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Chembiochem: a European Journal of Chemical Biology

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https://www.readbyqxmd.com/read/28340291/-head-to-head-prenyl-synthases-in-some-pathogenic-bacteria
#1
Christopher J Schwalen, Xinxin Feng, Weidong Liu, Bing O-Dowd, Tzu-Ping Ko, Christopher J Shin, Rey-Ting Guo, Douglas A Mitchell, Eric Oldfield
Many organisms contain "head-to-head" isoprenoid synthases and here, we investigate three types of such enzymes from the pathogens Neisseria meningitidis, N. gonorrhoeae, and Enterococcus hirae. The E. hirae enzyme was found to produce dehydrosqualene and we solved an inhibitor-bound structure which revealed a fold similar to that of CrtM from Staphylococcus aureus. In contrast, the homologous proteins from Neisseria spp. carried out only the "first half" reaction, yielding presqualene diphosphate (PSPP). Based on product analyses, bioinformatics, and mutagenesis we conclude that the Neisseria proteins are HpnDs (PSPP synthases)...
March 24, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28334484/amine-transaminase-engineering-for-spatially-bulky-substrate-acceptance
#2
Uwe Bornscheuer, Martin S Weiß, Ioannis V Pavlidis, Paul Spur, Steven P Hanlon, Beat Wirz, Hans Iding
Amine transaminase (ATA) catalysing stereoselective amination of prochiral ketones is an attractive alternative to transition metal catalysis. As wild-type ATAs accept only non-sterically hindered ketones, efforts to widen the substrate scope to more challenging targets are of general interest. We recently designed ATAs to accept aromatic and thus planar bulky amines, via a sequenced based motif that supports the identification of novel enzymes. However, these variants were not active against 2,2-dimethyl-1-phenyl-propan-1-one, which carries a spatially bulky tert-butyl substituent adjacent to the carbonyl function...
March 23, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28318088/twenty-five-years-of-dna-encoded-chemical-libraries
#3
EDITORIAL
Dario Neri
Reference library: The availability of DNA-encoded chemical libraries containing billions of compounds facilitates the discovery of binding molecules for pharmaceutical applications and for investigating biological processes. This Special Issue highlights the use of this library technology and some of the latest developments in the field.
March 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28318083/dienophile-modified-mannosamine-derivatives-for-metabolic-labeling-of-sialic-acids-a-comparative-study
#4
Jeremias E G A Dold, Jessica Pfotzer, Anne-Katrin Späte, Valentin Wittmann
Sialic acids play an important role in numerous cell adhesion processes and sialylation levels are known to be altered under certain pathogenic conditions such as cancer. Metabolic glycoengineering with mannosamine derivatives is a convenient way to introduce non-natural chemical reporter groups into sialylated glycoconjugates offering the opportunity to label sialic acids using bioorthogonal ligation chemistry. The labeling intensity not only depends on the rate of the ligation reaction but also on the extent to which the natural sialic acids are replaced by the modified ones, i...
March 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28318079/design-and-synthesis-of-galactosylated-bifurcated-ligands-with-nanomolar-affinity-for-lectin-leca-from-pseudomonas-aeruginosa
#5
Anthony Angeli, Muchen Li, Lucie Dupin, Gerard Vergoten, Mathieu Noel, Mimouna Madaoui, Shuai Wang, Albert Meyer, Thomas Gehin, Sebastien Vidal, Jean-Jacques Vasseur, Yann Chevolot, Francois Morvan
Lectin LecA of Pseudomonas aeruginosa is established as a virulent factor. Glycoclusters targeting LecA able to compete with human glycoconjugates present on epithelial cells are promising candidates to treat P. aeruginosa infection. A family of 32 glycodendrimers of generation 0 and 1 displaying bifurcated bis-galactosides has been designed to interact with LecA. The influence of both the central multivalent core and the aglycon of these glycodendrimers on their affinity toward LecA has been evaluated using a microarray technology both qualitatively for a rapid screening of the binding properties but also quantitatively (Kd) leading to high affinity LecA ligands with Kd values in the low nanomolar range (Kd = 22 nM for the best one)...
March 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28301711/conjugation-of-a-dipicolyl-chelate-to-polypeptide-conjugates-increases-binding-affinities-for-human-serum-albumin-and-survival-times-in-human-serum
#6
Aleksandra Balliu, Lars Baltzer
The affinity for human serum albumin (HSA) of a series of 2-5 kDa peptides covalently linked to 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid, a dipicolyl chelator with μM affinity for Zn2+, was found by surface plasmon resonance to increase in the presence of 1μM ZnCl2 at physiological pH. The dependence on polypeptide hydrophobicity was found to be minor, suggesting that the conjugates bound to the metal binding site and not to the fatty acid binding site. The affinity of the conjugates increased strongly with the positive charge of the polypeptides suggesting proximity to the negatively charged protein surface surrounding the metal binding site...
March 16, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28297127/a-biocatalytic-nanomaterial-for-the-label-free-detection-of-virus-like-particles
#7
Sabine Sykora, M Rita Correro, Negar Moridi, Gael Belliot, Pierre Pothier, Yves Dudal, Philippe Corvini, Patrick Shahgaldian
The design of nanomaterials that are capable of specific and sensitive biomolecular recognition is an on-going challenge in chemical and biochemical sciences. A number of sophisticated artificial systems have been designed to specifically recognize a variety of targets. However, methods based on natural biomolecular detection systems using antibodies are often superior. Besides greater affinity and selectivity, antibodies can be easily coupled to enzymatic systems that act as signal amplifiers, permitting tremendously low detection limits...
March 15, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28295942/gangliosides-structure-biosynthesis-analysis-and-roles-in-cancer
#8
Sophie Groux-Degroote, Yann Guérardel, Philippe Delannoy
Gangliosides are acidic glycosphingolipids containing one or more sialic acid residues. They are essential compounds at the outer leaflet of the plasma membrane where they interact with phospholipids, cholesterol and transmembrane proteins, forming lipid rafts. They are involved in cell adhesion, proliferation and recognition processes, as well as in the modulation of signal transduction pathways. These functions are mainly supported by the glycan moiety and changes in the structure of gangliosides occur under pathological conditions, particularly in neuro-ectoderm-derived cancers...
March 15, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28296179/the-5-ag%C3%A2-cc-3-fragment-from-the-human-cpeb3-ribozyme-forms-an-ultrastable-parallel-rna-g-quadruplex
#9
Katharina Kulikov, Senada Nozinovic, Stephanie Kath-Schorr
An unusually thermostable G-quadruplex is formed by a sequence fragment of a naturally occurring ribozyme, the human CPEB3 ribozyme. Strong evidence is provided for the formation of a uniquely stable intermolecular G-quadruplex structure consisting of five tetrad layers using CD-spectroscopy, UV-melting curves, two-dimensional NMR spectroscopy and gel shift analysis. The cationic porphyrin TMPyP4 destabilizes the complex.
March 13, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28295904/a-fungal-n-dimethylallyltryptophan-metabolite-from-fusarium-fujikuroi
#10
Birgit Arndt, Slavica Janevska, Robin Schmid, Florian Hübner, Bettina Tudzynski, Hans-Ulrich Humpf
The range of secondary metabolites (SMs) produced by the rice pathogen Fusarium fujikuroi is quite broad. Several polyketides, nonribosomal peptides and terpenes have been identified. However, no products of dimethylallyltryptophan synthases (DMATSs) have been elucidated so far, though two putative DMATS genes are present in the F. fujikuroi genome. In this study, the product derived from one of the two DMATSs, DMATS1 (FFUJ_09179), has been identified in vivo with the help of the software MZmine 2. Detailed structure elucidation showed that this metabolite is a reversely N-prenylated tryptophan, depicting a rather rare form of prenylation...
March 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28281333/discovering-drugs-with-dna-encoded-library-technology-from-concept-to-clinic-with-an-inhibitor-of-soluble-epoxide-hydrolase
#11
Svetlana Belyanskaya, Yun Ding, James Callahan, Aili Lazaar, David Israel
DNA encoded chemical library technology was developed with the vision of becoming a transformational platform for drug discovery. The hope was that a new screening paradigm for low molecular weight drugs would be enabled by combining the vast molecular diversity achievable with combinatorial chemistry, the information encoding attributes of DNA, the power of molecular biology and a streamlined selection-based discovery process. We describe the discovery and early clinical development of GSK2256294, an inhibitor of the enzyme soluble epoxide hydrolase (sEH, EPHX2) using Encoded Library Technology (ELT)...
March 9, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28266777/exploiting-sp2-hybridization-in-the-development-of-potent-1-5-a-l-arabinanase-inhibitors
#12
Travis Coyle, Aleksandra Debowski, Annabelle Varrot, Keith A Stubbs
The synthesis of potent inhibitors of GH93 arabinanases as well as a synthesis of a chromogenic substrate to measure GH93 arabinanase activity is described. An insight into the reasons behind the potency of the inhibitors was gained through X-ray crystallographic analysis using the arabinanase Arb93A from Fusarium graminearum. These compounds lay a foundation for future inhibitor development as well as for the use of the chromogenic substrate in biochemical studies of GH93 arabinanases.
March 7, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28258600/enlightening-the-role-of-subdomains-in-the-catalytic-behavior-of-lipases-acyltransferases-homologous-to-cplip2-through-rational-design-of-chimeric-enzymes
#13
Anne-Hélène Jan, Eric Dubreucq, Maeva Subileau
The lipases/acyltransferases homologous to CpLIP2 of Candida parapsilosis catalyze efficiently acyltransfer reactions in lipid/water media with high water activity (aW > 0.9). The characterization of two new enzymes of this family, CduLAc from Candida dubliniensis and CalLAc8 from Candida albicans, was performed. Despite their 82% identity, these 2 enzymes have significant differences in their catalytic behavior. To understand the role played by the different subdomains of these proteins (the main core, the cap and the C-term flap), chimeric enzymes were designed with rational exchanges of cap and C-term flap, between CduLAc and CalLAc8...
March 4, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28256791/conformational-behaviour-of-mannuronic-acid-based-azasugars
#14
Erwin van Rijssel, Antonius Janssen, Alexandra Males, Gideon Davies, Gijsbert van der Marel, Hermen S Overkleeft, Jeroen Codée
A set of mannuronic acid based iminosugars, comprising the C-5-carboxylic acid, -methyl ester and -amide analogues of 1-deoxymannorjirimicin (DMJ), was synthesized and their pH dependent conformational behavior studied. Under acidic conditions the methyl ester and the carboxylic acid took up an "inverted" 1C4 chair conformation as opposed to the "normal" 4C1 chair at basic pH. This conformational change is explained by the stereoelectronic effects of the ring substituents and it parallels the behavior of the mannuronic acid ester oxocarbenium ion...
March 3, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28256109/protein-nmr-studies-of-substrate-binding-to-human-blood-group-a-and-b-glycosyltransferases
#15
Thomas Peters, Lena Lisbeth Grimm, Sophie Weissbach, Friedemann Flügge, Nora Begemann, Monica Palcic
Donor and acceptor substrate binding to human blood group A and B glycosyltransferases (GTA, GTB) has been studied by a variety of protein NMR experiments. Prior crystallographic studies have shown these enzymes to adopt an open conformation in the absence of substrates. Binding of either the donor substrate UDP-Gal, or of UDP induces a semi-closed conformation. In the presence of both, donor- and acceptor substrates, the enzymes shift towards a closed conformation with ordering of an internal loop and the C-terminal residues, which then completely cover the donor-binding pocket...
March 3, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28253432/spectroscopic-and-computational-investigations-of-ligand-binding-to-isph-discovery-of-non-diphosphate-inhibitors
#16
Bing O'Dowd, Sarah Williams, Hongxin Wang, Joo Hwan No, Guodong Rao, Weixue Wang, J Andrew McCammon, Stephen P Cramer, Eric Oldfield
Isoprenoid biosynthesis is an important area for anti-infective drug development and one target is IspH, (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase, which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H+/2e- reduction. IspH contains a 4Fe-4S cluster and here, we first investigated how small molecules can bind to the cluster using HYSCORE and NRVS spectroscopies. The results of these as well as other structural and spectroscopic investigations led to the conclusion that in most cases, ligands bind to IspH 4Fe-4S clusters via 1 coordination, forming tetrahedral geometries at the unique 4th Fe, ligand side-chains preventing further ligand (e...
March 2, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28249101/azido-pentoses-a-new-tool-to-efficiently-label-mycobacterium-tuberculosis-clinical-isolates
#17
Katharina Kolbe, Leonhard Möckl, Victoria Sohst, Julius Brandenburg, Regina Engel, Sven Malm, Christoph Bräuchle, Otto Holst, Thisbe K Lindhorst, Norbert Reiling
Mycobacterium tuberculosis (Mtb), the main causative agent of tuberculosis (Tb), has a complex cell envelope which forms an efficient barrier to antibiotic stress, contributing to the obstacles of anti-tuberculosis therapy. However, the uniqueness of the Mtb cell wall can be considered an advantage and be utilized to selectively label Mtb bacteria. Here we introduce three azido pentoses, 3 azido arabinose (3AraAz), 3-azido ribose (3RiboAz) and 5-azido arabinofuranose (5AraAz), as new compounds for metabolic labeling of Mtb...
March 1, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28240414/tetrahydroisoquinolines-are-novel-inhibitors-of-neutrophil-extracellular-trap-net-formation
#18
Herbert Waldmann, Nancy E Martinez, Tobias J Zimmermann, Christian Goosmann, Tobias Alexander, Christian Hedberg, Slava Ziegler, Arturo Zychlinsky
Neutrophils are short-lived leukocytes that migrate to sites of infection as part of the acute immune response where they phagocytose, degranulate and form Neutrophil Extracellular Traps (NETs). During NET formation, the nuclear lobules of neutrophils disappear, the chromatin expands and, accessorized with neutrophilic granule proteins, is expelled. NETs can be pathogenic, for example in sepsis, cancer, autoimmune and cardiovascular diseases. Therefore, the identification of NET formation inhibitors is of high interest...
February 27, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28236354/synthetic-biomarker-design-using-analyte-responsive-acetaminophen
#19
Tatsuya Nishihara, Joe Inoue, Sho Tabata, Shinnosuke Murakami, Takamasa Ishikawa, Natsumi Saito, Shinji Fukuda, Masaru Tomita, Tomoyoshi Soga
The use of synthetic biomarkers is an emerging technique to improve disease diagnosis. Here, we report a novel design strategy using analyte-responsive acetaminophen (APAP) to expand the catalog of analytes available for synthetic biomarker development. As a proof-of-concept, we designed hydrogen peroxide (H₂O₂)-responsive APAP (HR-APAP) and succeeded in H₂O₂ detection with cellular and animal experiments. In fact, using blood samples following HR-APAP injection, we demonstrated that the plasma concentration ratio of [APAP + APAP conjugates]/[HR-APAP] could accurately represent differences of in vivo H₂O₂ levels...
February 25, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28233412/a-qcm-d-and-saxs-study-of-the-interaction-of-functionalised-lyotropic-liquid-crystalline-lipid-nanoparticles-with-sirna
#20
Behnoosh Tajik-Ahmadabad, Adam Mechler, Benjamin W Muir, Keith McLean, Tracey M Hinton, Frances Separovic, Anastasios Polyzos
Biophysical studies were undertaken to investigate the binding and release of short interfering ribonucleic acid (siRNA) from lyotropic liquid crystalline lipid nanoparticles (LNPs) using a quartz crystal microbalance (QCM). These carriers are based on phytantriol (Phy) and a cationic lipid, DOTAP (1, 2-dioleoyl-3 trimethylammonium propane). The non-lamellar phase LNPs were tethered to the surface of the QCM chip for analysis based on biotin-neutravidin binding, which enabled the controlled deposition of siRNA-LNP complexes with different lipid/siRNA charge ratios on a QCM-D crystal sensor...
February 23, 2017: Chembiochem: a European Journal of Chemical Biology
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