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  • 1.
    Bergquist, Helen
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Nikravesh, Abbas
    Fernández, Raquel Domingo
    Larsson, Veronica
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Nguyen, Chi-Hung
    Good, Liam
    Zain, Rula
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Structure-Specific Recognition of Friedreich’s Ataxia (GAA)n Repeats by Benzoquinoquinoxaline Derivatives2009In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, no 16, p. 2629-2637Article in journal (Refereed)
    Abstract [en]

    Expansion of GAA triplet repeats in intron 1 of the FXN gene reduces frataxin expression and causes Friedreich's ataxia. (GAA)nrepeats form non-B-DNA structures, including triple helix H-DNA and higher-order structures (sticky DNA). In the proposed mechanisms of frataxin gene silencing, central unanswered questions involve the characterization of non-B-DNA structure(s) that are strongly suggested to play a role in frataxin expression. Here we examined (GAA)nbinding by triplex-stabilizing benzoquinoquinoxaline (BQQ) and the corresponding triplex-DNA-cleaving BQQ-1,10-phenanthroline (BQQ-OP) compounds. We also examined the ability of these compounds to act as structural probes for H-DNA formation within higher-order structures at pathological frataxin sequences in plasmids. DNA-complex-formation analyses with a gel-mobility-shift assay and sequence-specific probing of H-DNA-forming (GAA)nsequences by single-strand oligonucleotides and triplex-directed cleavage demonstrated that a parallel pyrimidine (rather than purine) triplex is the more stable motif formed at (GAA)nrepeats under physiologically relevant conditions.

  • 2. Dorau, Robin
    et al.
    Görbe, Tamás
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Svedendahl Humble, Maria
    Improved Enantioselectivity of Subtilisin Carlsberg Towards Secondary Alcohols by Protein Engineering2018In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 19, no 4, p. 338-346Article in journal (Refereed)
    Abstract [en]

    Generally, the catalytic activity of subtilisin Carlsberg (SC) for transacylation reactions with secondary alcohols in organic solvent is low. Enzyme immobilization and protein engineering was performed to improve the enantioselectivity of SC towards secondary alcohols. Possible amino-acid residues for mutagenesis were found by combining available literature data with molecular modeling. SC variants were created by site-directed mutagenesis and were evaluated for a model transacylation reaction containing 1-phenylethanol in THF. Variants showing high E values (>100) were found. However, the conversions were still low. A second mutation was made, and both the E values and conversions were increased. Relative to that shown by the wild type, the most successful variant, G165L/M221F, showed increased conversion (up to 36 %), enantioselectivity (E values up to 400), substrate scope, and stability in THF.

  • 3. Ito, Mika
    et al.
    Shibata, Aya
    Zhang, Jie
    Hiroshima, Michio
    Sako, Yasushi
    Nakano, Yukiko
    Kojima-Aikawa, Kyoko
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Shuto, Satoshi
    Ito, Yoshihiro
    Morgenstern, Ralf
    Abe, Hiroshi
    Universal Caging Group for the in-Cell Detection of Glutathione Transferase Applied to 19F NMR and Bioluminogenic Probes2012In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 13, no 10, p. 1428-1432Article in journal (Refereed)
  • 4.
    Kasrayan, Alex
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bocola, Marco
    Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
    Sandström, Anders G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Lavén, Gaston
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-Erling
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Prediction of the Candida antarctica lipase A protein structure by comparative modeling and site-directed mutagenesis2007In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 8, no 12, p. 1409-1415Article in journal (Refereed)
    Abstract [en]

    A number of model structures of the CalA suggested by comparative modeling were tested by site-directed mutagenesis. Enzyme variants were created where amino acids predicted to play key roles for the lipase activity in the different models were replaced by an inert amino acid (alanine). The results from activity measurements of the overproduced and purified mutant enzymes indicate a structure where the active site consists of amino acid residues Ser184, His366, and Asp334 and in which there is no lid. This model can be used for future targeted modifications of the enzyme to obtain new substrate acceptance, better thermostability, and higher enantioselectivity.

  • 5.
    Löfgren, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Görbe, Tamás
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Oschmann, Michael
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Svedendahl Humble, Maria
    Bäckvall, Jan-E
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Transesterification of a Tertiary Alcohol by Engineered Candida antarctica Lipase A2019In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 20, no 11, p. 1438-1443Article in journal (Refereed)
    Abstract [en]

    Tertiary alcohols are known to be challenging substrates for applications in asymmetric synthesis due to their complexity and steric hinderance. The occurrence of tertiary alcohols and their esters in nature indicates the presence of natural biocatalytic synthetic routes for their preparation. Lipase A from Candida antarctica (CalA) is a hydrolase that has previously been shown to catalyze the transesterification of racemic 2-phenylbut-3-yn-2-ol at a low rate. In this work, the activity of that enzyme was improved by protein engineering through a semi-rational design strategy. An enzyme library was created and screened for transesterification activity towards racemic 2-phenylbut-3-yn-2-ol in an organic solvent. One successful enzyme variant (L367G) showed a tenfold increased reaction rate compared to the wild-type enzyme, while maintaining a high enantioselectivity.

  • 6.
    Nyhlén, Jonas
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Martín Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Sandström, Anders G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bocola, Marco
    Bäckvall, Jan-Erling
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Influence of delta-functional groups on the enantiorecognition of secondary alcohols by Candida antarctica lipase B2008In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 12, p. 1968-1974Article in journal (Refereed)
    Abstract [en]

    The selectivity of acetylation of delta-functionalized secondary alcohols catalyzed by Candida antarctica lipase B has been examined by molecular dynamics. The results from the simulation show that a delta-alcohol functionality forms a hydrogen bond with the carbonyl group of Thr 40. This interaction stabilizes the tetrahedral intermediate and thus leads to selective acetylation of the R enantiomer. A stabilizing interaction of the delta-(R)-acetoxy group with the peptide NH of alanine 282 was also observed. No stabilizing interaction could be found for the delta-keto functionality, and it is proposed that this is the reason for the experimentally observed decrease in enantioselectivity. From these results, it was hypothesized that the enantioselectivity could be restored by mutating the alanine in position 281 for serine. The mutation was made experimentally, and the results show that the E value increased from 9 to 120.

  • 7.
    Rönnols, Jerk
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Schnupf, Udo
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Brady, John W.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Inter-residual Hydrogen Bonding in Carbohydrates Unraveled by NMR Spectroscopy and Molecular Dynamics Simulations2019In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 20, p. 2519-2528Article in journal (Refereed)
    Abstract [en]

    Carbohydrates, also known as glycans in biological systems, are omnipresent in nature where they as glycoconjugates occur as oligo- and polysaccharides linked to lipids and proteins. Their three-dimensional structure is defined by two or three torsion angles at each glycosidic linkage. In addition, transglycosidic hydrogen bonding between sugar residues may be important. Herein we investigate the presence of these inter-residue interactions by NMR spectroscopy in D2O/[D-6]DMSO (70:30) or D2O and by molecular dynamics (MD) simulations with explicit water as solvent for disaccharides with structural elements alpha-d-Manp-(1 -> 2)-d-Manp, beta-d-GlcpNAc-(1 -> 2)-d-Manp, and alpha-d-Glcp-(1 -> 4)-beta-d-Glcp, all of which have been suggested to exhibit inter-residue hydrogen bonding. For the disaccharide beta-d-GlcpNAc-(1 -> 2)-beta-d-Manp-OMe, the large extent of O5 '...HO3 hydrogen bonding as seen from the MD simulation is implicitly supported by the H-1 NMR chemical shift and (3)J(HO3,H3) value of the hydroxy proton. In the case of alpha-d-Glcp-(1 -> 4)-beta-d-Glcp-OMe, the existence of a transglycosidic hydrogen bond O2 '...HO3 was proven by the presence of a cross-peak in H-1,C-13 HSQC-TOCSY experiments as a result of direct TOCSY transfer between HO3 of the reducing end residue and H2 ' (detected at C2 ') of the terminal residue. The occurrence of inter-residue hydrogen bonding, albeit transient, is judged important for the stabilization of three-dimensional structures, which may be essential in maintaining a conformational state for carbohydrate-protein interactions of glycans to take place in biologically important environments.

  • 8. Schaal, J.
    et al.
    Dekowski, B.
    Wiesner, B.
    Eichhorst, J.
    Marter, K.
    Vargas, C.
    Keller, S.
    Eremina, Nadja
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Baumann, A.
    Eisenhardt, D.
    Hagen, V.
    Coumarin-based octopamine phototriggers and their effects on an insect octopamine receptor2012In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 13, no 10, p. 1458-1464Article in journal (Refereed)
    Abstract [en]

    We have developed and characterized efficient caged compounds of the neurotransmitter octopamine. For derivatization, we introduced [6-bromo-8-(diethylaminomethyl)-7-hydroxycoumarin-4-yl]methoxycarbonyl (DBHCMOC) and {6-bromo-7-hydroxy-8-[(piperazin-1-yl)methyl]coumarin-4-yl}methoxycarbonyl (PBHCMOC) moieties as novel photo-removable protecting groups. The caged compounds were functionally inactive when applied to heterologously expressed octopamine receptors (AmOctα1R). Upon irradiation with UV–visible or IR light, bioactive octopamine was released and evoked Ca2+ signals in AmOctα1R-expressing cells. The pronounced water solubility of compounds 24 in particular holds great promise for these substances as excellent phototriggers of this important neurotransmitter.

  • 9. Schlagnitweit, Judith
    et al.
    Friebe Sandoz, Sarah
    Jaworski, Aleksander
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Guzzetti, Ileana
    Aussenac, Fabien
    Carbajo, Rodrigo J.
    Chiarparin, Elisabetta
    Pell, Andrew J.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Petzold, Katja
    Observing an Antisense Drug Complex in Intact Human Cells by in-Cell NMR Spectroscopy2019In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 20, p. 2474-2478Article in journal (Refereed)
    Abstract [en]

    Gaining insight into the uptake, trafficking and target engagement of drugs in cells can enhance understanding of a drug's function and efficiency. However, there are currently no reliable methods for studying untagged biomolecules in macromolecular complexes in intact human cells. Here we have studied an antisense oligonucleotide (ASO) drug in HEK 293T and HeLa cells by NMR spectroscopy. Using a combination of transfection, cryoprotection and dynamic nuclear polarization (DNP), we were able to detect the drug directly in intact frozen cells. Activity of the drug was confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). By applying DNP NMR to frozen cells, we overcame limitations both of solution-state in-cell NMR spectroscopy (e.g., size, stability and sensitivity) and of visualization techniques, in which (e.g., fluorescent) tagging of the ASO decreases its activity. The capability to detect an untagged, active drug, interacting in its natural environment, represents a first step towards studying molecular mechanisms in intact cells.

  • 10.
    Wikmark, Ylva
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engelmark Cassimjee, Karim
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Lihammar, Richard
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Removing the Active-Site Flap in Lipase A from Candida antarctica Produces a Functional Enzyme without Interfacial Activation2016In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 17, no 2, p. 141-145Article in journal (Refereed)
    Abstract [en]

    A mobile region is proposed to be a flap that covers the active site of Candida antarctica lipase A. Removal of the mobile region retains the functional properties of the enzyme. Interestingly interfacial activation, required for the wild-type enzyme, was not observed for the truncated variant, although stability, activity, and stereoselectivity were very similar for the wild-type and variant enzymes. The variant followed classical Michaelis-Menten kinetics, unlike the wild type. Both gave the same relative specificity in the transacylation of a primary and a secondary alcohol in organic solvent. Furthermore, both showed the same enantioselectivity in transacylation of alcohols and the hydrolysis of alcohol esters, as well as in the hydrolysis of esters chiral at the acid part.

  • 11.
    Wärmländer, Sebastian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tiiman, Ann
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Tallinn Technical University, Estonia.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Leiden University, Netherlands.
    Söderberg, Kajsa L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Biophysical Studies of the Amyloid beta-Peptide: Interactions with Metal Ions and Small Molecules2013In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 14, p. 1692-1704Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is the most common of the protein misfolding (amyloid) diseases. The deposits in the brains of afflicted patients contain as a major fraction an aggregated insoluble form of the so-called amyloid beta-peptides (A beta peptides): fragments of the amyloid precursor protein of 39-43 residues in length. This review focuses on biophysical studies of the A beta peptides: that is, of the aggregation pathways and intermediates observed during aggregation, of the molecular structures observed along these pathways, and of the interactions of A beta with Cu and Zn ions and with small molecules that modify the aggregation pathways. Particular emphasis is placed on studies based on high-resolution and solid-state NMR methods. Theoretical studies relating to the interactions are also included. An emerging picture is that of A beta peptides in aqueous solution undergoing hydrophobic collapse together with identical partners. There then follows a relatively slow process leading to more ordered secondary and tertiary (quaternary) structures in the growing aggregates. These aggregates eventually assemble into elongated fibrils visible by electron microscopy. Small molecules or metal ions that interfere with the aggregation processes give rise to a variety of aggregation products that may be studied in vitro and considered in relation to observations in cell cultures or in vivo. Although the heterogeneous nature of the processes makes detailed structural studies difficult, knowledge and understanding of the underlying physical chemistry might provide a basis for future therapeutic strategies against the disease. A final part of the review deals with the interactions that may occur between the A beta peptides and the prion protein, where the latter is involved in other protein misfolding diseases.

  • 12.
    Zhou, Shu
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pettersson, Pontus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    NMR Study of Rcf2 Reveals an Unusual Dimeric Topology in Detergent Micelles2018In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 19, no 5, p. 444-447Article in journal (Refereed)
    Abstract [en]

    The Saccharomyces cerevisiae mitochondrial respiratory supercomplex factor2 (Rcf2) plays a role in assembly of supercomplexes composed of cytochromebc(1) (complexIII) and cytochromec oxidase (complexIV). We expressed the Rcf2 protein in Escherichia coli, refolded it, and reconstituted it into dodecylphosphocholine (DPC) micelles. The structural properties of Rcf2 were studied by solution NMR, and near complete backbone assignment of Rcf2 was achieved. The secondary structure of Rcf2 contains seven helices, of which five are putative transmembrane (TM) helices, including, unexpectedly, a region formed by a charged 20-residue helix at the Cterminus. Further studies demonstrated that Rcf2 forms a dimer, and the charged TM helix is involved in this dimer formation. Our results provide a basis for understanding the role of this assembly/regulatory factor in supercomplex formation and function.

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