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Chembiochem: a European Journal of Chemical Biology

Robert Thomas
The reported acetate-derived labelling of the fungal naphthalene γ-pyrone fonsecin, two streptomycete dodecaketide αpyrones TW93f and TW93g, and the streptomycete phenanthraquinones piloquinone, murayaquinone and haloquinone appear to be exceptions to the generalisation that fungi and streptomycetes produce fused-ring aromatic polyketides by different modes of cyclisation. A review of their 1) originally assigned formulae, 2) [(13) C2 ]acetate-derived labelling patterns, and 3) modes of cyclisation leads to the recognition of feasible alternative chemical structures or biosynthetic pathways, which are in accord with the originally proposed classification system...
October 18, 2016: Chembiochem: a European Journal of Chemical Biology
Alex Maolanon, Helle Kristensen, Luke Leman, Reza Ghadiri, Christian Adam Olsen
Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration (FDA) in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme-selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen...
October 17, 2016: Chembiochem: a European Journal of Chemical Biology
Tadao Takada, Misa Ido, Akane Ashida, Mitsunobu Nakamura, Kazushige Yamana
DNA is considered to be a promising biomolecule as a template and scaffold for arranging and organizing functional molecules on the nanoscale. The construction and evaluation of DNAs containing multiple functional molecules that are useful for optoelectronic devices and sensors has been studied. In this paper we report the efficient incorporation of perylenediimide (PDI) units into DNA by using abasic sites both as binding sites and as reactive sites and the construction of PDI stacks within the DNA structure, accomplished through the preorganization of the PDI units in the hydrophobic pocket within the DNA...
October 14, 2016: Chembiochem: a European Journal of Chemical Biology
Andrew G Palmer, Arijit Mukherjee, Danielle M Stacy, Stephen Lazar, Jean-Michel Ané, Helen E Blackwell
Density-dependent phenotypic switching in bacteria, the phenomenon of quorum sensing (QS), is instrumental in many pathogenic and mutualistic behaviors. In many Gram-negative bacteria, QS is regulated by N-acylated-l-homoserine lactones (AHLs). Synthetic analogues of these AHLs hold significant promise for regulating QS at the host-symbiont interface. Regulation depends on refined temporal and spatial models of quorums under native conditions. Critical to this is an understanding of how the presence of these signals may affect a prospective host...
October 14, 2016: Chembiochem: a European Journal of Chemical Biology
Sibongile Mafu, Emil Fischer, Bennett Addisson, Isabel Riberio Barbosana, Philipp Zerbe
Diterpenes form a vast and diverse class of natural products that is of both ecological and economic importance. The family of class II diterpene synthase (diTPS) enzymes controls the committed biosynthetic reactions underlying diterpene chemical diversity. Integrating homology modelling and site-directed mutagenesis in the horehound (Marrubium vulgare) class II diTPS peregrinol diphosphate synthase (MvCPS1) identified two active site residues, select substitutions of which abolished the unique MvCPS1-catalyzed water capture reaction at C9 and redirected enzyme activity toward formation of an alternate product verified as halima-5(10),13-dienyl diphosphate...
October 13, 2016: Chembiochem: a European Journal of Chemical Biology
Andy Beier, Sven Bordewick, Maika Genz, Sandy Schmidt, Tom Van Den Bergh, Christin Peters, Henk-Jan Joosten, Uwe Bornscheuer
Baeyer-Villiger monooxygenases (BVMOs) catalyze the oxidation of ketones to esters or lactones by utilizing molecular oxygen and a cofactor. Type I BVMOs display a strong preference for NADPH. However, for industrial purposes NADH is the preferred cofactor, as it is ten times cheaper and more stable. Thus, we created a variant of the cyclohexanone monooxygenase from Acinetobacter sp. NCIMB 9871 (CHMOAcineto), which utilizes NADH 4,200-fold better than NADPH. By combining structure analysis, sequence alignments and literature data, 21 residues in proximity of the cofactor were identified and targeted for mutagenesis...
October 13, 2016: Chembiochem: a European Journal of Chemical Biology
Rachel Anne Valenzuela, Kazumitsu Onizuka, Alexi Ball-Jones, Tiannan Hu, Scott Ryan Suter, Peter A Beal
Short interfering RNA (siRNA)-triggered gene knockdown via the RNA interference (RNAi) pathway is widely used to study gene function and siRNA-based therapeutics are in development.However, since the guide strand of an siRNA can function like a natural microRNA (miRNA), siRNAs often repress hundreds of off-target transcripts with complementary only to the seed region (nucleotides 2-8) of the guide strand. Here we describe novel guide strand 3' end modifications derived from 1-ethynylribose and copper-catalyzed azide/alkyne cycloaddition reactions and evaluate their impact on target vs miRNA-like off-target knockdown...
October 12, 2016: Chembiochem: a European Journal of Chemical Biology
Inge Leonie Van 't Veer, Nadia Leloup, Alexander Egan, Bert Janssen, Nathaniel Martin, Waldemar Vollmer, Eefjan Breukink
Surface Plasmon Resonance (SPR) is one of the most powerful label free methods to determine kinetic parameters of molecular interactions in real time and in a high sensitive way. Penicillin binding proteins (PBPs) are peptidoglycan synthesis enzymes present in most bacteria. The established protocols to analyze interactions of PBPs by SPR involves immobilization to an ampicillin coated chip surface, a β-lactam antibiotic mimicking its substrate, forming a covalent complex with the PBPs transpeptidase (TP) active site...
October 6, 2016: Chembiochem: a European Journal of Chemical Biology
Anibal Cuetos, Fabian Steffen-Munsberg, Juan Mangas Sanchez, Amina Frese, Uwe T Bornscheuer, Matthias Höhne, Gideon Grogan
PLP-dependent enzymes catalyze a remarkable diversity of chemical reactions in Nature. A1RDF1 from Arthrobacter aurescens TC1 is a Fold Type I, PLP-dependent enzyme in the Class III transaminase (TA) subgroup. Despite sharing 28% sequence identity with its closest structural homologs, including β-alanine:pyruvate and γ-amino butyrate:α-ketoglutarate TAs, A1RDF1 displayed no TA activity. Activity screening revealed the enzyme to possess phospholyase (E.C. activity towards O-phosphoethanolamine (PEtN), an activity described previously for vertebrate enzymes such as human AGXT2L1, and for which no structure has yet been reported...
October 6, 2016: Chembiochem: a European Journal of Chemical Biology
Fabien B L Cougnon
A new symmetry-based approach allowed the self-assembly of an octahedral protein nanostructure. This work may provide the basis for a more general and flexible strategy to control protein self-assembly.
October 4, 2016: Chembiochem: a European Journal of Chemical Biology
Santosh Lakshmi Gande, Krishna Saxena, Sridhar Sreeramulu, Verena Linhard, Denis Kudlinzki, Stephanie Heinzlmeir, Andreas J Reichert, Arne Skerra, Bernhard Kuster, Harald Schwalbe
The receptor tyrosine kinase EPHA2 is overexpressed in several cancer entities (breast, head and neck, non-small cell lung cancer). Small molecule-based inhibition of the activity of the EPHA2 kinase domain (KD) has been seen as an important strategy for achieving therapeutic intervention. However, obtaining structural information by protein crystallography or by NMR spectroscopy aiding drug discovery, has been severely hampered due to the lack of pure and homogeneous protein. Here different fragments of the EPHA2 KD were expressed and purified from both bacterial (Escherichia coli BL21 (DE3) cells) and insect cells (Spodoptera frugiperda, Sf9 cells)...
September 29, 2016: Chembiochem: a European Journal of Chemical Biology
Emma V Ainsworth, Colin Wj Lockwood, Gaye F White, Ee Taek Hwang, Tsubasa Sakai, Manuela A Gross, David J Richardson, Thomas A Clarke, Lars Jc Jeuken, Erwin Reisner, Julea N Butt
The transfer of photoenergized electrons from extracellular photosensitizers across a bacterial cell envelope to drive intracellular chemical transformations represents an attractive way to harness Nature's catalytic machinery for solar to chemicals conversion. In Shewanella oneidensis MR-1 (MR-1) trans-outermembrane electron transfer is performed by the extracellular cytochromes MtrC and OmcA acting together with the outermembrane spanning porin:cytochrome complex (MtrAB). Here we demonstrate photoreduction of solutions of MtrC, OmcA and the MtrCAB complex by soluble photosensitizers, namely, eosin Y, fluorescein, proflavine, flavin adenine dinucleotide and two compounds secreted by MR-1, riboflavin and flavin mononucleotide...
September 29, 2016: Chembiochem: a European Journal of Chemical Biology
Jérémy Ruiz, Régis Boehringer, Marcel Grogg, Jésus Raya, Alicia Schirer, Corinne Crucifix, Petra Hellwig, Patrick Schultz, Vladimir Torbeev
Polymorphism is a common property of amyloid fibers that complicates their detailed structural and functional studies. Here we report experiments illustrating the chemical principles that enable the formation of amyloid polymorphs with distinct stoichiometric composition. Using appropriate covalent tethering we programmed self-assembly of a model peptide corresponding to the [20-41]-fragment of human β2-microglobulin into fibers with either trimeric or dimeric amyloid cores. Using a set of biophysical and biochemical methods we demonstrated their distinct structural, morphological and templating properties...
September 26, 2016: Chembiochem: a European Journal of Chemical Biology
Lindsay E Guzman, Flora W Kimani, John C Jewett
Recent work on triazabutadienes has shown that they possess the ability to release aryl diazonium ions under exceptionally mild acidic conditions. There are instances that require that this release be prevented or minimized. Accordingly, a base-labile protection strategy for the triazabutadiene is presented allowing for enhanced synthetic and practical utility of the triazabutadiene. Herein the effects of steric and electronic factors in the rate of removal are discussed. Finally, the triazabutadiene protection is shown to be compatible with the traditional acid-labile protection strategy used in solid phase peptide synthesis...
September 23, 2016: Chembiochem: a European Journal of Chemical Biology
Zahra Mashhadi, Marcia E Newcomer, Alan R Brash
This review focuses on a group of heme peroxidases that retain the catalase fold in structure, yet show little or no reaction with hydrogen peroxide. Instead of having a role in oxidative defense, these enzymes are involved in secondary metabolite biosynthesis. The prototypical enzyme is catalase-related allene oxide synthase, an enzyme that converts a specific fatty acid hydroperoxide to the corresponding allene oxide (epoxide). Other catalase-related enzymes form allylic epoxides, aldehydes, or a bicyclobutane fatty acid...
September 22, 2016: Chembiochem: a European Journal of Chemical Biology
Yun Shi, Cinzia Colombo, Jijin Ra Kuttiyatveetil, Nataliya Zalatar, Karin E Van Sraaten, Sankar Mohan, David Ar Sanders, B Mario Pinto
UDP-galactopyranose mutase (UGM), a key enzyme in the biosynthesis of mycobacterial cell walls, is a potential target for the treatment of tuberculosis.In this work, we investigate binding models of a non-substrate-like inhibitor, MS-208, with M. tuberculosis UGM.Initial saturation transfer difference NMR experiments indicate lack of direct competition between MS-208 and the enzyme substrate, and subsequent kinetic assays show mixed inhibition. We thus hypothesized that MS-208 binds at an allosteric binding site instead of the enzyme active site (S-site)...
September 21, 2016: Chembiochem: a European Journal of Chemical Biology
Greg Mann, Liujie Huo, Sebastian Adam, Brunello Nardone, Jeremie Vendome, Nicholas James Westwood, Rolf Müller, Jesko Koehnke
The bottromycins are a family of highly modified peptide natural products displaying potent antimicrobial activity against Gram-positive bacteria including methicillin-resistant Staphyloccoccus aureus. Bottromycins have recently been shown to be ribosomally synthesized and post-translationally modified peptides (RiPPs). Uniquely amongst RiPPs the precursor peptide BotA contains a C-terminal follower, rather than the canonical N- terminal leader sequence. We report the structural and biochemical characterization of BotP, a leucyl-aminopeptidase like enzyme from the bottromycin pathway...
September 21, 2016: Chembiochem: a European Journal of Chemical Biology
Stephanie M Jensen, Flora W Kimani, John C Jewett
Chemical crosslinking is a versatile tool for the examination of biochemical interactions, in particular host-pathogen interactions. Herein we report the use of a new heterobifunctional crosslinker with a triazabutadiene scaffold. This compound is stable to protein conjugation and liberates a reactive aryl diazonium species upon irradiation with 350 nm light. We highlight the use of this technology by decorating the surface of dengue virus with this uniquely reactive chemical warhead.
September 20, 2016: Chembiochem: a European Journal of Chemical Biology
Yiyan Wang, Meng-Lin Tsao
A new method has been developed to reassign the rare codon AGA in Escherichia coli by engineering an orthogonal tRNA/aminoacyl-tRNA synthetase pair derived from Methanocaldococcus jannaschii. The tRNA mutant was introduced with a UCU anticodon, and the synthetase was evolved to correctly recognize the modified tRNA anticodon loop and to selectively charge a target noncanonical amino acid (NAA) onto the tRNA. In order to maximize the efficiency of AGA codon reassignment, while avoiding the lethal effects caused by global codon reassignment in cellular proteins, an inducible promoter (araBAD) was utilized to provide temporal controls for overexpression of the aminoacyl-tRNA synthetase and switch on codon reassignment...
September 20, 2016: Chembiochem: a European Journal of Chemical Biology
Gregory D Mc Cluskey, Samy Mohamady, Scott D Taylor, Stephen L Bearne
CTP synthase (CTPS) catalyzes the conversion of UTP to CTP and is a target for the development of antiviral, anticancer, antiprotozoal, and immunosuppressive agents.Inhibition by the antineoplastic cytidine analogue gemcitabine causes depletion of intracellular CTP levels, but the direct inhibition of CTPS by its metabolite gemcitabine-5'-triphosphate (dF-dCTP) has not been demonstrated.We show that dF-dCTP is a potent competitive inhibitor of Escherichia coli CTPS with respect to UTP (Ki = 3.0 ± 0.1 µM), and its binding affinity exceeds that of CTP by ~75-fold...
September 19, 2016: Chembiochem: a European Journal of Chemical Biology
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