Cover image for ChemBioChem

April 8, 2005

Volume 6, Issue 4

Pages 577–766

    1. Cover Picture: A Novel Mycolactone from a Clinical Isolate of Mycobacterium ulcerans Provides Evidence for Additional Toxin Heterogeneity as a Result of Specific Changes in the Modular Polyketide Synthase (ChemBioChem 4/2005) (page 577)

      Hui Hong, Jonathan B. Spencer, Jessica L. Porter, Peter F. Leadlay and Tim Stinear

      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200590012

      The cover picture shows the structure (in red, right) of the lipophilic polyketide toxin mycolactone obtained from the reference Ghana strain of Mycobacterium ulcerans, the causative agent of the emerging disease Buruli ulcer, and that (in red, left) of a molecular variant of mycolactone newly identified from a clinical isolate of M. ulcerans from China. The new variant bears a single additional methyl group in the sidechain, as shown by mass spectrometry. Also shown at the top is the difference detected between the structural genes; this difference is dictated by a precise acyltransferase (AT) domain swap in the chain-building polyketide synthase, so that a propionate (Pr) unit is recruited rather than an acetate (Ac) unit. Detailed information about this apparent natural example of polyketide biosynthetic engineering is reported by P. Leadley et al. on p. 643 ff.

    2. Searching Sequence Space: Two Different Approaches to Dihydrofolate Reductase Catalysis (pages 590–600)

      Elizabeth E. Howell

      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200400237

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      A glimpse of evolution? In this review, two dihydrofolate reductases (DHFRs) that have totally different tertiary and quaternary structures as well as disparate catalytic strategies are compared. The two proteins are the well-evolved E. coli chromosomal DHFR (left) and the primitive, type II, R-plasmid-encoded DHFR, typified by R67 DHFR (right).

    3. A Widely Distributed Bacterial Pathway for Siderophore Biosynthesis Independent of Nonribosomal Peptide Synthetases (pages 601–611)

      Gregory L. Challis

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400283

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      Catch Fe if you can. Many siderophores are peptides biosynthesised by the well-studied nonribosomal peptide synthetase (NRPS) multienzyme family. However, recent research has demonstrated that several siderophores, for example desferrioxamine E, are assembled via an NRPS-independent siderophore (NIS) pathway. In this minireview, research progress to date on the NIS pathway is summarised, and the distribution and mechanistic rationalisations of the pathway are analysed.

    4. The Chemistry and Biology of Nitroxyl (HNO): A Chemically Unique Species with Novel and Important Biological Activity (pages 612–619)

      Jon M. Fukuto, Andrew S. Dutton and Kendall N. Houk

      Version of Record online: 27 DEC 2004 | DOI: 10.1002/cbic.200400271

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      Small species, big impact. Nitroxyl (HNO) is chemically unique and biologically important. In the past few years, major discoveries of its novel biological actions have been made as well as revelations regarding its fundamental chemistry. These new findings, for example those relating to the relative energies of the various nitroxyl species (see figure) are presented and discussed.

    5. New Allosteric Modulators of Metabotropic Glutamate Receptor 5 (mGluR5) Found by Ligand-Based Virtual Screening (pages 620–625)

      Steffen Renner, Tobias Noeske, Christopher G. Parsons, Petra Schneider, Tanja Weil and Gisbert Schneider

      Version of Record online: 2 MAR 2005 | DOI: 10.1002/cbic.200400332

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      Ligand-based pharmacophore searching identified new allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), a class III G protein-coupled receptor. This virtual-screening approach can be seen as a working alternative to more demanding structure-based design techniques with the main aim of developing novel lead series.

    6. Toward Semisynthetic Lipoproteins by Convergent Strategies Based on Click and Ligation Chemistry (pages 625–628)

      Hans-Jürgen Musiol, Shouliang Dong, Markus Kaiser, Ralf Bausinger, Andreas Zumbusch, Uwe Bertsch and Luis Moroder

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400351

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      A new convergent strategy is proposed for the semisynthesis of C-terminally lipidated proteins that is based on the copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes in synthetic peptides to dimyristoylphosphatidylethanol azide followed by native chemical ligation (NCL) or expressed protein ligation (EPL) of the lipopeptide with synthetic or expressed polypeptide thioesters.

    7. Inhibition of Fibril Formation of Aβ by Guanidiniocarbonyl Pyrrole Receptors (pages 628–631)

      Carsten Schmuck, Peter Frey and Martin Heil

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400270

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      Choosing the target. Inhibition of the formation of β-amyloid fibrils, formed by self assembly from the amyloid β-peptide (Aβ) is an attractive target for the treatment of Alzheimer's disease. Artificial receptors such as 1, specifically designed for Aβ's C-terminal VVIA sequence, are capable in vitro of selectively inhibiting fibril formation of Aβ (1–42) but not of Aβ (1–40), which lacks that specific C-terminal target sequence.

    8. Elucidation of the Glycosylation Sequence of Mithramycin Biosynthesis: Isolation of 3A-Deolivosylpremithramycin B and Its Conversion to Premithramycin B by Glycosyltransferase MtmGII (pages 632–636)

      Mohammad Nur-e-Alam, Carmen Méndez, José A. Salas and Jürgen Rohr

      Version of Record online: 11 FEB 2005 | DOI: 10.1002/cbic.200400309

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      The last step at last. The isolation and structure elucidation of the novel premithramycin-type compound 3A-deolivosylpremithramycin B (1) allowed cross-feeding experiments with this compound to two glycosyltransferase-minus mutants of the mithramycin producer S. argillaceus; this has solved the sequence of the last glycosylation steps of mithramycin biosynthesis.

    9. Directed Evolution of an Amine Oxidase for the Preparative Deracemisation of Cyclic Secondary Amines (pages 637–639)

      Reuben Carr, Marina Alexeeva, Michael J. Dawson, Vicente Gotor-Fernández, Cara E. Humphrey and Nicholas J. Turner

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400329

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      Off the rac. Directed evolution of the amine oxidase from Aspergillus niger (MAO-N), by using 1-methyltetrahydroisoquinoline as the target substrate, led to the identification of a variant enzyme (Asn336Ser/Ile246Met) that possessed a greater kcat value (5.5-fold) than the parent as well as high enantioselectivity (see scheme). This new variant was used for the deracemisation of cyclic secondary amines on a preparative scale.

    10. Immuno-Carbon Nanotubes and Recognition of Pathogens (pages 640–643)

      Tara Elkin, Xiuping Jiang, Shelby Taylor, Yi Lin, Lingrong Gu, Hua Yang, Jessica Brown, Susan Collins and Ya-Ping Sun

      Version of Record online: 1 MAR 2005 | DOI: 10.1002/cbic.200400337

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      Tubular warning bells. Water-soluble, protein-functionalized, single-walled carbon nanotubes (immuno-SWNTs) have been prepared that can recognize and capture pathogenic E. coli cells selectively by antibody–antigen conjugation in a physiological environment, as shown in the scanning electron microscopy image.

    11. A Novel Mycolactone from a Clinical Isolate of Mycobacterium ulcerans Provides Evidence for Additional Toxin Heterogeneity as a Result of Specific Changes in the Modular Polyketide Synthase (pages 643–648)

      Hui Hong, Jonathan B. Spencer, Jessica L. Porter, Peter F. Leadlay and Tim Stinear

      Version of Record online: 7 MAR 2005 | DOI: 10.1002/cbic.200400339

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      New analogues of the toxin mycolactone have been identified in a pathogenic Chinese strain of Mycobacterium ulcerans. They possess an extra methyl group at C2′ (shown in red) compared to mycolactone A as a result of the recruitment of a single catalytic domain of altered specificity in the mycolactone polyketide synthase.

    12. Design, Synthesis and Antimalarial Activity of Trifluoromethylartemisinin–Mefloquine Dual Molecules (pages 648–652)

      Fabienne Grellepois, Philippe Grellier, Danièle Bonnet-Delpon and Jean-Pierre Bégué

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400347

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      Caught in the ACT. Two novel antimalarial molecules combining a CF3-artemisinin derivative (blue) and mefloquine (pink) have been synthesized. In vitro and in vivo assays of this artemisinin-based combination therapy (ACT) showed the high efficacy of both chimeras against Plasmodium falciparum.

    13. Heme Alkylation by Artesunic Acid and Trioxaquine DU1301, Two Antimalarial Trioxanes (pages 653–658)

      Sophie A.-L. Laurent, Christophe Loup, Sophie Mourgues, Anne Robert and Bernard Meunier

      Version of Record online: 2 MAR 2005 | DOI: 10.1002/cbic.200400249

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      Boomerang bullet. Activated by iron(II)-heme, the two antimalarial trioxanes artesunic acid and trioxaquine DU1301 are efficient alkylating agents toward heme itself. Under mild in vitro conditions, heme is both the trigger and the target of these peroxide-based drugs.

    14. Convenient Access Both to Highly Antimalaria-Active 10-Arylaminoartemisinins, and to 10-Alkyl Ethers Including Artemether, Arteether, and Artelinate (pages 659–667)

      Richard K. Haynes, Ho-Wai Chan, Wing-Yan Ho, Cliff Ki-Fung Ko, Lucia Gerena, Dennis E. Kyle, Wallace Peters and Brian L. Robinson

      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200400366

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      Economic antimalarials. 10-Arylaminoartemisinins, such as 1, are very easily prepared from DHA (2), and some possess very good antimalarial activities in in vivo screens relative to the most widely used of the current artemisinins. Whilst the oral activity against Plasmodium berghei in mice is less than that of 10-alkylamino artemisinins, the subcutaneous activity is comparable.

    15. Ring-Closing Metathesis of C-Terminal Allylglycine Residues with an N-Terminal β-Vinyl-Substituted Phosphotyrosyl Mimetic as an Approach to Novel Grb2 SH2 Domain-Binding Macrocycles (pages 668–674)

      Shinya Oishi, Zhen-Dan Shi, Karen M. Worthy, Lakshman K. Bindu, Robert J. Fisher and Terrence R. Burke Jr.

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400298

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      Going full circle. Ring-closing metathesis (RCM) that follows placement of allylglycine residues at the intended sites of ring juncture is an important approach toward peptide macrocyclization; however, loss of biological potency can result. Using Grb2 SH2 domain-binding peptides, we report RCM macrocyclization between allylglycine residues and a β-vinyl-containing phosphotyrosyl mimetic that allows retention of critical ring-juncture functionality. The resulting macrocycles (2 and 3) exhibit significant enhancement of Grb2 SH2 domain-binding affinity relative to the open-chain parent (1).

    16. Generation of Novel Landomycins M and O through Targeted Gene Disruption (pages 675–678)

      Andriy Luzhetskyy, Lili Zhu, Miranda Gibson, Marta Fedoryshyn, Clemens Dürr, Carsten Hofmann, Dirk Hoffmeister, Bohdan Ostash, Cynthia Mattingly, Val Adams, Victor Fedorenko, Jürgen Rohr and Andreas Bechthold

      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200400316

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      New deoxylandomycins. Targeted inactivation of the landomycin reductase gene, lanZ4, and the oxygenase gene, lanZ5, in Streptomyces cyanogenus S136 resulted in the formation of new derivatives that lack the unique hydroxyl group in the C-11 position. The new landomycins posses much weaker antitumor activities; this highlights the importance of the C-11 hydroxyl group of the angucycline moiety. Our data suggest that that LanZ4 and LanZ5 are responsible for the unique C-11-hydroxylation that occurs during landomycin biosynthesis, as shown in the scheme.

    17. A 4′-Phosphopantetheinyl Transferase Mediates Non-Ribosomal Peptide Synthetase Activation in Aspergillus fumigatus (pages 679–685)

      Claire Neville, Alan Murphy, Kevin Kavanagh and Sean Doyle

      Version of Record online: 18 FEB 2005 | DOI: 10.1002/cbic.200400147

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      Breaking the mould. Aspergillus fumigatus (see picture) is an opportunistic pathogen of immunocompromised individuals. The organism produces a range of secondary metabolites, some of which are produced by non-ribosomal peptide (NRP) synthesis. This article presents data that demonstrate that at least one NRP synthetase is activated by a 4′-phosphopantetheinyl transferase in A. fumigatus.

    18. Cytostatic Activity of 1,10-Phenanthroline Derivatives Generated by the Clip-Phen Strategy (pages 686–691)

      Marguerite Pitié, Alain Croisy, Danièle Carrez, Christophe Boldron and Bernard Meunier

      Version of Record online: 11 MAR 2005 | DOI: 10.1002/cbic.200400243

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      Improved antiproliferative activity through alkoxy tethering. The cytostatic activity of a series of twelve 1,10-phenanthroline (Phen) derivatives and of their copper complexes was studied. A large increase in the biological activity was observed for compounds of the 3-Clip-Phen series in which two Phen components were bridged at their C3 positions by an alkoxy linker.

    19. Electrostatic Effects on the Thermodynamics of Protonation of Reduced Plastocyanin (pages 692–696)

      Gianantonio Battistuzzi, Marco Borsari, Giulia Di Rocco, Alan Leonardi, Antonio Ranieri and Marco Sola

      Version of Record online: 7 MAR 2005 | DOI: 10.1002/cbic.200400310

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      Electrochemical rewiring. Net charges were inserted near the metal site of four variants of spinach pastocyanin, and the thermodynamics of protonation and detachment from the copper(I) ion of the His87 ligand were evaluated (see figure). Contributions from the reorganization of the H-bonding network within the hydration sphere of the molecule in the proximity of the metal center mask the differences in transition thermodynamics from protein-based effects. These can be recognized only after the solvent-based terms are factorized out.

    20. Lipidic Membranes Are Potential “Catalysts” in the Ligand Activity of the Multifunctional Pentapeptide Neokyotorphin (pages 697–702)

      Sílvia C. D. N. Lopes, Aleksander Fedorov and Miguel A. R. B. Castanho

      Version of Record online: 7 MAR 2005 | DOI: 10.1002/cbic.200400318

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      Come together. Neokyotorphin is a multifunctional pentapeptide and is involved in diverse biological functions. Lipidic membranes are potential “catalysts” in the ligand activity of this pentapeptide since they modulate the exposure and orientation of the phenolic ring, which is most likely involved in docking to receptors.

    21. Potentiometric Detection of Single Nucleotide Polymorphism by Using a Genetic Field-effect transistor (pages 703–710)

      Toshiya Sakata and Yuji Miyahara

      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200400253

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      Measurement of allele-specific oligonucleotide hybridization. The scheme shows potentiometric detection of DNA-recognition events by use of a genetic field-effect transistor (FET). Since the charged molecules on the gate surface interact electrostatically with electrons in Si through the Si3N4/SiO2 thin-gate insulator, the charge-density change caused by DNA-recognition events can be measured as the threshold voltage shift.

    22. Inversion of Stereoselectivity by Applying Mutants of the Hydroxynitrile Lyase from Manihot esculenta (pages 711–717)

      Holger Bühler, Burkhard Miehlich and Franz Effenberger

      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200400302

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      Open the gate and let the substrates flow in. The formation of cyanohydrin from aldehydes, catalyzed by the wild-type hydroxynitrile lyase from Manihot esculenta (MeHNL), is strongly (S)-selective. However, HCN addition to aldehydes with stereogenic centers in the α-position that is catalyzed by MeHNL Trp128 mutants becomes increasingly (R)-selective with decreasing size of the amino acids exchanged for Trp128 (see scheme). Since position 128 is at the channel entrance to the active site, these results are unexpected, but can be explained by molecular modeling of the transition states.

    23. Smart Polyion Complex Micelles for Targeted Intracellular Delivery of PEGylated Antisense Oligonucleotides Containing Acid-Labile Linkages (pages 718–725)

      Motoi Oishi, Fumi Nagatsugi, Shigeki Sasaki, Yukio Nagasaki and Kazunori Kataoka

      Version of Record online: 8 MAR 2005 | DOI: 10.1002/cbic.200400334

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      A novel pH-sensitive and targetable antisense ODN delivery system was successfully prepared by assembling lactosylated PEG–antisense ODN conjugates containing acid-labile β-thiopropionate linkages into polyion complex (PIC) micelles through mixing with poly(L-lysine; see figure). The lactosylated PIC micelles enhanced gene silencing in hepatoma cells remarkably; this indicated that this approach is feasible for a targetable antisense ODN delivery system.

    24. Synthesis and Antiapoptotic Activity of a Novel Analogue of the Neutral Sphingomyelinase Inhibitor Scyphostatin (pages 726–737)

      Ralf A. Claus, Annette Wüstholz, Stefan Müller, Clemens L. Bockmeyer, Norman H. Riedel, Ralf Kinscherf and Hans-Peter Deigner

      Version of Record online: 7 MAR 2005 | DOI: 10.1002/cbic.200400228

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      Inhibiting cell death. Inhibitors of sphingomyelinases have attracted considerable interest as drug candidates. The aim of this study was the synthetic preparation of a stable desepoxy analogue of scyphostatin that retains the biological properties of the parent compound (see structure). Evidence of specific interactions with selected targets in a cell-based assay system, as well as of the inhibition of apoptosis, is provided.

    25. Calculation of the Redox Potential of the Protein Azurin and Some Mutants (pages 738–746)

      Marieke van den Bosch, Marcel Swart, Jaap G. Snijders†, Herman J. C. Berendsen, Alan E. Mark, Chris Oostenbrink, Wilfred F. van Gunsteren and Gerard W. Canters

      Version of Record online: 3 MAR 2005 | DOI: 10.1002/cbic.200400244

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      Thermodynamic integration and MD simulations have been used to calculate the effect of mutations on the redox potential of the copper protein azurin. The thermodynamic cycle depicted here is used as a check for consistency.

    26. The Effects of Ligand Exchange and Mobility on the Peroxidase Activity of a Bacterial Cytochrome c upon Unfolding (pages 747–758)

      Jonathan A. R. Worrall, Rutger E. M. Diederix, Miguel Prudêncio, Christian E. Lowe, Simone Ciofi-Baffoni, Marcellus Ubbink and Gerard W. Canters

      Version of Record online: 2 MAR 2005 | DOI: 10.1002/cbic.200400291

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      Open for activity. In its native state, ferricytochrome c-550 possesses residual peroxidase activity due to a dynamic process involving the breaking of the methionine–iron bond (see figure). The activity increases spectacularly upon unfolding. In the early stages of this process, the heme goes through a succession of partly unfolded forms with different ligands.

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      Version of Record online: 6 APR 2005 | DOI: 10.1002/cbic.200590014