Cover image for ChemBioChem

October 7, 2005

Volume 6, Issue 10

Pages 1709–1910

    1. Cover Picture: A Mass Spectrometric and Molecular Modelling Study of Cisplatin Binding to Transferrin (ChemBioChem 10/2005) (page 1709)

      Isam Khalaila, Claire S. Allardyce, Chandra S. Verma and Paul J. Dyson

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200590032

      The cover picture shows a representation of blood flow through an artery that carries cisplatin-bound transferrin. The cisplatin-bound transferrin is encased by a platinum ring, which reflects the platinum question: "Could the unprecedented clinical success of cisplatin be due, in part, to transferrin-mediated delivery to cancer cells?" In the article by P. J. Dyson and co-workers on p. 1788 ff, mass spectrometric based evidence is provided to suggest that cisplatin binds to the iron-binding site of transferrin, and the implications of this evidence are discussed.

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      Pseudo 3D Single-Walled Carbon Nanotube Film for BSA-Free Protein Chips (page 1718)

      Hye Ryung Byon, Bong Jin Hong, Yong Song Gho, Joon Won Park and Hee Cheul Choi

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200590034

    3. Geometrical trans Lipid Isomers: A New Target for Lipidomics (pages 1722–1734)

      Carla Ferreri and Chryssostomos Chatgilialoglu

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200500109

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      The significance of geometry. The cis and trans lipid geometries have attracted attention in different fields, and a multidisciplinary research project was developed to study trans lipids. Geometrical trans lipid isomers can result from a free-radical-induced transformation. They represent a new target for lipidomics and are ideal substrates for a chemical biology approach that addresses the biochemical significance of the cis and trans geometries, as either a signal or an alteration in the biological environment.

    4. The RAD6 Pathway: Control of DNA Damage Bypass and Mutagenesis by Ubiquitin and SUMO (pages 1735–1743)

      Helle D. Ulrich

      Version of Record online: 5 SEP 2005 | DOI: 10.1002/cbic.200500139

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      Tolerance mechanisms against DNA damage allow cells to complete DNA replication in the presence of lesions that would otherwise inhibit the progression of the replication fork. As these bypass systems often operate with reduced fidelity, a tight control over their activity is required to prevent the accumulation of unwanted mutations. In eukaryotes, control of damage tolerance is exerted by the modification of PCNA, an essential regulator of the replication fork, by the small proteins ubiquitin and SUMO.

    5. Benzofuroindole Analogues as Potent BKCa Channel Openers (pages 1745–1748)

      Ahmet E. Gormemis, Tal Soo Ha, Isak Im, Kwan-Young Jung, Ju Yeon Lee, Chul-Seung Park and Yong-Chul Kim

      Version of Record online: 8 SEP 2005 | DOI: 10.1002/cbic.200400448

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      Toward drugs to treat neuronal damage. The design and synthesis of new, potent, large-conductance, calcium-activated potassium-channel (BKCa) openers that show calcium-independent activation in electrophysiological evaluations have been brought about through optimizing the structure of the benzofuroindole skeleton by comparison with a known BKCa-channel opener (BMS-204352; see scheme). These new channel openers might find therapeutic use in stroke, asthma, hypertension, convulsion, and traumatic brain injury.

    6. Discovery of Mycobacterium Tuberculosis Protein Tyrosine Phosphatase A (MptpA) Inhibitors Based on Natural Products and a Fragment-Based Approach (pages 1749–1753)

      Michael Manger, Michael Scheck, Heino Prinz, Jens Peter von Kries, Thomas Langer, Krishna Saxena, Harald Schwalbe, Alois Fürstner, Jörg Rademann and Herbert Waldmann

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200500171

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      Naturally inspired or fragment based. Mcyobacterium tuberculosis has two functional phosphatases, protein tyrosine phosphates A and B (MptpA and B), which are thought to mediate mycobacterial survival in the host. Here we describe the first inhibitors of MptpA (see scheme). Initial hits were identified in screening collections that were inspired by natural products and composed by fragment-based approach.

    7. The Role of an Aliphatic–Aromatic Interaction in the Stabilization of a Model β-Hairpin Peptide (pages 1753–1756)

      M. Teresa Pastor, Ana Giménez-Giner and Enrique Pérez-Payá

      Version of Record online: 8 SEP 2005 | DOI: 10.1002/cbic.200500178

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      Was the β-hairpin fished out from a conformationally defined peptide library of close to 140 000 structures really stabilized? Or was the unexpected Ile residue at the hydrogen-bonded position a mistake in the selection procedure? It seems that the answer is yes, it was. The β-branched side chains of Ile and Val (at position 9) are preferred to stabilize the hydrophobic minicore defined by Trp4, Tyr6, and Tyr11in MBH12, a model β-hairpin peptide (see figure).

    8. A Novel Method to Synthesize Versatile Multiple-Branched DNA (MB-DNA) by Reversible Photochemical Ligation (pages 1756–1760)

      Shinzi Ogasawara and Kenzo Fujimoto

      Version of Record online: 12 SEP 2005 | DOI: 10.1002/cbic.200500188

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      Branching out into the nano world. We have demonstrated that DNA containing 5-carboxyvinyldeoxyuridine (CVU) at midstream can be used to synthesize multiple-branched DNA with high efficiency by irradiation at 366 nm (see scheme). This novel method is well suited to DNA nanodevices such as the DNA walker, DNA computer, and DNA architecture, as well as to signal amplification.

    9. Shotgun Cloning and Heterologous Expression of the Patellamide Gene Cluster as a Strategy to Achieving Sustained Metabolite Production (pages 1760–1765)

      Paul F. Long, Walter C. Dunlap, Christopher N. Battershill and Marcel Jaspars

      Version of Record online: 29 JUN 2005 | DOI: 10.1002/cbic.200500210

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      Shotgun cloning into E. coli of genomic DNA from Prochloron sp., symbiont of the seasquirt Lissoclinum patella, resulted in the heterologous expression of the patellamide gene cluster and subsequent production of patellamide D (1) and ascidiacyclamide (2) at levels of 80–100 ng mL−1.

    10. Direct Conversion of Ethane to Ethanol by Engineered Cytochrome P450 BM3 (pages 1765–1768)

      Peter Meinhold, Matthew W. Peters, Michael M. Y. Chen, Katsuyuki Takahashi and Frances H. Arnold

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200500261

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      Picking on someone smaller. Cytochromes P450 catalyze the hydroxylation of thousands of substrates, including alkanes. No naturally occurring P450, however, is known to oxidize the smallest alkanes, ethane and methane. Here we report the direct and selective oxidation of ethane to ethanol using dioxygen, catalyzed by a cytochrome P450 BM-3 variant engineered for high activity towards small alkanes (see scheme). Achieving P450-catalyzed oxidation of ethane is a key step in the pathway to P450-catalyzed methane oxidation and opens new opportunities for the bioconversion of natural gas to fuels and chemicals.

    11. Competitive MS Binding Assays for Dopamine D2 Receptors Employing Spiperone as a Native Marker (pages 1769–1775)

      Karin V. Niessen, Georg Höfner and Klaus T. Wanner

      Version of Record online: 7 SEP 2005 | DOI: 10.1002/cbic.200500074

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      Displacing the radioligand Competitive radioligand-binding experiments represent an essential tool in primary drug screening . Radioligands may be substituted in this kind of assay by a “native” unlabelled marker when mass spectrometry is used for monitoring the marker. In the present study, the application of this concept is demonstrated for dopamine D2 receptor binding experiments by employing unlabelled spiperone as a marker.

    12. Novel Fluorescent Phosphonic Acid Esters for Discrimination of Lipases and Esterases (pages 1776–1781)

      Hannes Schmidinger, Ruth Birner-Gruenberger, Gernot Riesenhuber, Robert Saf, Heidrun Susani-Etzerodt and Albin Hermetter

      Version of Record online: 11 AUG 2005 | DOI: 10.1002/cbic.200500013

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      Rapid identification and characterization of lipolytic enzymes in pure and crude enzyme preparations is achieved by the application of a novel set of mechanism-based, fluorescently labelled inhibitors. Based on the specific reactivities of serine hydrolases towards certain inhibitors, the enzymes can be clustered into subgroups, namely lipases, esterases and phospholipases. The gel shows the active hydrolases that are individually labelled in commercial bovine cholesterol esterase.

    13. Nanostructured Ordering of Fluorescent Markers and Single Proteins on Substrates (pages 1782–1787)

      Juergen Groll, Krystyna Albrecht, Peter Gasteier, Silke Riethmueller, Ulrich Ziener and Martin Moeller

      Version of Record online: 20 SEP 2005 | DOI: 10.1002/cbic.200500041

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      A pattern of dots between the stars: Specific binding of avidin to biotin-modified gold nanodots in a hexagonal pattern on glass is reported (see schematic representation and SFM image). The surface in between the gold dots is functionalized by a layer of star-shaped poly(ethylene oxide-stat-propylene oxide) prepolymers (Star PEG) to prevent unspecific protein adsorption. Due to steric reasons, only one protein is attached to each gold dot.

    14. A Mass Spectrometric and Molecular Modelling Study of Cisplatin Binding to Transferrin (pages 1788–1795)

      Isam Khalaila, Claire S. Allardyce, Chandra S. Verma and Paul J. Dyson

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200500067

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      Transferring platinum. The binding of cisplatin to transferrin has been investigated by mass spectrometry (MS; see spectra) and MS/MS, which provide evidence that cisplatin binds to the Fe3+-binding site. The implication of this observation with respect to cisplatin delivery and the targeting of cancer cells is discussed.

    15. Synthesis of Glycopeptides from Type II Collagen-Incorporating Galactosylated Hydroxylysine Mimetics and Their Use in Studying the Fine Specificity of Arthritogenic T Cells (pages 1796–1804)

      Julien Marin, Marie-Agnès Blaton, Jean-Paul Briand, Gilles Chiocchia, Catherine Fournier and Gilles Guichard

      Version of Record online: 23 AUG 2005 | DOI: 10.1002/cbic.200500075

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      Analogues of the immunodominant glycopeptide 1, derived from CII collagen, modified at the hydroxylysine side chain were synthesised and tested for recognition by CII-reactive T cells in collagen-induced arthritis. The T-cell receptor is extremely sensitive to transformations of the ε-amino group, but shows a certain plasticity by accommodating some changes at C-5.

    16. A New Strategy for the Synthesis of Dinucleotides Loaded with Glycosylated Amino Acids—Investigations on in vitro Non-natural Amino Acid Mutagenesis for Glycoprotein Synthesis (pages 1805–1816)

      Christoph H. Röhrig, Oliver A. Retz, Lars Hareng, Thomas Hartung and Richard R. Schmidt

      Version of Record online: 5 SEP 2005 | DOI: 10.1002/cbic.200500079

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      Site-specific introduction of artificial amino acids into proteins. A versatile and efficient approach to the synthesis of aminoacyl-loaded dinucleotides has been developed and applied to the synthesis of glycosylamino acid-loaded su tRNAs. The glycosylated amino acids were incorporated in vitro into the human granulocyte colony-stimulating factor (hG-CSF) by non-natural amino acid mutagenesis.

    17. Adsorption of Amyloid β (1–40) Peptide at Phospholipid Monolayers (pages 1817–1824)

      Elena Maltseva, Andreas Kerth, Alfred Blume, Helmuth Möhwald and Gerald Brezesinski

      Version of Record online: 20 SEP 2005 | DOI: 10.1002/cbic.200500116

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      Secondary structure of adsorbed Aβ: This peptide adsorbs at air/water (buffer) interfaces and inserts into uncompressed phospholipid monolayers as a β-sheet oriented almost parallel to the surface (a). Upon compression, the peptide desorbs completely from zwitterionic and negatively charged monolayers on buffer, but remains adsorbed in the β-sheet conformation at negatively charged monolayers on water (b).

    18. Site-Selective DNA Hydrolysis by CeIV–EDTA with the Use of One Oligonucleotide Additive Bearing Two Monophosphates (pages 1825–1830)

      Wen Chen and Makoto Komiyama

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200500119

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      The cutting edge. By using an oligonucleotide additive that bears two monophosphates, site-selective DNA hydrolysis was achieved at the formed bulge with CeIV–EDTA at pH 7.0 (see picture). Site-selective DNA hydrolysis with this one-additive system is successful even at relatively high reaction temperatures, such as 55 °C.

    19. A Simple Approach to Well-Defined Sugar-Coated Surfaces for Interaction Studies (pages 1831–1838)

      Miquel Vila-Perelló, Ricardo Gutiérrez Gallego and David Andreu

      Version of Record online: 5 SEP 2005 | DOI: 10.1002/cbic.200500125

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      Carbohydrate chips. A novel method of carbohydrate immobilization to solid supports by means of a sugar-capturing peptide module is described (see scheme). The chemical definition of the sugar–peptide tag was thoroughly established by mass spectrometric sequencing. The usefulness of the method was demonstrated by surface plasmon resonance monitoring of the interaction of chip-bound chitin analogues with large, well-known lectins, such as wheat germ agglutinin and small sugar-binding domains, like the minihevein, HEV32.

    20. Design, Synthesis and Biological Evaluation of Sugar-Derived Ras Inhibitors (pages 1839–1848)

      Francesco Peri, Cristina Airoldi, Sonia Colombo, Enzo Martegani, Anske Stephanie van Neuren, Matthias Stein, Chiara Marinzi and Francesco Nicotra

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200400420

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      No exchange, no growth. The design and synthesis of new D-arabinose-derived ligands for the Ras protein are described. Molecular-modelling calculations suggest that binding with Ras occurs near the Switch II region of the protein (see figure). All the compounds are active in inhibiting nucleotide exchange on p21 human Ras in vitro, and two of them selectively inhibit Ras-dependent cell growth in mutated mammalian cells containing tumourigenic Ras.

    21. Regions of Tau Implicated in the Paired Helical Fragment Core as Defined by NMR (pages 1849–1856)

      Alain Sillen, Arnaud Leroy, Jean-Michel Wieruszeski, Anne Loyens, Jean-Claude Beauvillain, Luc Buée, Isabelle Landrieu and Guy Lippens

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200400452

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      The dynamics of tau. NMR and fluorescence spectroscopy were used to obtain data on the dynamics of tau when it is integrated into mature Alzheimer-like filaments (see picture). We found different regions of residual mobility for tau. These included an N-terminal domain that maintains solution-like dynamics and is followed by a large domain of decreasing mobility; the core region was distinguished by a solid-like character.

    22. One-Bead–One-Inhibitor–One-Substrate Screening of Neuraminidase Activity (pages 1857–1865)

      Laiqiang Ying and Jacquelyn Gervay-Hague

      Version of Record online: 8 SEP 2005 | DOI: 10.1002/cbic.200500006

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      Kept in the dark. One-bead–two-compound platforms for monitoring neuraminidase activity have been developed. When treated with neuraminidase, sialic acid is readily cleaved from beads that do not display inhibitors and they fluoresce strongly. In contrast, inhibitor-functionalized beads remain dark and can be selected as positive hits.

    23. A Fragment-Based Approach to Understanding Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (pages 1866–1874)

      Ludovic Mercklé, Ana de Andrés-Gómez, Bethany Dick, Russell J. Cox and Christopher R. A. Godfrey

      Version of Record online: 23 AUG 2005 | DOI: 10.1002/cbic.200500061

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      Closing the loop. Kinetic analysis of the binding of fosmidomycin to the active site of E. coli deoxyxylulose-5-phosphate reductoisomerase (DXR) reveals unusual cooperative effects in addition to the expected slow-binding inhibition. Cooperativity was investigated through the use of fosmidomycin fragments and analogues (see scheme). Kinetic data indicate that loop movement, which encloses the active site upon inhibitor binding, might be responsible for both the slow-binding and cooperative behaviour.

    24. Stochastic Sensing of TNT with a Genetically Engineered Pore (pages 1875–1881)

      Xiyun Guan, Li-Qun Gu, Stephen Cheley, Orit Braha and Hagan Bayley

      Version of Record online: 24 AUG 2005 | DOI: 10.1002/cbic.200500064

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      Pore detection. Engineered versions of the transmembrane protein pore α-hemolysin were used for the detection of nitroaromatic analytes at the single-molecule level. Individual binding events were observed by monitoring the ionic current that passes through a single pore at a fixed applied potential (see picture). Simple rings of seven aromatic amino acid side chains (Phe, Tyr or Trp) within the lumen of the heptameric pore were found to confer a response to molecules such as the explosive, TNT.

    25. An Experimental and Molecular-Modeling Study of the Binding of Linked Sulfated Tetracyclitols to FGF-1 and FGF-2 (pages 1882–1890)

      Siska Cochran, Cai Ping Li and Ian Bytheway

      Version of Record online: 20 SEP 2005 | DOI: 10.1002/cbic.200500089

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      Inhibiting angiogenesis. The binding affinities of complexes formed between linked sulfated tetracyclitols and the fibroblast growth factors FGF-1 and FGF-2 have been determined by a surface plasmon resonance assay and explored computationally with Monte Carlo conformational search and linear interaction energy calculations.

    26. How Much NMR Data Is Required To Determine a Protein–Ligand Complex Structure? (pages 1891–1898)

      Ulrich Schieborr, Martin Vogtherr, Bettina Elshorst, Marco Betz, Susanne Grimme, Barbara Pescatore, Thomas Langer, Krishna Saxena and Harald Schwalbe

      Version of Record online: 13 JUL 2005 | DOI: 10.1002/cbic.200500092

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      Getting a grip on your complex. An NMR-based approach to solving protein–ligand structures is presented (see figure). An experimental protocol is proposed that starts with calculations that make use of readily available chemical-shift perturbations as experimental constraints. If necessary, more sophisticated experimental results must then be added to improve the accuracy of the protein–ligand complex.

    27. Probing Lectin and Sperm with Carbohydrate-Modified Quantum Dots (pages 1899–1905)

      Anandakathir Robinson, Jim-Min Fang, Pi-Tai Chou, Kuang-Wen Liao, Rea-Min Chu and Shyh-Jye Lee

      Version of Record online: 7 SEP 2005 | DOI: 10.1002/cbic.200500112

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      Multivalent interactions of GlycoQDs with lectin and sperm. β-N-Acetylglucosamine-encapsulated CdSe/ZnS core-shell fluorescent nanoparticles (see scheme) enter into sensitive multivalent interactions with WGA lectin and specifically at the heads of live sperm, as shown by fluorimetry, transmission electron microscopy, dynamic light scattering microscopy, confocal imaging technique, and flow cytometry.

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      Preview: ChemBioChem 10/2005 (page 1910)

      Version of Record online: 29 SEP 2005 | DOI: 10.1002/cbic.200590035