sites for the swapping of such domains together as intact units (reductive loops) significantly increases the chances of success in engineering an altered product, and also reveals new aspects of stereochemical control on these multienzymes.

  9. Book Review

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
    11. Preview
  10. Preview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Book Review
    11. Preview
    1. Preview: ChemBioChem 17/2008 (page 2754)

      Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200890065

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