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Merz T.,University of Zürich | Heck T.,Eawag - Swiss Federal Institute of Aquatic Science and Technology | Geueke B.,Eawag - Swiss Federal Institute of Aquatic Science and Technology | Mittl P.R.E.,University of Zürich | And 4 more authors.
Structure | Year: 2012

The β-aminopeptidase BapA from Sphingosinicella xenopeptidilytica belongs to the N-terminal nucleophile (Ntn) hydrolases of the DmpA-like family and has the unprecedented property of cleaving N-terminal β-amino acid residues from peptides. We determined the crystal structures of the native (αβ)4 heterooctamer and of the 153 kDa precursor homotetramer at a resolution of 1.45 and 1.8 Å, respectively. These structures together with mutational analyses strongly support mechanisms for autoproteolysis and catalysis that involve residues Ser250, Ser288, and Glu290. The autoproteolytic mechanism is different from the one so far described for Ntn hydrolases. The structures together with functional data also provide insight into the discriminating features of the active site cleft that determine substrate specificity. © 2012 Elsevier Ltd All rights reserved.

Araghi R.R.,Free University of Berlin | Jackel C.,Laboratory of Organic Chemistry | Colfen H.,Max Planck Institute of Colloids and Interfaces | Salwiczek M.,Free University of Berlin | And 6 more authors.
ChemBioChem | Year: 2010

(Figure Presented) The combination of the properties of β- and γ-amino acids produce extended artificial fragments that recreate the properties of a natural α-helix. The substitution of two a-helical turns in an otherwise natural coiled-coil motif by a fragment of alternating β- and γ-amino acids with retention of global conformation and stability of the fold was established. The new chimeric system shows a high potency in helical quaternary structure formation. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Junker K.,ETH Zurich | Luginbuhl S.,ETH Zurich | Schuttel M.,ETH Zurich | Bertschi L.,Laboratory of Organic Chemistry | And 4 more authors.
ACS Catalysis | Year: 2014

The aniline dimer PADPA (= p-aminodiphenylamine = N-phenyl-1,4-phenylenediamine) was polymerized to poly(PADPA) at 25 °C with Trametes versicolor laccase (TvL)/O2 as catalyst and oxidant and in the presence of vesicles formed from sodium bis(2-ethylhexyl) sulfosuccinate (AOT) as templates. In comparison to the previously studied polymerization of aniline with the same type of enzyme-vesicle system, the polymerization of PADPA is much faster, and considerably fewer enzymes are required for complete monomer conversion. Turbidity measurements indicate that PADPA strongly binds to the vesicle surface before oxidation and polymerization are initiated. Such binding is confirmed by molecular dynamics (MD) simulations, supporting the assumption that the reactions which lead to poly(PADPA) are localized on the vesicle surface. The poly(PADPA) obtained resembles the emeraldine salt form of polyaniline (PANI-ES) in its polaron state with a high content of unpaired electrons, as judged from UV/vis/NIR, EPR, and FTIR absorption measurements. There are, however, also notable spectroscopic differences between PANI-ES and the enzymatically prepared poly(PADPA). Poly(PADPA) appears to be similar to a chemically synthesized poly(PADPA) as obtained in a previous work with ammonium peroxydisulfate (APS) as the oxidant in a mixture of 50 vol % ethanol and 50 vol % 0.2 M sulfuric acid (J. Phys. Chem. B 2008, 112, 6976-6987). ESI-MS measurements of early intermediates of the reaction with TvL and AOT vesicles indicate that the presence of the vesicles decreases the extent of formation of unwanted oxygen-containing species in comparison to the reaction in the absence of vesicles. This is the first information about the differences in the chemical composition of early reaction intermediates when the reaction carried out in the presence of vesicles under optimal conditions is compared with a template-free system. © 2014 American Chemical Society.

Parviainen H.,Laboratory of Polymer Chemistry | Parviainen A.,Laboratory of Organic Chemistry | Virtanen T.,Laboratory of Polymer Chemistry | Kilpelainen I.,Laboratory of Organic Chemistry | And 5 more authors.
Carbohydrate Polymers | Year: 2014

In this work, interactions between cellulose and ionic liquids were studied calorimetrically and by optical microscopy. Two novel ionic liquids (1,5-Diazabicyclo[4.3.0]non-5-enium propionate and N-methyl-1,5-diazabicyclo[4. 3.0]non-5-enium dimethyl phosphate) and 1-ethyl-3-methylimidazolium acetate-water mixtures were used as solvents. Optical microscopy served in finding the extent of dissolution and identifying the dissolution pattern of the cellulose sample. Calorimetric studies identified a peak relating to dissolution of cellulose in solvent. The transition did, however, not indicate complete dissolution, but rather dissolution inside fibre or fibrils. This method was used to study differences between four cellulose samples with different pretreatment or origins. © 2014 Elsevier Ltd.

Jakub Saadi and Helma Wennemers from the Laboratory of Organic Chemistry at ETH Zurich have developed a general biomimetic method that uses fluoromalonic acid half thioesters as fluoroacetate surrogates, which allows for an enantioselective aldol reaction that selectively places a fluoroacetate on an organic compound. Their work appears in Nature Chemistry. Acetate is a common building block for many natural produces and pharmaceuticals, including statins and polyketides. One way to incorporate fluorine into a common pharmaceutical would be to use fluoroacetate as a building block since its reactivity would be very similar to acetate. The problem is that fluoroacetate aldol reactions lead to a racemic mixture of products. In pharmaceuticals the "handedness" of a molecule is important for its biocompatibility. Racemic mixtures have both left- and right-handed molecules which are typically not able to be separated. The ideal case would be an enantioselective fluoroacetate reaction. Saadi and Wennemers devised a strategy using Meldrum's acid as a precursor to a reaction that produces fluoromalonic acid half thioesters (F-MAHT). Meldrum's acid is a rigid ring structure. Fluorine can displace the hydrogen between the two carbonyl groups on Meldrum's acid in a three-step process. This compound then undergoes a nucleophilic ring-opening reaction in which it is reacted with a silylated thiophenol to produce the silyl ester intermediate that is hydrolyzed to the F-MAHT. F-MAHT is used rather than fluoroacetate in an aldol reaction because it allows for mild and selective reaction conditions as well as evolving CO , thus driving it toward the products. Furthermore, using a quinidine-urea catalyst would allow control over which face of the F-MAHT reacts with an aldehyde. Using this strategy, once Saadi and Wennemers optimized their reaction conditions, they were able to obtain several fluoroaldol products of reactions between F-MAHT derivatives and various aromatic and aliphatic aldehydes with enantioselective control. They then tested whether their procedure would work for a real life target by making a short total synthesis of a fluorinated analog of atorvastatin (Lipitor) in which they ended up with product (30% overall yield). The key step involved their F-MAHT aldol reaction and reduction to the fluoroaldehyde intermediate. By this they also demonstrated that F-MAHTs can also serve as fluoroacetaldehyde surrogates. Fluoroacetaldehyde is highly reactive and yields complex mixtures of many products. Saadi and Wennemers's method overcomes this problem. Just as fluorinated versions of several other compounds, such as hydrocortisone, showed enhanced biological activity, the hope is that this mechanism will open the door to many other fluorinated pharmaceuticals with improved properties compared to their non-fluorinated analogs. Explore further: Introduction of fluorine atoms into organic molecules could have applications for synthesis of pharmaceuticals More information: Jakub Saadi et al. Enantioselective aldol reactions with masked fluoroacetates, Nature Chemistry (2016). DOI: 10.1038/nchem.2437 Abstract Despite the growing importance of organofluorines as pharmaceuticals and agrochemicals, the stereoselective introduction of fluorine into many prominent classes of natural products and chemotherapeutic agents is difficult. One long-standing unsolved challenge is the enantioselective aldol reaction of fluoroacetate to enable access to fluorinated analogues of medicinally relevant acetate-derived compounds, such as polyketides and statins. Herein we present fluoromalonic acid halfthioesters as biomimetic surrogates of fluoroacetate and demonstrate their use in highly stereoselective aldol reactions that proceed under mild organocatalytic conditions. We also show that the methodology can be extended to formal aldol reactions with fluoroacetaldehyde and consecutive aldol reactions. The synthetic utility of the fluorinated aldol products is illustrated by the synthesis of a fluorinated derivative of the top-selling drug atorvastatin. The results show the prospects of the method for the enantioselective introduction of fluoroacetate to access a wide variety of highly functionalized fluorinated compounds.

Wauer T.,University of Oxford | Wauer T.,University of Cambridge | Gerlach H.,University of Oxford | Mantri S.,University of Oxford | And 5 more authors.
ACS Nano | Year: 2014

Previously, we reported the manual assembly of lipid-coated aqueous droplets in oil to form two-dimensional (2D) networks in which the droplets are connected through single lipid bilayers. Here we assemble lipid-coated droplets in robust, freestanding 3D geometries: for example, a 14-droplet pyramidal assembly. The networks are designed, and each droplet is placed in a designated position. When protein pores are inserted in the bilayers between specific constituent droplets, electrical and chemical communication pathways are generated. We further describe an improved means to construct 3D droplet networks with defined organizations by the manipulation of aqueous droplets containing encapsulated magnetic beads. The droplets are maneuvered in a magnetic field to form simple construction modules, which are then used to form larger 2D and 3D structures including a 10-droplet pyramid. A methodology to construct freestanding, functional 3D droplet networks is an important step toward the programmed and automated manufacture of synthetic minimal tissues. © 2013 American Chemical Society.

Moussouni S.,Mediterranean Agronomic Institute of Chania | Detsi A.,Laboratory of Organic Chemistry | Majdalani M.,Mediterranean Agronomic Institute of Chania | Makris D.P.,Technological Educational Institute of Larissa | Kefalas P.,Mediterranean Agronomic Institute of Chania
Tetrahedron Letters | Year: 2010

The potential of a crude peroxidase (POD) from onion solid waste as a biocatalyst for the synthesis of a naturally occurring aurone is described. The crude enzyme preparation effectively promotes the cyclization of 2′,3,4,4′,6′-pentahydroxy-chalcone (which is not a natural substrate of onion POD) into aureusidin. © 2010 Elsevier Ltd. All rights reserved.

Kukovec B.-M.,Laboratory of General and Inorganic Chemistry | Kodrin I.,Laboratory of Organic Chemistry | Mihalic Z.,Laboratory of Organic Chemistry | Furic K.,Ruder Boskovic Institute | Popovic Z.,Laboratory of General and Inorganic Chemistry
Inorganica Chimica Acta | Year: 2010

Pyridine and 4-picoline cobalt(II) complexes with 3-hydroxypicolinic acid, [Co(3-OHpic)2(py)2], (2), and [Co(3-OHpic)2(4-pic)2], (3), were prepared, their molecular and crystal structures were determined by X-ray structure analysis and their thermal stability by TGA/DTA methods. Complex 2 appears only as trans isomer and 3 as cis isomer. Based on DFT calculations, the most significant effect on orientation of (un)substituted ligands around cobalt, i.e. cis-trans isomerism, comes from crystal packing. Theoretical calculations show that exchange of methyl group in pyridine does not affect relative stability of one monomer unit, i.e. cis isomer is for about 1 kcal mol-1 more stable than trans isomer. Hydrogen bonds of the O-H···O type are present only as intramolecular ones in the crystal structures of 2 and 3, while intermolecular C-H···O hydrogen bonds and π-π stacking interactions (π-π interactions present only in 3) assemble molecules in 3D architecture. Interactions between two monomer units in crystal packing could be separated and theoretically investigated to calculate interaction energy. In our case, both non-hypothetical models, i.e. trans isomer of 2 and cis isomer of 3, show more favorable interaction energies than hypothetical ones, i.e. cis isomer of 2 and trans isomer of 3, for the same type of interaction. © 2010 Elsevier B.V. All rights reserved.

Madler S.,Laboratory of Organic Chemistry
Analytical and Bioanalytical Chemistry | Year: 2011

The 59th Conference on Mass Spectrometry and Allied Topics of the American Society for Mass Spectrometry (ASMS) was held on June 5, 2011 to June 9, 2011 at the Colorado Convention Center in Denver, Colorado. The conference offered short courses covering the basics of the most important mass spectrometric techniques. It covered several presentations focusing on the latest instrumental developments and applications of mass spectrometry (MS). Other presentations covered several areas such as systems biology/cellular pathways, energy, petroleum and biofuels, drug discovery and development, identification of posttranslational modifications, imaging of biological samples, plant proteomics, and drug metabolism and pharmacokinetics. Several sessions focused on methodological and instrumental developments for H/D exchange, biomolecular structure analysis, microscale and nanoscale separations, LC-MS detection of reactive metabolites, and imaging MS.

Nielen M.W.F.,Laboratory of Organic Chemistry
Food Additives and Contaminants - Part A Chemistry, Analysis, Control, Exposure and Risk Assessment | Year: 2012

For years it has been suspected that natural hormones are illegally used as growth promoters in cattle in the European Union. Unfortunately there is a lack of methods and criteria that can be used to detect the abuse of natural hormones and distinguish treated from non-treated animals. Pattern recognition of steroid profiles is a promising approach for tracing/detecting the abuse of natural hormones administered to cattle. Traditionally steroids are analysed in urine as free steroid after deconjugation of the glucuronide (and sulphate) conjugates. The disadvantage of this deconjugation is that valuable information about the steroid profile in the sample is lost. In this study we develop a method to analyse steroids at very low concentration levels (ng l~) for the free steroid, glucuronide and sulphate conjugates in urine samples. This method was used to determine concentrations of natural (pro)hormones in a large population (n = 620) of samples from male and female bovine animals and from bovine animals treated with testosterone-cypionate, estradiol-benzoate, dihydroepiandrosterone and pregnenolone. The data acquired were used to build a statistical model applying the multivariate technique 'Soft Independent Modeling of Class Analogy' (SIMCA). It is demonstrated that by using this model the results of the urine analysis can indicate which animal may have had illegal treatment with natural (pro)hormones. ©2012 Taylor & Francis.

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