ChemBioChem

Cover image for ChemBioChem

May 6, 2005

Volume 6, Issue 5

Pages 769–930

    1. Cover Picture: Protein-Detecting Microarrays: Current Accomplishments and Requirements (ChemBioChem 5/2005) (page 769)

      Kin-ya Tomizaki, Kenji Usui and Hisakazu Mihara

      Version of Record online: 22 APR 2005 | DOI: 10.1002/cbic.200590015

      The cover picture shows an emerging protein-detecting microarray technology that has the potential to uncover complex protein networks in a miniaturized and parallelized fashion. The microarray system comprises capture agents, such as antibodies, recombinant proteins, and peptides immobilized onto solid surfaces, and provides a large number of important parameters on molecular interactions in a single experiment. The system is supported by three independent but strongly correlated basic technologies that involve screening/production of capture agents, engineering of surface modification methodologies of solid supports, and development of detection methods. Although the system is currently in progress, it could be employed conveniently as a diagnostic/research tool in the near future. Further information on the current accomplishments and requirements of the technology can be found in the Review by Mihara and co-workers on p. 782 ff.

    2. Protein-Detecting Microarrays: Current Accomplishments and Requirements (pages 782–799)

      Kin-ya Tomizaki, Kenji Usui and Hisakazu Mihara

      Version of Record online: 24 MAR 2005 | DOI: 10.1002/cbic.200400232

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      Protein and chips: The protein-detecting microarray is a promising and indispensable research tool, as well as a potential diagnostic tool, which allows two different types of analysis to be performed (identifying the abundances of proteins and the functions of proteins). The three key technologies of surface chemistry, detection methods, and capture agents should be tied in with each other to develop valuable protein-detecting systems (see picture). This technology is heading towards a final destination where a tiny chip provides a large number of important parameters in a single experiment precisely and rapidly.

    3. New Studies on the Murchison Meteorite Shed Light on the Pre-RNA World (pages 801–803)

      Henry Strasdeit

      Version of Record online: 24 MAR 2005 | DOI: 10.1002/cbic.200400435

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      Begin at the beginning. The Murchison meteorite is a treasure trove for prebiotic chemical research. Its extensive inventory of organic compounds is as old as our solar system and probably reflects some of the chemical conditions by which the early steps in the origin of life proceeded. Thus, enantiomeric excesses in certain meteoritic α-amino acids might have triggered biological homochirality (see scheme).

    4. Fast Directed Evolution of Non-Immunoglobulin Proteins by Somatic Hypermutation in Immune Cells (pages 804–806)

      Christian Heinis and Kai Johnsson

      Version of Record online: 16 MAR 2005 | DOI: 10.1002/cbic.200500011

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      New, improved phenotypes. Somatic hypermutation in immune cells can be used for the fast directed evolution of proteins other than immunoglobulins (e.g., autofluorescent proteins). The target gene is inserted into the genome of activated B lymphocytes where it is mutated. Cells expressing a desired phenotype are selected and subjected to further evolution cycles to accumulate beneficial mutations.

    5. Serum Albumin-Catalyzed Trigger System by Using a Tandem Kemp Elimination/β-Elimination Reaction (pages 807–810)

      Guillaume Boucher, Sylvain Robin, Valérie Fargeas, Thierry Dintinger, Monique Mathé-Allainmat, Jacques Lebreton and Charles Tellier

      Version of Record online: 31 MAR 2005 | DOI: 10.1002/cbic.200400255

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      Prodrug activation: Serum albumins (BSA or HSA) are shown to catalyze a reaction cascade that involves the ring-opening of an isoxazole ring followed by a β-elimination reaction, as per the scheme. The 4-(aryloxymethyl)isoxazole derivative of estrone is selectively removed in vitro by albumins, thus demonstrating the potential of this new protective group.

    6. A New Embedded Process for Compartmentalized Cell-Free Protein Expression and On-line Detection in Microfluidic Devices (pages 811–814)

      Petra S. Dittrich, Michael Jahnz and Petra Schwille

      Version of Record online: 13 APR 2005 | DOI: 10.1002/cbic.200400321

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      Just a drop. In the field of biological research and biotechnology, fast and efficient screening for particular properties of minute quantities down to single-particle level has become increasingly important. This work describes the implementation of a lab-on-chip device to generate small reaction containers, that is, a homodisperse water-in-oil emulsion, and cell-free expression of the green fluorescent protein inside the aqueous droplets. Detection of the autofluorescent protein was performed by confocal fluorescence spectroscopy.

    7. Synthesis of Diazirinyl Photoprobe Carrying a Novel Cleavable Biotin (pages 814–818)

      Jong-jip Park, Yutaka Sadakane, Katsuyoshi Masuda, Takenori Tomohiro, Taku Nakano and Yasumaru Hatanaka

      Version of Record online: 11 APR 2005 | DOI: 10.1002/cbic.200400342

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      Rapid screening of receptor proteins is possible through the development of novel cleavable biotinylated photoaffinity probes that bear an acylsulfonamide linkage. The method purified photoaffinity biotinylated proteins by simple sequential steps without significant levels of contamination.

    8. New Insights for Pursuing High Relaxivity MRI Agents from Modelling the Binding Interaction of GdIII Chelates to HSA (pages 818–820)

      Silvio Aime, Eliana Gianolio, Dario Longo, Roberto Pagliarin, Clara Lovazzano and Massimo Sisti

      Version of Record online: 24 MAR 2005 | DOI: 10.1002/cbic.200400364

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      Sticking out. This work is aimed at obtaining new insights into the design of novel Gd chelates that form high-affinity adducts with HSA. Two new GdIII complexes that differ in the size of the hydrophobic moiety responsible for the interaction with the protein have been synthesised. It was shown that the two complexes protrude to a different extent from the surface of the protein (see picture), and this difference has an effect on the exchange of the coordinated water molecule.

    9. Rapid and Quantitative Cyclization of Multiple Peptide Loops onto Synthetic Scaffolds for Structural Mimicry of Protein Surfaces (pages 821–824)

      Peter Timmerman, Joris Beld, Wouter C. Puijk and Rob H. Meloen

      Version of Record online: 5 APR 2005 | DOI: 10.1002/cbic.200400374

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      No need for side-chain protection in the cyclization reaction of cysteine-containing linear peptides onto bromomethylated aromatic scaffolds (see scheme). The reaction is extremely fast and clean and runs to completion in less than 15 min at room temperature.

    10. Solid-Phase Synthesis of Double-Headed Epoxysuccinyl Activity-Based Probes for Selective Targeting of Papain Family Cysteine Proteases (pages 824–827)

      Steven H. L. Verhelst and Matthew Bogyo

      Version of Record online: 18 MAR 2005 | DOI: 10.1002/cbic.200400377

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      Checking out cathepsins. A solid-phase protocol was devised in order to synthesize activity-based probes (1) that contain peptides on both ends of an epoxysuccinyl moiety. The feasibility of this strategy was illustrated by the synthesis of selective probes for cathepsin B, one of the major lysosomal Papain family cysteine proteases.

    11. Gold Glyconanoparticles as Probes to Explore the Carbohydrate-Mediated Self-Recognition of Marine Sponge Cells (pages 828–831)

      Adriana Carvalho de Souza, Koen M. Halkes, Johannes D. Meeldijk, Arie J. Verkleij, Johannes F. G. Vliegenthart and Johannis P. Kamerling

      Version of Record online: 16 MAR 2005 | DOI: 10.1002/cbic.200400380

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      Carbohydrate–carbohydrate interactions. TEM imaging shows that gold glyconanoparticles coated with the synthetic disaccharide epitope β-D-GlcpNAc3S-(1[RIGHTWARDS ARROW]3)-α-L-Fucp(1[RIGHTWARDS ARROW]O) (Au-1 a) can mimic the proteoglycan self-recognition that is responsible for marine sponge cell adhesion. This interaction is highly specific; any structural changes in the disaccharide completely eradicated the self-recognition phenomenon.

    12. Detection of Covalent Intermediates Formed in the Reaction of 4-Amino-4-deoxychorismate Synthase (pages 832–834)

      Esther M. M. Bulloch and Chris Abell

      Version of Record online: 16 MAR 2005 | DOI: 10.1002/cbic.200400385

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      Caught in the act. The enzyme 4-amino-4-deoxychorismate synthase (ADCS) catalyses the amination of chorismate by using glutamine as the ammonia source. ADCS consists of a chorismate-aminating subunit, PabB, and a glutamine amidotransferase subunit, PabA. Using electrospray mass spectrometry, we have directly detected the formation of enzyme-bound covalent intermediates on both PabB (as shown in figure) and PabA.

    13. A Homologue of the Mycobacterium tuberculosis PapA5 Protein, Rif-Orf20, Is an Acetyltransferase Involved in the Biosynthesis of Antitubercular Drug Rifamycin B by Amycolatopsis mediterranei S699 (pages 834–837)

      Yeping Xiong, Xiumei Wu and Taifo Mahmud

      Version of Record online: 24 MAR 2005 | DOI: 10.1002/cbic.200400387

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      Toward antitubercular drugs. Rif-Orf20, a homologue of M. tuberculosis PapA5 protein, is an acetyltransferase that is responsible for the conversion of DMDARSV to DMRSV in rifamycin B biosynthesis. This enzyme, together with PapA5, represents a new class of acyltransferases. The enzyme also utilizes propionyl-CoA as substrate to give rise to a new analogue of rifamycin that appears, from spectroscopic results, to have the structure 1.

    14. The Oxidative Ring Cleavage in Jadomycin Biosynthesis: A Multistep Oxygenation Cascade in a Biosynthetic Black Box (pages 838–845)

      Uwe Rix, Chenchen Wang, Yihua Chen, Fredilyn M. Lipata, Lily L. Remsing Rix, Lisa M. Greenwell, Leo C. Vining, Keqian Yang and Jürgen Rohr

      Version of Record online: 18 MAR 2005 | DOI: 10.1002/cbic.200400395

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      Backbone-breaking oxygenase clusters. Inactivation of the oxygenase-encoding genes jadH and jadG and structure elucidation of novel accumulation products illustrate the essential interactions within the biosynthetic protein complex that govern the oxygenation cascade leading to the cleavage of the angucycline backbone during jadomycin biosynthesis by Streptomyces venezuelae. These results also allow the elucidation of the dehydration sequence (shown) that yields the aromatic ring A of the jadomycin scaffold.

    15. Potent and Selective Inhibition of Class II α-D-Mannosidase Activity by a Bicyclic Sulfonium Salt (pages 845–848)

      Aloysius Siriwardena, Heather Strachan, Samer El-Daher, Gemma Way, Bryan Winchester, John Glushka, Kelley Moremen and Geert-Jan Boons

      Version of Record online: 31 MAR 2005 | DOI: 10.1002/cbic.200400397

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      Salted away. Shortcomings in the potency and selectivity of natural glycosidase inhibitors, such as swainsonine (1), have led to the proposal of a host of alternative synthetic structural motifs. This paper reports the synthesis of the polyhydroxylated sulfonium salt 2 and demonstrates it to be a potent inhibitor of various human class II α-D-mannosidase activities.

    16. Remarkable Stabilization of Duplex DNA Containing an Abasic Site by Non-Nucleosidic Phenanthroline and Pyrene Building Blocks (pages 848–851)

      Simon M. Langenegger and Robert Häner

      Version of Record online: 18 MAR 2005 | DOI: 10.1002/cbic.200400370

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      Filling the gap. Abasic sites represent a frequently occurring lesion in DNA. If not repaired, such lesions can lead to mutations or cell death. Stabilization of DNA containing abasic sites is investigated as a therapeutic approach for the treatment of cancer. Non-nucleosidic phenanthroline and pyrene derivatives were found to have a profound stabilizing effect (ΔTm=8 °C) on DNA missing a nucleobase.

    17. Homology Modeling and Molecular Dynamics Simulations of the Mu Opioid Receptor in a Membrane–Aqueous System (pages 853–859)

      Yan Zhang, Yuk Y. Sham, Ramkumar Rajamani, Jiali Gao and Philip S. Portoghese

      Version of Record online: 18 MAR 2005 | DOI: 10.1002/cbic.200400207

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      Characterizing binding modes. A homology model of the mu opioid receptor was constructed based on the X-ray crystal structure of bovine rhodopsin. The model was further optimized in a complete membrane matrix. The opioid ligand naltrexone was docked into the optimized model (see figure), and the critical amino acid residues for binding were identified.

    18. Malassezin, a Novel Agonist of the Aryl Hydrocarbon Receptor from the Yeast Malassezia furfur, Induces Apoptosis in Primary Human Melanocytes (pages 860–865)

      Hans-Joachim Krämer, Monika Podobinska, Andrea Bartsch, Achim Battmann, Wiebke Thoma, August Bernd, Wolfgang Kummer, Bernhard Irlinger, Wolfgang Steglich and Peter Mayser

      Version of Record online: 5 APR 2005 | DOI: 10.1002/cbic.200400247

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      Active agent in skin depigmentation. Pityriasis versicolor, a very common human skin mycosis, is often accompanied by long-lasting depigmentations with a still unknown mechanism. The yeast Malassezia furfur, regarded as one causative agent, is able to convert tryptophan into a variety of indole alkaloids including malassezin, the active compound inducing apoptosis in human melanocytes.

    19. Developing Promiscuous Glycosidases for Glycoside Synthesis: Residues W433 and E432 in Sulfolobus solfataricus β-Glycosidase are Important Glucoside- and Galactoside-Specificity Determinants (pages 866–875)

      Susan M. Hancock, Kevin Corbett, Anthony P. Fordham-Skelton, John A. Gatehouse and Benjamin G. Davis

      Version of Record online: 22 APR 2005 | DOI: 10.1002/cbic.200400341

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      Broader choice. We report the successful broadening of substrate specificity of the β-glycosidase from Sulfolobus solfataricus by mutagenesis of the substrate-binding site. This led to 24- and 20-fold changes in the Man:Gal and Xyl:Gal preference ratios. The synthetic utility of these new versatile catalysts is illustrated by the parallel synthesis of balanced glycoside libraries and the formation of alkyl glycosides of various sugars. Evidence towards the conformational itinerary mechanism (see figure) of glycosidases is presented.

    20. GPCR Antitarget Modeling: Pharmacophore Models for Biogenic Amine Binding GPCRs to Avoid GPCR-Mediated Side Effects (pages 876–889)

      Thomas Klabunde and Andreas Evers

      Version of Record online: 24 MAR 2005 | DOI: 10.1002/cbic.200400369

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      Making predictions. The central role that biogenic amine-binding GPCRs and their ligands play in cell signaling poses a risk in new drug candidates with side affinities towards these receptor sites. Predictive pharmacophore models can describe the key chemical features mediating the affinity towards these sites and can thus rationalize undesired side affinities and lead to improved clinical safety profiles. The figure shows one of the models mapped onto the respective topographical receptor model (TM=transmembrane helix).

    21. Exo-Mechanism Proximity-Accelerated Alkylations: Investigations of Linkers, Electrophiles and Surface Mutations in Engineered Cyclophilin–Cyclosporin Systems (pages 890–899)

      Konstantin Levitsky, Melissa D. Boersma, Christopher J. Ciolli and Peter J. Belshaw

      Version of Record online: 14 APR 2005 | DOI: 10.1002/cbic.200400383

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      Reaching further. Exo-mechanism proximity-accelerated alkylations in engineered cyclophilin–cyclosporin systems were systematically investigated. We found that acrylamides and epoxides were the optimal electrophiles, remote cysteine residues could be alkylated efficiently, and that the local environment dominates the reactivity of surface cysteines.

    22. Investigation of Molecular Beacon Aptamer-Based Bioassay for Platelet-Derived Growth Factor Detection (pages 900–907)

      Marie C. Vicens, Arup Sen, Andrew Vanderlaan, Timothy J. Drake and Weihong Tan

      Version of Record online: 5 APR 2005 | DOI: 10.1002/cbic.200400308

      Guidance system. Synthetic DNA aptamers selected for high-affinity binding to platelet-derived growth factor (PDGF) mediates fluorescence resonance energy transfer (FRET) arising from unique conformational change of the DNA bound to PDGF. We report the use of molecular beacon aptamers in bioassay development for PDGF.

    23. Functional Analysis of the Aureothin Iterative Type I Polyketide Synthase (pages 908–912)

      Jing He and Christian Hertweck

      Version of Record online: 5 APR 2005 | DOI: 10.1002/cbic.200400333

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      Works twice as hard. In contrast to the processing line model for modular polyketide synthases (PKS), the aureothin PKS acts in a noncolinear fashion. Heterologous expression of fused PKS modules revealed that the first module is truly iterative and catalyzes two rounds of elongation and chain processing (see Figure). Furthermore, point mutations suggest that the fourth module is functional despite its aberrant acyltransferase domain.

    24. Mechanistic Studies on the Tyrosinase-Catalyzed Formation of the Anachelin Chromophore (pages 913–919)

      Karl Gademann

      Version of Record online: 12 APR 2005 | DOI: 10.1002/cbic.200400343

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      Biosynthesis of a unique tetrahydroquinolinium-derived chromophore: A combination of spectrophotometric reaction monitoring and kinetic studies allowed a detailed insight into the putative biosynthesis of the unique anachelin chromophore. These experiments support the biogenetic hypothesis that an oxidative aza-annulation is a key step in the synthesis (see scheme).

    25. A Novel Homogenous Assay for Topoisomerase II Action and Inhibition (pages 920–926)

      Michael Jahnz, Miguel Ángel Medina and Petra Schwille

      Version of Record online: 5 APR 2005 | DOI: 10.1002/cbic.200400379

      Application of biophysics in drug discovery. This article explains how a single-molecule-sensitive spectroscopy technique can be used to search for new anticancer compounds. This article reports a new separation-free assay in homogenous solution, capable of characterizing topoisomerase II inhibitors by dual-color fluorescence cross-correlation spectroscopy.

    26. Catalytic Antibodies. Edited by Ehud Keinan. (page 927)

      Dick B. Janssen

      Version of Record online: 22 APR 2005 | DOI: 10.1002/cbic.200500126

    27. You have free access to this content
      Preview: ChemBioChem 5/2005 (page 930)

      Version of Record online: 22 APR 2005 | DOI: 10.1002/cbic.200590017

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