Cover image for ChemBioChem

November 4, 2005

Volume 6, Issue 11

Pages 1913–2110

    1. Cover Picture: Light-Induced Formation of G-Quadruplex DNA Secondary Structures (ChemBioChem 11/2005) (page 1913)

      Günter Mayer, Lenz Kröck, Vera Mikat, Marianne Engeser and Alexander Heckel

      Article first published online: 26 OCT 2005 | DOI: 10.1002/cbic.200590036

      The cover picture shows in the magnifying lens oligodeoxynucleotides that have been modified with a photolabile group, represented as a green star. This temporary modification blocks the interaction properties of the respective nucleobase. One of these "caged oligodeoxynucleotides" has just been hit with light, thus removing the modification. The unmodified oligodeoxynucleotide can now fold into the active conformation—-in this case a G-quadruplex. The background suggests possible applications. Confocal microscopy can be used to apply light with high spatiotemporal control and allow the triggering of biologically active oligodeoxynucleotides; in the future maybe even in individual cells. For more details, see the communication by Mayer, Heckel, et al. on p. 1966 ff.

    2. Graphical Abstract: ChemBioChem 11/2005 (pages 1915–1923)

      Article first published online: 26 OCT 2005 | DOI: 10.1002/cbic.200590037

    3. Mechanism and Substrate Specificity of tRNA–Guanine Transglycosylases (TGTs): tRNA-Modifying Enzymes from the Three Different Kingdoms of Life Share a Common Catalytic Mechanism (pages 1926–1939)

      Bernhard Stengl, Klaus Reuter and Gerhard Klebe

      Article first published online: 5 OCT 2005 | DOI: 10.1002/cbic.200500063

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      Base exchange in different kingdoms: Detailed analysis of tRNA–guanine transglycosylase (TGT) crystal structures (see structure; preQ1=7-(aminomethyl)-7-deazaguanine, preQ0=7-cyano-7-deazaguanine, ArcTGT=archaeosine TGT, QueTGT=queuosine TGT) in complex with RNA substrates of an archaeon and a eubacterial species allow the extraction of valuable information about substrate recognition, reaction pathway, substrate specificity, and classification within enzymes adopting a triose-phosphate isomerase type barrel fold.

    4. The Expanding Role of Mass Spectrometry in Metabolite Profiling and Characterization (pages 1941–1951)

      Elizabeth J. Want, Benjamin F. Cravatt and Gary Siuzdak

      Article first published online: 4 OCT 2005 | DOI: 10.1002/cbic.200500151

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      A weighty issue. The growing interest in metabolite profiling stems from the need to understand the biochemical events of cells and tissues, and the potential for identifying both disease and pharmaceutical biomarkers. Advances in liquid chromatography/mass spectrometry (LC/MS) technology as well as data-analysis tools have enabled more comprehensive metabolite analyses, thus affording new levels of sensitivity, accuracy, and quantitation. This has added impetus to the growing area of metabolite profiling, making it one of the most exciting areas of biological discovery.

    5. Reaching the Target: Small Molecules Aim to Probe Barrier Quality (pages 1953–1955)

      Christopher Cordier and Adam Nelson

      Article first published online: 18 OCT 2005 | DOI: 10.1002/cbic.200500250

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      Slipping through. Small molecules can give insight into the mechanisms controlled by proteins other than their direct molecular targets. A range of toxic compounds with diverse physicochemical properties has been used to investigate the quality of the outer-membrane barriers in E. coli strains, see graphic. A chemical genetic approach was used in combination with a forward classical genetic approach to identify some of the proteins involved in outer-membrane biogenesis.

    6. The Folding and Unfolding Kinetics of the i-Motif Structure Formed by the C-Rich Strand of Human Telomere DNA (pages 1957–1960)

      Yong Zhao, Zhi-xiong Zeng, Zhong-yuan Kan, Yu-hua Hao and Zheng Tan

      Article first published online: 5 OCT 2005 | DOI: 10.1002/cbic.200500175

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      Return to the fold. Nucleic acids with four tandem cytidine-rich repeats can fold into a structure called the i-motif at acidic pH. The folding- and unfolding-rate constants of such a sequence in vertebrate telomere DNA were measured. Protons were found to promote i-motif formation by increasing the folding and decreasing the unfolding.

    7. Activation of the Anaerobic Ribonucleotide Reductase by S-Adenosylmethionine (pages 1960–1962)

      Serge Gambarelli, Florence Luttringer, Dominique Padovani, Etienne Mulliez and Marc Fontecave

      Article first published online: 22 SEP 2005 | DOI: 10.1002/cbic.200500182

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      HYSCORE experiments with class III ribonucleotide reductase (RNR) provide a clear signature of S-adenosylmethionine (SAM) bound to the (4 Fe[BOND]4 S) cluster of the activating enzyme β. Experiments with 2H-labeled RNR α demonstrate that, under reducing conditions, the SAM-derived adenosyl radical is the direct precursor of the key glycyl radical found in the active enzyme.

    8. A Practical Enzymatic Synthesis of UDP Sugars and NDP Glucoses (pages 1963–1966)

      Jungdon Bae, Kwang-Ho Kim, Dooil Kim, Yongseok Choi, Joong Su Kim, Sukhoon Koh, Suk-In Hong and Dae-Sil Lee

      Article first published online: 4 OCT 2005 | DOI: 10.1002/cbic.200500183

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      Mix and match. Nucleotide sugars are essential as glycoside donors to glycosyltransferases for the synthesis of bioactive metabolites. With 45 combinations of reactions with five NTPs and nine sugar-1-phosphates (Su1Ps) by recombinant UDP-sugar pyrophosphorylase (UP) from Thermus caldophilus GK24, the enzyme showed broad substrate specificity toward five types of NTP with glucose-1-phosphate as well as four Su1Ps with UTP, affording all nine nucleotide sugars.

    9. Light-Induced Formation of G-Quadruplex DNA Secondary Structures (pages 1966–1970)

      Günter Mayer, Lenz Kröck, Vera Mikat, Marianne Engeser and Alexander Heckel

      Article first published online: 22 SEP 2005 | DOI: 10.1002/cbic.200500198

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      A little light release: Temporarily blocked (“caged”) dG nucleosides that can be incorporated into oligodeoxynucleotides are presented (see figure). Their hydrogen-bond-recognition site is inaccessible in the inactive form; this prevents, for example, the formation of secondary structures. Light can trigger the release of the unmodified oligonucleotide and thus induce correct folding.

    10. RNA Abasic Sites: Preparation and Trans-Lesion Synthesis by HIV-1 Reverse Transcriptase (pages 1970–1973)

      Pascal A. Küpfer and Christian J. Leumann

      Article first published online: 18 OCT 2005 | DOI: 10.1002/cbic.200500204

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      Abasic RNA and the “A-rule”. Abasic RNA was chemically synthesized by using a novel building block in which the anomeric center of the ribose unit was protected by the photocleavable R-1-(2-nitrophenyl)ethyl group. Upon reverse transcription of the abasic RNA template–DNA primer duplex, HIV-1 reverse transcriptase was found to preferentially incorporate a deoxyadenosine residue opposite the abasic site (see figure). This extends the A-rule to include abasic RNA.

    11. 3′-Enolpyruvyl-UMP, a Novel and Unexpected Metabolite in Nikkomycin Biosynthesis (pages 1974–1976)

      Cristian Ginj, Heinz Rüegger, Nikolaus Amrhein and Peter Macheroux

      Article first published online: 5 OCT 2005 | DOI: 10.1002/cbic.200500208

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      An unexpected turn. NikO, the putative enolpyruvyl transferase involved in the formation of the aminohexuronic acid moiety of nikkomycins catalyzes the formation of 3′-enolpyruvyl-UMP from UMP (see scheme). This finding contradicts the current model for the biosynthesis of aminohexuronic acid.

    12. Preparation of Cyclo-Phen-Type Ligands: Chelators of Metal Ions as Potential Therapeutic Agents in the Treatment of Neurodegenerative Diseases (pages 1976–1980)

      Christophe Boldron, Ingrid Van der Auwera, Céline Deraeve, Heinz Gornitzka, Stefaan Wera, Marguerite Pitié, Fred Van Leuven and Bernard Meunier

      Article first published online: 6 OCT 2005 | DOI: 10.1002/cbic.200500220

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      A promising strategy for the therapy of neurodegenerative diseases consists of the use of chelators. A new cyclic derivative, Cyclo-bi-Phen, was synthesized in one step and found to complex copper and zinc. When used in i.p. injection at 5 mg kg−1 three times per week on double-transgenic mice, this Cyclo-bi-Phen ligand (shown) was able to reduce in vivo Thioflavin-S-stainable amyloid plaques involved in the deleterious effects of the Alzheimer's disease.

    13. Aldolisation of Bis(glycolaldehyde) Phosphate and Formaldehyde (pages 1980–1982)

      James M. Smith and John D. Sutherland

      Article first published online: 19 SEP 2005 | DOI: 10.1002/cbic.200500267

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      Subtle aldolisation behaviour: An intermolecular aldol reaction between bis(glycolaldehyde) phosphate and formaldehyde does occur (see scheme), but subsequent oligomerisation to the pyranosyl-RNA backbone is not observed. Instead, intramolecular aldolisation is preferred, and tetrose- and pentose-2,4-cyclic phosphates are produced in good yield.

    14. Photolabile Protection for One-Pot Sequential Native Chemical Ligation (pages 1983–1986)

      Satoshi Ueda, Mizuno Fujita, Hirokazu Tamamura, Nobutaka Fujii and Akira Otaka

      Article first published online: 5 OCT 2005 | DOI: 10.1002/cbic.200500272

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      Newly developed phenacyl-type protection (Mapoc) for amines provides a facile and efficient synthetic protocol for peptides/proteins, in which sequential native chemical ligation (NCL) in the same reaction vessel can be conducted in a purification-free manner. A synthetic strategy of sequential NCL followed by oxidation with DMSO for disulfide-bond formation was successfully applied to the one-pot preparation of the human-brain natriuretic peptide (hBNP).

    15. Sunflower-Shaped Cyclodextrin-Conjugated Poly(ε-Lysine) Polyplex as a Controlled Intracellular Trafficking Device (pages 1986–1990)

      Hak Soo Choi, Atsushi Yamashita, Tooru Ooya, Nobuhiko Yui, Hidetaka Akita, Kentaro Kogure, Rie Ito and Hideyoshi Harashima

      Article first published online: 13 OCT 2005 | DOI: 10.1002/cbic.200500242

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      Lowering your cholesterol. Outward-facing β-cyclodextrins in a conjugated poly(ε-lysine) polyplex (see scheme) promote the removal of cholesterol from the cell membrane; this can induce local membrane disturbances and assist the transfer of pDNA into cells. Furthermore, we propose that the secondary amines of the polyplex promote a proton-sponge effect to significantly enhance transfection.

    16. Potent Inhibitors of LXXLL-Based Protein–Protein Interactions (pages 1991–1998)

      Amit K. Galande, Kelli S. Bramlett, John O. Trent, Thomas P. Burris, James L. Wittliff and Arno F. Spatola

      Article first published online: 13 OCT 2005 | DOI: 10.1002/cbic.200500083

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      Protein mimicry with unnatural amino acids. Neopentyl glycine, an unnatural amino acid, shows picomolar binding affinity when substituted in the NR box peptide that interacts with the estrogen receptor, shown in green. The neopentyl glycine residue forms noncovalent van der Waals contacts with the isoleucine residue within the peptide chain, inducing the preferential helical conformation for receptor association.

    17. Two Nucleophilic Mutants of the Micromonospora viridifaciens Sialidase Operate with Retention of Configuration by Two Different Mechanisms (pages 1999–2004)

      Jacqueline N. Watson, Simon Newstead, Arun A. Narine, Garry Taylor and Andrew J. Bennet

      Article first published online: 4 OCT 2005 | DOI: 10.1002/cbic.200500114

      Go your own way. The wild-type and three nucleophilic mutants of sialidase from Micromonospora viridifaciens are catalytically active enzymes. Interestingly, the two mutants reported here, which lead to retention of configuration, each react by a different mechanism. Furthermore, these mechanisms are different from that of the wild-type and a previously reported inverting mutant.

    18. Synthesis and Biological Evaluation of Novel Eg5 Inhibitors (pages 2005–2013)

      Vasiliki Sarli, Stefan Huemmer, Nils Sunder-Plassmann, Thomas U. Mayer and Athanassios Giannis

      Article first published online: 10 OCT 2005 | DOI: 10.1002/cbic.200500168

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      Disorganising the mitotic spindle. This paper describes the design and synthesis of new antimitotics that target kinesin Eg5. We have investigated the biological properties of 3,4-dihydrophenylquinazoline-2(1H)-thione-type of compounds and identified VS-83 as a potent and selective Eg5 inhibitor.

    19. Recombinant Production of Human Microsomal Cytochrome P450 2D6 in the Methylotrophic Yeast Pichia pastoris (pages 2014–2022)

      Matthias Dietrich, Lisa Grundmann, Katja Kurr, Laura Valinotto, Tanja Saussele, Rolf D. Schmid and Stefan Lange

      Article first published online: 13 OCT 2005 | DOI: 10.1002/cbic.200500200

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      Metabolites of drugs and other xenobiotics generated by cytochrome P450-catalysed phase 1 reactions in the liver are often decisive in determining the success or failure of novel drug candidates. The methylotrophic yeast Pichia pastoris is able to produce active human cytochrome P450 2D6 by coexpression with NADPH P450 oxidoreductase (see vector map). It thus allows the generation of kinetic data to be used in the systems biology of hepatocytes, as well as the production of metabolites by biotransformation.

    20. Biosynthesis and Identification of Volatiles Released by the Myxobacterium Stigmatella aurantiaca (pages 2023–2033)

      Jeroen S. Dickschat, Helge B. Bode, Silke C. Wenzel, Rolf Müller and Stefan Schulz

      Article first published online: 6 OCT 2005 | DOI: 10.1002/cbic.200500174

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      Ketone construction kit: Agar plate cultures of two strains of the myxobacterium Stigmatella aurantiaca emit a bouquet of more than 80 odor compounds from different substance classes. The biosynthesis of ketones was investigated in feeding experiments with labeled precursors. An unusual head-to-head coupling of several acyl-CoA starter units and fatty acyl-CoA precursors is the key step in a new pathway to a structurally diverse array of ketones.

    21. Titanium Implant Materials with Improved Biocompatibility through Coating with Phosphonate-Anchored Cyclic RGD Peptides (pages 2034–2040)

      Jörg Auernheimer, Daniel Zukowski, Claudia Dahmen, Martin Kantlehner, Anja Enderle, Simon L. Goodman and Horst Kessler

      Article first published online: 4 OCT 2005 | DOI: 10.1002/cbic.200500031

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      Giving cells some stick. Osteoblast adhesion to titanium, which is a common material for implants, was stimulated by coating the titanium with an optimized and highly specific RGD ligand for the αvβ3 integrin. The ligands were immobilized directly onto the metal surface with a branched phosphonate anchor; the structure shows the cyclic RGD peptide with these anchors.

    22. Stochasticity of Manganese Superoxide Dismutase mRNA Expression in Breast Carcinoma Cells by Molecular Beacon Imaging (pages 2041–2047)

      Timothy J. Drake, Colin D. Medley, Arup Sen, Richard J. Rogers and Weihong Tan

      Article first published online: 4 OCT 2005 | DOI: 10.1002/cbic.200500046

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      A distinct change in patterns following induction of manganese superoxide dismutase (MnSOD) in human breast-carcinoma cells is revealed when using ratiometric imaging with molecular beacons (see graphs); this allows for the visual and quantitative monitoring of cell-to-cell variations. Interestingly, the pattern of cell-to-cell variation in a cell line stably transfected with a plasmid bearing a cDNA clone of MnSOD and overproducing the enzyme is significantly different from the pattern associated with MnSOD induction.

    23. Enantiomeric 1,2,4-Trioxanes Display Equivalent in vitro Antimalarial Activity Versus Plasmodium falciparum Malaria Parasites: Implications for the Molecular Mechanism of Action of the Artemisinins (pages 2048–2054)

      Paul M. O’Neill, Sarah L. Rawe, Kristina Borstnik, Alison Miller, Stephen A. Ward, Patrick G. Bray, Jill Davies, Chang Ho Oh and Gary H. Posner

      Article first published online: 13 OCT 2005 | DOI: 10.1002/cbic.200500048

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      Working in stereo: Enantiomeric 1,2,4-trioxane analogues (+)-7 a, (−)-7 a and (+)-7 b, (−)-7 b (illustrated in the scheme) show equivalent in vitro activities against different strains of the malaria parasite, Plasmodium falciparum. These results indicate a lack of chiral recognition at the intraparasitic site(s) of drug action.

    24. Investigation of the Mechanism of Resistance to Third-Generation Cephalosporins by Class C β-Lactamases by Using Chemical Complementation (pages 2055–2067)

      Brian T. Carter, Hening Lin, Shalom D. Goldberg, Eric A. Althoff, Jessica Raushel and Virginia W. Cornish

      Article first published online: 26 OCT 2005 | DOI: 10.1002/cbic.200500058

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      Complementing antibiotics: Chemical complementation provides a general method to study enzyme reactions involving both bond cleavage and formation in vivo (see schematic representation; E=enzyme). Here the chemical complementation system has been used in a high-throughput application to study how class C β-lactamases gain resistance to the third-generation cephalosporin cefotaxime.

    25. Synthesis, Characterization and Biological Activity of trans-Platinum(II) and trans-Platinum(IV) Complexes with 4-Hydroxymethylpyridine (pages 2068–2077)

      Alberto Martínez, Julia Lorenzo, Maria J. Prieto, Rafael de Llorens, Mercè Font-Bardia, Xavier Solans, Francesc X. Avilés and Virtudes Moreno

      Article first published online: 13 OCT 2005 | DOI: 10.1002/cbic.200500108

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      Don't discounttrans. Two new trans platinum complexes, trans-[PtCl2NH3(4-hydroxymethylpyridine)] (1) and trans-[PtCl4NH3(4-hydroxymethylpyridine)] (2) are described, and their cytotoxicities are compared with that of cisplatin. The water-soluble complex 1 presents an interesting antiproliferative behavior against HL-60 tumor cell lines, inducing apoptotic death (see graph).

    26. Synthesis of N-Heteroaryl Retinals and their Artificial Bacteriorhodopsins (pages 2078–2087)

      Susana López, Virginia Rodríguez, Javier Montenegro, Carlos Saá, Rosana Alvarez, Carlos Silva López, Angel R. de Lera, Rosana Simón, Tzvetana Lazarova and Esteve Padrós

      Article first published online: 18 OCT 2005 | DOI: 10.1002/cbic.200500148

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      New rhodopsin analogues. The first artificial bacteriorhodopsins derived from heteroaryl (indolyl, 1- and 3-indolizinyl) trienyl retinals are reported; they display pKa values significantly different from those of the wild-type pigment, presumably due to nonoptimal binding-site occupancy by the chromophores. Although unstable, the regioisomeric indolizinyl analogues form noticeably red-shifted artificial pigments, of interest for bioelectronic applications.

    27. Synthesis and Proinflammatory Properties of Muramyl Tripeptides Containing Lysine and Diaminopimelic Acid Moieties (pages 2088–2097)

      Abhijit Roychowdhury, Margreet A. Wolfert and Geert-Jan Boons

      Article first published online: 13 OCT 2005 | DOI: 10.1002/cbic.200500181

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      Novel muropeptide analogues: The synthesis of muramyl tripeptides (1) containing either Gram-negative Dap or Gram-positive Lys units at R2 is described, and the ability of these compounds to induce TNF-α mRNA and protein production in a human monocytic cell line has been investigated.

    28. As Fast and Selective as Enzymatic Ligations: Unpaired Nucleobases Increase the Selectivity of DNA-Controlled Native Chemical PNA Ligation (pages 2098–2103)

      Simon Ficht, Christian Dose and Oliver Seitz

      Article first published online: 6 OCT 2005 | DOI: 10.1002/cbic.200500229

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      The ligation architecture holds the key. The fidelity of “conventional” nick-ligation systems can be increased by more than one order of magnitude when an abasic site is allowed to form (see scheme). Rates and selectivity are as high as in the best performing enzymatic single-base mutation assays. Native chemical PNA ligation might therefore offer a true alternative to enzymatic strategies.

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      Preview: ChemBioChem 11/2005 (page 2110)

      Article first published online: 26 OCT 2005 | DOI: 10.1002/cbic.200590038