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  • 1.
    Abdalla, Abdel-Monem
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Bruns, Christopher M
    Tainer, John A
    Mannervik, Bengt
    Stenberg, Gun
    Design of a monomeric human glutathione transferase GSTP1, a structurally stable but catalytically inactive protein2002In: Protein Engineering, Vol. 15, p. 827-834Article in journal (Refereed)
  • 2. Abdurahman, S
    et al.
    Höglund, Stefan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Goobar-Larsson, L
    Vahlne, A
    Selected amino acid substitutions in the C-terminal region of human immunodeficiency virus type 1 capsid protein affect virus assembly and release2004In: J. gen. Virol, Vol. 85, p. 2903-2913Article in journal (Refereed)
  • 3.
    Abramson, Jeff
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Structural studies on the integral membrane protein, ubiquinol oxidase from Escherichia coli2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heme-copper oxidases are redox-driven proton pumps that couple the reduction of molecular oxygen to water with the vectorial translocation of protons across the membrane. The proton gradient generated by heme-copper oxidases and the other members of the aerobic respiratory chain is ultimately used to drive the synthesis of ATP. There are two main branches of the heme-copper oxidases that are characterized by the electron donating substrate; the cytochrome c oxidases, which use cytochrome c as the electron donor, and the ubiquinol oxidases, which use a lipid-soluble molecule, ubiquinol, as their electron donor. These enzymes share important structural and functional features.

    This thesis presents the procedures that have led to the first crystal structure of a ubiquinol oxidase, cytochrome bo, oxidase from Escherichia coli, at a resolution of 3.5 Å. The overall structure of the enzyme is similar to those of cytochrome c oxidases; however the membrane spanning region of subunit I contains a cluster of polar residues exposed to the interior of the lipid bilayer. No such structural feature is present in cytochrome c oxidases. Mutagenesis studies on residues in this region strongly suggest that this area forms a ubiquinone binding site. A comparison of this region with known ubiquinone binding sites shows remarkable similarities. In light of these findings specific roles for these polar residues is proposed in electron and proton transfer in ubiquinol oxidase.

    A fusion protein of cytochrome bo3-Protein Z was generated in an attempt to increase the hydrophilic surface of the protein, thus extending protein-protein contacts within the crystal lattice structure. Such an approach can be used to facilitate crystallization.

  • 4.
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Structure-activity and resistance studies of HIV-1 protease inhibitors2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present investigation was undertaken in order to identify inhibitors of HIV-1 protease that would be efficient in vivo and against HIV-1 protease carrying mutations known to confer resistance to inhibitors in clinical use. A second interest was to understand details of inhibitory mechanisms and to gain understanding of the molecular details of resistance.

    Linear inhibitors of transition-state type showed to have a resistance pattern similar to protease inhibitors in clinical use, whereas cyclic inhibitors of sulfonamide were somewhat different in their inhibitory profiles. It was found that mutation L90M in some situations could lessen the decrease in overall efficiency suffered by the enzyme when aquiring other mutations. Also presented are results from the characterization of double mutation I84V/L90M, formerly not investigated. Testing of triple and quadruple mutant confirmed the additive features of some mutations. In an attempt to find new leads for inhibitor development, extracts from bee propolis, a natural product, was investigated, and it was found that one extract inhibited wild-type enzyme with an I50-value of 0.2 μg/mL. Even more interesting is the result that propolis extract also inhibited all the investigated mutant enzymes.

  • 5.
    Ahlsén, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Hultén, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Shuman, Cynthia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Poliakov, Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lindgren, Maria T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Resistance profiles of cyclic and linear inhibitors of HIV-1 protease2002In: Antiviral Chemistry & Chemotherapy, ISSN 0956-3202, E-ISSN 2040-2066, Vol. 13, no 1, p. 27-37Article in journal (Refereed)
    Abstract [en]

    Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used. Kinetic analysis of the mutants revealed that catalytic efficiency was 1-30% of that for the wild-type enzyme, a consequence of reduced kcat in all cases and an increased KM for all mutants except for the G48V enzyme. The overall structure-inhibitory profiles of the cyclic compounds were similar, and the inhibition of the V82A, 184V and G48V/L90M mutants were less efficient than of the wild-type enzyme. The greatest increase in Ki was generally observed for the 184V mutant and least for the G48V/L90M mutant, and additional combinations of mutations did not result in improved inhibition profiles for the cyclic compounds. An extended analysis of additional mutants, and including a set of linear compounds, showed that the profile was unique for each compound, and did not reveal any general structural features associated with a certain inhibition profile. The effects of structural modifications in the inhibitors, or of mutations, were not additive and they differed depending on their context. The results demonstrate the difficulties in predicting resistance, even for closely related compounds, and designing compounds with improved resistance profiles.

  • 6. Akoachere, Monique
    et al.
    Iozef, Rimma
    Rahlfs, Stefan
    Deponte, Marcel
    Mannervik, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Creighton, Donald J
    Schirmer, Heiner
    Becker, Katja
    Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts.2005In: Biol Chem, ISSN 1431-6730, Vol. 386, no 1, p. 41-52Article in journal (Refereed)
    Abstract [en]

    The glyoxalase system consisting of glyoxalase I (GloI) and glyoxalase II (GloII) constitutes a glutathione-dependent intracellular pathway converting toxic 2-oxoaldehydes, such as methylglyoxal, to the corresponding 2-hydroxyacids. Here we describe a complete glyoxalase system in the malarial parasite Plasmodium falciparum. The biochemical, kinetic and structural properties of cytosolic GloI (cGloI) and two GloIIs (cytosolic GloII named cGloII, and tGloII preceded by a targeting sequence) were directly compared with the respective isofunctional host enzymes. cGloI and cGloII exhibit lower K(m) values and higher catalytic efficiencies (k(cat)/K(m) ) than the human counterparts, pointing to the importance of the system in malarial parasites. A Tyr185Phe mutant of cGloII shows a 2.5-fold increase in K(m) , proving the contribution of Tyr185 to substrate binding. Molecular models suggest very similar active sites/metal binding sites of parasite and host cell enzymes. However, a fourth protein, which has highest similarities to GloI, was found to be unique for malarial parasites; it is likely to act in the apicoplast, and has as yet undefined substrate specificity. Various S-(N-hydroxy-N-arylcarbamoyl)glutathiones tested as P. falciparum Glo inhibitors were active in the lower nanomolar range. The Glo system of Plasmodium will be further evaluated as a target for the development of antimalarial drugs.

  • 7.
    Alterman, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, Hans O.
    Garg, Neeraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lövgren, Seved
    Classon, Björn
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Kvarnström, Ingemar
    Vrang, Lotta
    Unge, Torsten
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1'-modified HIV-1 protease inhibitors1999In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 42, no 19, p. 3835-3844Article in journal (Refereed)
  • 8.
    Alterman, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Björsne, Magnus
    Mühlman, Anna
    Classon, Björn
    Kvarnstrom, Ingemar
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Markgren, Per-Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Nillroth, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Unge, Torsten
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Samuelsson, Bertil
    Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors: Use of L-mannaric acid as a peptidomimetic scaffold1998In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 41, no 20, p. 3782-3792Article in journal (Refereed)
  • 9.
    Alterman, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sjöbom, Hans
    Säfsten, Pär
    Markgren, Per-Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Hämäläinen, Markku
    Löfås, Stefan
    Hultén, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Classon, Björn
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    P1/P1' modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays2001In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 13, no 2, p. 203-212Article in journal (Refereed)
    Abstract [en]

    The commonly used HIV-1 protease assays rely on measurements of the effect of inhibitions on the hydrolysis rate of synthetic peptides. Recently an assay based on surface plasmon resonance (SPR) was introduced. We have taken advantage of the fact that the SPR signal is proportional to the mass of the analyte interacting with the immobilised molecule and developed two new improved efficient competition assay methods. Thus, high molecular weight binders were used as amplifiers of the surface plasmon resonance signal. Linkers were attached by a Heck reaction to the para-positions of the P1/P1′ benzyloxy groups of a linear C2-symmetric C-terminal duplicated inhibitor to enable (a) biotin labelling or (b) direct immobilisation of the inhibitor to the biosensor surface matrix. The interaction properties of a series of 17 structurally diverse inhibitors was assessed and compared to previously reported data. The most sensitive assay was obtained by immobilising the enzyme and amplifying the signal with an antibody, giving a detection range between 0.1 nM and 10 μM. Immobilisation of the inhibitor resulted in a stable and durable surface but a narrower detection range (1–100 nM). The two competition assays are anticipated to be very suitable for fast screening of potential HIV inhibitors.

  • 10.
    Andersson, Hans O.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Fridborg, Kerstin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Löwgren, Seved
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mühlman, Anna
    Björsne, Magnus
    Garg, Neeraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kvarnström, Ingemar
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Classon, Björn
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Nillroth, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Vrang, Lotta
    Öberg, Bo
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors2003In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 8, p. 1746-1758Article in journal (Refereed)
  • 11.
    Andersson, Malena
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Mannervik, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Exploring protein evolution by saturation mutagenesis of the GST M2-2 active site residue 2102005In: FEBS Journal, Vol. 272, p. 81 Suppl-Article in journal (Other scientific)
  • 12.
    Andreu, AL
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Checcarelli, N
    Iwata, S
    Shanske, S
    DiMauro, S
    A missense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy2000In: PEDIATRIC RESEARCH, ISSN 0031-3998, Vol. 48, no 3, p. 311-314Article in journal (Refereed)
    Abstract [en]

    We describe a pathogenic mutation in the mitochondrial cytochrome b gene in a patient with a multisystem disorder presenting as histiocytoid cardiomyopathy in whom a defect of ubiquinol cytochrome c oxidonductase of the electron transport chain had been d

  • 13.
    Backman, Dan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Interaction Studies of Secreted Aspartic Proteases (Saps) from Candida albicans: Application for Drug Discovery2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is focused on enzymatic studies of the secreted aspartic proteases (Saps) from Candida albicans as a tool for discovery of anti-candida drugs. C. albicans causes infections in a number of different locations, which differ widely in the protein substrates available and pH. Since C. albicans needs Saps during virulent growth, these enzymes are good targets for drug development.

    In order to investigate the catalytic characteristics of Saps and their inhibitor affinities, substrate-based kinetic assays were developed. Due to the low sensitivity of these assays, especially at the sub-optimal pH required to mimic the different locations of infections, these assays were not satisfactory. Therefore, a biosensor assay was developed whereby, it was possible to study interaction between Saps and inhibitors without the need to optimise catalytic efficacy. Furthermore, the biosensor assay allowed determination of affinity, as well as the individual association and dissociation rates for inhibitor interactions.

    Knowledge about substrate specificity, Sap subsite adaptivity, and the pH dependencies of catalytic efficacy has been accumulated. Also, screening of transition-state analogue inhibitors designed for HIV-1 protease has revealed inhibitors with affinity for Saps. Furthermore, the kinetics and pH dependencies of their interaction with Saps have been investigated. One of these inhibitors, BEA-440, displayed a complex interaction with Saps, indicating a conformational change upon binding and a very slow dissociation rate. A time dependent interaction was further supported by inhibition measurements. The structural information obtained affords possibilities for design of new more potent inhibitors that might ultimately become drugs against candidiasis. The strategy to combine substrate specificity studies with inhibitor screening has led to complementary results that generate a framework for further development of potent inhibitors.

    List of papers
    1. Discovery of the subsite specificity of Candida albicans Sap1 and Sap2 and the design of potent peptidomimetic inhibitors
    Open this publication in new window or tab >>Discovery of the subsite specificity of Candida albicans Sap1 and Sap2 and the design of potent peptidomimetic inhibitors
    Show others...
    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-93113 (URN)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2009-11-27Bibliographically approved
    2. Substrate specificity and pH dependence of secreted aspartic proteases Sap1, Sap2 and Sap3 from Candida albicans
    Open this publication in new window or tab >>Substrate specificity and pH dependence of secreted aspartic proteases Sap1, Sap2 and Sap3 from Candida albicans
    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-93114 (URN)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2009-11-27Bibliographically approved
    3. Kinetic and mechanistic analysis of the association and dissociation of inhibitors interacting with secreted aspartic acid proteases 1 and 2 from Candida albicans
    Open this publication in new window or tab >>Kinetic and mechanistic analysis of the association and dissociation of inhibitors interacting with secreted aspartic acid proteases 1 and 2 from Candida albicans
    2003 (English)In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1646, no 1-2, p. 184-195Article in journal (Refereed) Published
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-93115 (URN)10.1016/S1570-9639(03)00022-0 (DOI)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2017-12-14Bibliographically approved
    4. Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap1, Sap2 and Sap3 from Candida albicans
    Open this publication in new window or tab >>Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap1, Sap2 and Sap3 from Candida albicans
    2006 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 11, no 2, p. 165-175Article in journal (Refereed) Published
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-93116 (URN)10.1177/1087057105284270 (DOI)16418316 (PubMedID)
    Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2017-12-14Bibliographically approved
  • 14.
    Backman, Dan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Kinetic and mechanistic analysis of the association and dissociation of inhibitors interacting with secreted aspartic acid proteases 1 and 2 from Candida albicans2003In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1646, no 1-2, p. 184-195Article in journal (Refereed)
  • 15.
    Backman, Dan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Substrate specificity and pH dependence of secreted aspartic proteases Sap1, Sap2 and Sap3 from Candida albicansManuscript (Other (popular science, discussion, etc.))
  • 16.
    Backman, Dan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Monod, Michel
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap1, Sap2 and Sap3 from Candida albicans2006In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 11, no 2, p. 165-175Article in journal (Refereed)
  • 17.
    Badelek, B
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Kwiecinski, J
    Ziaja, B
    Spin structure function g 1(x,Q**2) and the DHGHY integral I(Q**2) at low Q**2: Predictions from the GVMD model2002In: EUROPEAN PHYS JOURNAL, Vol. C26, p. 45-49Article in journal (Other scientific)
  • 18.
    Baker, SC
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Saunders, NFW
    Willis, AC
    Ferguson, SJ
    Hajdu, J
    Fulop, V
    Cytochrome cd(1) structure: Unusual haem environments in a nitrite reductase and analysis of factors contributing to beta-propeller folds1997In: JOURNAL OF MOLECULAR BIOLOGY, ISSN 0022-2836, Vol. 269, no 3, p. 440-455Article in journal (Refereed)
    Abstract [en]

    The central tunnel of the eight-bladed beta-propeller domain of cytochrome cd(1) (nitrite reductase) is seen, from a 1.28 Angstrom, resolution structure, to contain hydrogen donors and accepters that are satisfied by interaction either with water or the

  • 19. Ban, FQ
    et al.
    Lundqvist, Maria J.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Quantum Chemistry. Chemistry, Department of Physical and Analytical Chemistry, Quantum Chemistry.
    Boyd, Russel J.
    Eriksson, Leif A.
    Department of Biochemistry. Chemistry, Department of Physical and Analytical Chemistry, Quantum Chemistry.
    Theoretical studies of the cross-linking mechanisms between cytosine and tyrosine2002In: Journal of the American Chemical Society, Vol. 124, no 11, p. 2753-2761Article in journal (Refereed)
  • 20.
    Ban, F.Q.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Physics.
    Lundqvist, M.J.
    Chemistry, Department of Biochemistry.
    Boyd, R.J.
    Eriksson, L.A
    Theoretical Studies of the Cross-Linking Mechanisms between Cytosine and Tyrosine2002In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol. 124, no 11, p. 2753-2761Article in journal (Refereed)
  • 21.
    Beigi, Farideh
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Partition chromatography of drugs on immobilized liposomes and biomembranes: A method applicable to screening in drug design2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One of the main pathways for drug passage into cells is diffusion across the lipid bilayer ofthe cell membrane. A key factor in this process is the drug partitioning into the bilayer, whichcan be translated into a retention in a chromatographic system. Liposomes, proteoliposomesand cytoskeleton-depleted red cell membrane vesicles were therefore entrapped in gel beads tobe used as biomimetic models in drug partition chromatography. Red cells were adsorbed ongel particles for similar use as a stationary phase, whereby ghosts were formed. Each retentionvolume was divided by the amount of immobilized phospholipids, as determined byphosphorus analysis, to define a capacity factor (Ks). I verified that the chromatographicretention volumes were proportional to the amounts of immobilized phospholipids. The loss oflipids with time was small and allowed many series of runs. Short columns containing smallamounts of lipids allowed quick analysis of highly lipophilic drugs. The logarithm of Ksvalues for positively charged drugs on negatively charged liposomes decreased as the ionicstrength was increased, increased with increasing negative charge of the liposomes as the pHwas increased and varied linearly with the temperature. On red cells/ghosts the range of thelog Ks values was more narrow than on liposomes and vesicles. The log Ks values on neutralliposomes decreased with increasing cholesterol fraction and mostly increased as the temperature was increased. Insertion of transmembrane proteins into lipid bilayers changed the log Ksvalues for charged drugs, and in some cases also for neutral drugs. Comparison of log Ksvalues with values from the literature for octanol/water distribution ratios, apparent partitioning in liposome suspensions, retention on immobilized artificial membranes, calculateddynamic polar molecular surface areas, permeability values on cultured monolayers of Caco-2cells and absorption of orally administered drugs in humans showed different recti- or curvilinear correlations. The results obtained have shown that immobilized liposome or biomembrane chromatography is a reproducible, robust and simple method for characterization ofdrug partitioning. The method is applicable for drug screening.

  • 22.
    Beigi, Farideh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Gottschalk, Ingo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lagerquist Hägglund, Christine
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Haneskog, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Brekkan, Eggert
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Zhang, Yanxiao
    Österberg, Thomas
    Lundahl, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Immobilized liposome and biomembrane partitioning chromatography of drugs for prediction of drug transport1998In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 164, no 1-2, p. 129-137Article in journal (Refereed)
    Abstract [en]

    Drug partitioning into lipid bilayers was studied by chromatography on liposomes and biomembranes immobilized in gel beads by freeze–thawing. The drug retention volume was expressed as a capacity factor, Ks, normalized with respect to the amount of immobilized phospholipid. Log Ks values for positively charged drugs on brain phosphatidylserine (PS)/egg phosphatidylcholine (PC) liposomes decreased as the ionic strength was increased, increased as the PS:PC ratio or the pH was increased and varied linearly with the temperature. Log Ks values for beta-blockers, phenothiazines and benzodiazepines on egg phospholipid (EPL) liposomes correlated well with corresponding values on red cell membrane lipid liposomes (r2=0.96), and on human red cell membrane vesicles containing transmembrane proteins (r2=0.96). A fair correlation was observed between the values on EPL liposomes and those on native membranes of adsorbed red cells (r2=0.86). Compared to the data obtained with liposomes, the retentions of hydrophilic drugs became larger and the range of log Ks values more narrow on the vesicles and the membranes, which expose hydrophilic protein surfaces and oligosaccharides. Lower correlations were observed between drug retention on EPL liposomes and egg PC liposomes; and between retention on liposomes (or vesicles) and immobilized artificial membrane (IAM) monolayers of PC analogues. Absorption of orally administered drugs in humans (literature data) was nearly complete for drugs of log Ks values in the interval 1.2–2.5 on vesicles. Both vesicles and liposomes can thus be used for chromatographic analysis of drug–membrane interaction and prediction of drug absorption.

  • 23.
    Berglund, GI
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Carlsson, Gunilla H.
    Smith, AT
    Henriksen, A
    Hajdu, J
    The catalytic pathway of horseradish peroxidase at high resolution2002In: NATURE, Vol. 417, no 6887, p. 463-468Article in journal (Refereed)
  • 24. Blumenzweig, I
    et al.
    Baraz, L
    Friedler, A
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Gilon, C
    Steinitz, M
    Kotler, M
    HIV-1 Vif-derived peptide inhibits drug-resistant HIV proteases2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 292, no 4, p. 832-840Article in journal (Refereed)
  • 25.
    Boija, Elisabet
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Partitioning of Drugs and Lignin Precursor Models into Artificial Membranes2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main aim of this thesis was to characterize membrane-solute interactions using artificial membranes in immobilized liposome chromatography or capillary electrophoresis. The partitioning of a solute into a cell membrane is an essential step in diffusion across the membrane. It is a valid parameter in drug research and can be linked to the permeability as well as the absorption of drugs. Immobilized liposome chromatography was also used to study partitioning of lignin precursor models. Lignin precursors are synthesized within plant cells and need to pass the membrane to be incorporated into lignin in the cell wall.

    In immobilized liposome chromatography, liposomes or lipid bilayer disks were immobilized in gel beads and the partitioning of solutes was determined. Capillary electrophoresis using disks as a pseudostationary phase was introduced as a new approach in drug partitioning studies. In addition, octanol/water partitioning was used to determine the hydrophobicity of the lignin precursor models.

    Electrostatic interactions occurred between bilayers and charged drugs, whereas neutral drugs were less affected. However, neutral lignin precursor models exhibited polar interactions. Moreover, upon changing the buffer ionic strength or the buffer ions, the interactions between charged drugs and neutral liposomes were affected. Hydrophobic interactions were also revealed by including a fatty acid or a neutral detergent into the bilayer or by using a buffer with a high salt concentration. The bilayer manipulation had only a moderate effect on drug partitioning, but the high salt concentration had a large impact on partitioning of lignin precursor models.

    Upon comparing the partitioning into liposomes and disks, the latter showed a more pronounced partitioning due to the larger fraction of lipids readily available for interaction. Finally, bilayer disk capillary electrophoresis was successfully introduced for partitioning studies of charged drugs. This application will be evaluated further as an analytical partitioning method and separation technique.

    List of papers
    1. Effects of ions and detergents in drug partition chromatography on liposomes
    Open this publication in new window or tab >>Effects of ions and detergents in drug partition chromatography on liposomes
    Show others...
    2004 In: Journal of Chromatography A, Vol. 1030, p. 273-278Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94747 (URN)
    Available from: 2006-09-08 Created: 2006-09-08Bibliographically approved
    2. Interactions of drugs and an oligonucleotide with charged membranes analyzed by immobilized liposome chromatography
    Open this publication in new window or tab >>Interactions of drugs and an oligonucleotide with charged membranes analyzed by immobilized liposome chromatography
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    2006 In: Biomedical Chromatography, Vol. 20, p. 83-87Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94748 (URN)
    Available from: 2006-09-08 Created: 2006-09-08Bibliographically approved
    3. Interactions between model membranes and lignin-related compounds studied by immobilized liposome chromatography
    Open this publication in new window or tab >>Interactions between model membranes and lignin-related compounds studied by immobilized liposome chromatography
    2006 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1758, no 5, p. 620-626Article in journal (Refereed) Published
    Abstract [en]

    In order to elucidate the modes of interaction between lignin precursors and membranes, we have studied the influence of temperature, lipid composition and buffer composition on the partitioning of monolignol and dilignol model substances into phospholipid bilayers. The partitioning was determined by immobilized liposome chromatography, which is an established method for studies of pharmaceutical drugs but a new approach in studies of lignin synthesis. The temperature dependence of the retention and the effect of a high ammonium sulfate concentration in the mobile phase demonstrated that the interaction involved both hydrophobic effects and polar interactions. There was also a good correlation between the partitioning and the estimated hydrophobicity, in terms of octanol/water partitioning. The partitioning behavior of the model substances suggests that passive diffusion over the cell membrane is a possible transport route for lignin precursors. This conclusion is strengthened by comparison of the present results with the partitioning of pharmaceutical drugs that are known to pass cell membranes by diffusion.

    Keywords
    Lignin, liposomes, membrane, transport, plant
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-94749 (URN)10.1016/j.bbamem.2006.04.007 (DOI)000239102300008 ()
    Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2017-12-14Bibliographically approved
    4. Evaluation of bilayer disks as plant cell membrane models in partition studies
    Open this publication in new window or tab >>Evaluation of bilayer disks as plant cell membrane models in partition studies
    2007 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 364, no 2, p. 145-152Article in journal (Refereed) Published
    Abstract [en]

    We have studied the partitioning of a set of phenolic compounds used as lignin precursor models into lipid bilayer disks and liposomes. The bilayer disks are open bilayer structures stabilized by polyethylene glycol-conjugated lipids. Our results indicate that disks generate more accurate partition data than do liposomes. Furthermore, we show that the partitioning into the membrane phase is reduced slightly if disks composed of 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol are exchanged for disks with a lipid composition mimicking that of the root tissue of Zea mays L.

    Keywords
    Immobilized liposome chromatography, Lignin, Lipid bilayer disks, Liposomes, Monolignol, Partitioning, Phenols, Plant cell membrane lipids
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-10738 (URN)10.1016/j.ab.2007.02.012 (DOI)000245960400007 ()17391634 (PubMedID)
    Available from: 2008-09-01 Created: 2008-09-01 Last updated: 2017-12-11Bibliographically approved
    5. Bilayer disk capillary electrophoresis: a novel method to study drug partitioning into membranes
    Open this publication in new window or tab >>Bilayer disk capillary electrophoresis: a novel method to study drug partitioning into membranes
    Show others...
    2008 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, no 16, p. 3377-3383Article in journal (Refereed) Published
    Abstract [en]

    CE in the presence of lipid bilayer disks was introduced as a new approach in membrane partitioning studies. The disks were used as a pseudostationary phase in the partial-filling mode of CE and the partitioning of cationic drugs was determined. The migration times of the analytes increased linearly with the lipid amount in the system. An appropriate algorithm for the calculation of a partition coefficient is presented. In the disk-shaped bilayers, which have excellent stability and shelf life, all of the lipids are readily available for interaction and the disks can be used as realistic cell membrane models.

    Keywords
    bilayer disks, capillary electrophoresis, drugs, model membrane, partitioning
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94751 (URN)10.1002/elps.200700682 (DOI)000258856900012 ()18702061 (PubMedID)
    Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2017-12-14Bibliographically approved
  • 26.
    Boija, Elisabet
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Lundquist, Anna
    Martínez Pla, Juan José
    Engvall, Caroline
    Lundahl, Per
    Effects of ions and detergents in drug partition chromatography on liposomes2004In: Journal of Chromatography A, Vol. 1030, p. 273-278Article in journal (Refereed)
  • 27. Boija, Elisabet
    et al.
    Lundquist, Anna
    Martínez Pla, Juan José
    Engvall, Caroline
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Lundahl, Per
    Effects of ions and detergents in drug partition chromatography on liposomes2004In: Journal of Chromatography A, Vol. 1030, no 1-2, p. 273-278Article in journal (Refereed)
  • 28.
    Boija, Elisabet
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Lundquist, Anna
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Physical Chemistry.
    Martínez Pla, Juan José
    Engvall, Caroline
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Lundahl, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Effects of ions and detergents in drug partition chromatography on liposomes2004In: Journal of chromatography A, Vol. 1030, p. 273-278Article in journal (Refereed)
    Abstract [en]

    We have determined drug partitioning into phospholipid bilayers by immobilized-liposome chromatography. Electrostatic effects on the drug partitioning were observed on neutral bilayers at low ionic strength. The size of the counterions affected the partitioning. When liposomes were supplemented with ionic detergents the partitioning of charged drugs was strongly affected, allowing complete separation of drugs of different charges which showed similar retention on neutral bilayers. Partial separation was obtained on bilayers containing fatty acid. Detergent ions or fatty acid inserted into phospholipid bilayers affected the partitioning of drugs much more than did free ions or phospholipid head group charges.

  • 29.
    Broo, Kerstin
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Larsson, Anna-Karin
    Jemth, Per
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mannervik, Bengt
    An ensemble of Theta class glutathione transferases with novel catalytic properties generated by stochastic recombination of fragments of two mammalian enzymes2002In: Journal of Molecular Biology, Vol. 318, p. 59-70Article in journal (Refereed)
  • 30. Broo, Kerstin
    et al.
    Larsson, Anna-Karin
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Jemth, Per
    Mannervik, Bengt
    An essemble of theta class glutathione transferases with novel catalytic properties generated by stochastic recombination of fragments of two mammalien enzymes2002In: Journal of molecular biology, Vol. 19, no 318, p. 59-70Article in journal (Refereed)
  • 31.
    Brändas, Erkki
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Physics. Chemistry, Department of Biochemistry. QUANTUM CHEMISTRY.
    Öhrn, Yngve
    Aims & Scope International Journal of Quantum Chemistry2001In: International Journal Of Quantum Chemistry, Vol. 81, no 3Other (Other scientific)
  • 32. Brånalt, J
    et al.
    Kvarnstrom, I
    Classon, B
    Samuelsson, B
    Nillroth, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    A convenient synthesis of 1-(S)-[1'-(S)-(t-butyloxycarbonylamino)-2'-phenylethyl]oxirane: a useful building block in the synthesis of HIV protease inhibitors1997In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 38, no 19, p. 3483-3486Article in journal (Refereed)
  • 33.
    Budesinsky, M
    et al.
    Academy of Sciences of the Czech Republic.
    Ragnarsson, U
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Lankiewicz, L
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Grehn, L
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Slaninova, J
    Academy of Sciences of the Czech Republic.
    Hlavacek, J
    Academy of Sciences of the Czech Republic.
    Synthesis and utilization of 13C and 15N backbone-labeled proline: NMR study of synthesized oxytocin with backbone-labeled C-terminal tripeptide amide2005In: Amino Acids, Vol. 29, p. 151-160Article in journal (Refereed)
  • 34.
    Bull, Arthur W
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Seeley, Stacy K
    Geno, Jason
    Mannervik, Bengt
    Conjugation of the linoleic acid oxidation product, 13-oxooctadeca-9,11-dienoic acid, a bioactive endogenous substrate for mammalian glutathione transferase2002In: Biochimica Biophysica Acta, Vol. 1571, p. 77-82Article in journal (Refereed)
  • 35. Cervenanský, C
    et al.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Karlsson, Evert
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Role of arginine residues for the activity of fasciculin1995In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 229, no 1, p. 270-275Article in journal (Refereed)
    Abstract [en]

    The West African green mamba, Dendroaspis angusticeps, has two toxins, fasciculins, that are non-competitive inhibitors of acetylcholinesterase. Arginine residues of fasciculin 2 were modified with 1,2-cyclohexanedione. Two of these residues, Arg24 and Arg37, reacted very slowly or not at all. Modification of Arg28 reduced the activity only by 13%. Arg11 and Arg27 are unique for fasciculins; a comparison of the sequences of 175 snake toxins homologous to fasciculins showed that no other toxin has arginine in the corresponding positions. Modification of the two unique arginines had a large effect and decreased the activity by 73% (Arg11) and 85% (Arg27). This was apparently not due to structural perturbations, since the modification did not change the circular dichroic spectra. The two arginine residues probably participate in the binding to acetylcholinesterase. They are located on the same side of the toxin molecule and the distance between their alpha-carbons is 2.7 nm. This may indicate binding to sites that are far apart and suggests that fasciculin covers a large area of the enzyme

  • 36.
    Cimitan, Samanta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lindgren, Maria T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Bertucci, Carlo
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Early absorption and distribution analysis of antitumor and anti-AIDS drugs: lipid membrane and plasma protein interactions2005In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 10, p. 3536-46Article in journal (Refereed)
  • 37.
    Cocco, R
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Stenberg, G
    Dragani, B
    Principe, DR
    Paludi, D
    Mannervik, B
    Aceto, A
    The folding and stability of human alpha class glutathione transferase A1-1 depend on distinct roles of a conserved N-capping box and hydrophobic staple motif2001In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 276, no 34, p. 32177-32183Article in journal (Refereed)
    Abstract [en]

    An N-capping box and a hydrophobic staple motif are strictly conserved in the core of all known glutathione S-transferases (GST). In the present work, mutations of hGSTA1-1 enzyme residues forming these motifs have been generated. The analysis of S154A, D

  • 38.
    Danielson, Helena
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lindgren, Maria T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Markgren, Per-Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Nillroth, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Investigation of an allosteric site of HIV-1 proteinase involved in inhibition by Cu2+1998In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 436, p. 99-103Article in journal (Refereed)
  • 39.
    David van der Spoel, Paul J. van Maaren and Herman J.C. Berendsen
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    A systematic study of water models for molecular simulation: Derivation of water models optimized for use with a reaction field.1998In: J Chem Phys, Vol. 108, p. 10220-10230Article in journal (Refereed)
  • 40.
    Dragani, B
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Stenberg, G
    Cocco, R
    Mannervik, B
    Aceto, A
    Role of conserved local motifs in folding and stability of hGSTP1-12001In: CHEMICO-BIOLOGICAL INTERACTIONS, ISSN 0009-2797, Vol. 133, no 1-3, p. 17-18Article in journal (Refereed)
    Abstract [en]

    We investigated, by site directed mutagenesis, the role played by a conserved N-capping box and hydrophobic staple motif in the folding and stability of human GSTPl-1. The corresponding mutants, I149A, S150A, D153A and Y154A, in which these motifs have be

  • 41.
    Dreij, Kristian
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Sundberg, Kathrin
    Jernström, Bengt
    Johansson, Ann-Sofie
    Mannervik, Bengt
    Seidel, Albrecht
    Inactivation of carcinogenic diol epoxides of dibenzo[A,L]pyrene (dibenzo[DEF,P]chrysene) by human Alpha class glutathione transferases2002In: Polycyclic Aromatic Compounds, Vol. 22, p. 823-829Article in journal (Refereed)
  • 42.
    Dreij, Kristian
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Sundberg, Kathrin
    Johansson, Ann-Sofie
    Nordling, Erik
    Seidel, Albrecht
    Persson, Bengt
    Mannervik, Bengt
    Jernström, Bengt
    Catalytic activities of human Alpha class glutathione transferases toward carcinogenic dibenzo[a,l]pyrene diol epoxides2002In: Chemical Research of Toxicology, Vol. 15, p. 825-831Article in journal (Refereed)
  • 43.
    E Karlsson, A L Harvey, C Cerveñansky, G J Kleywegt, M Harel, I Silman & J L Sussman
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Fasciculins, cholinesterase inhibitors from mamba venom1998In: Enzymes from Snake Venom, Alaken Inc., Fort Collins, CO , 1998, p. 633-688Chapter in book (Refereed)
  • 44.
    Edalat, Maryam
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Multiple Functions of Glutathione Transferases: A Study on Enzymatic Function, Regulatory Role and Distribution in Mouse and Man2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To cope with various endogenous toxin and xenobiotics nature has equipped the organisms with a proper protection system. Glutathione transferases (GSTs) are important components of the cellular defense against oxidative stress. These proteins appear to be suited for different tasks.

    Based on catalytic activity of GSTs with monochlorobimane (MCB), a screening method was developed for identification of active GSTs in bacterial colonies and for characterization of combinatorial GST libraries.

    Solvent viscosity effects on kcat and kcat/Km on wild-type human GST A1-1 and phenylalanine-220 mutants indicate a physical step being the rate-limiting step in the catalytic mechanism.

    Three residues that were under evolutionary selection pressure were identified in Mu class GSTs. By changing these residues in human GSTM2-2, a 1000-fold change of catalytic activity towards GSTM1-1 was accomplished.

    Using peptide phage display, a peptide sequence was found that acts as non-substrate ligand for human GST M2-2. The peptide sequence was shown to be highly similar to the C-terminal region of c-Jun N-terminal kinase (JNK). JNK is a kinase linked to activating protein-1 (AP-1) transcriptional activity, which is part of the regulation of cell proliferation and apoptosis in response to cellular stress. Reporter gene assays in cell lines showed that human GST M2-2 coactivates the transcriptional activity of AP-1.

    GSTs as part of the cellular defense against oxidative stress could be important in inflammatory processes. The distribution of GSTs in the intestine of both mice and human in abnormal inflammatory state was investigated immunohistochemically. Using an experimental mouse model, it was shown that mouse GST A4-4 is markedly induced while, the expression of Mu and Pi class GSTs is reduced in the colon of conventional and germ-free mice with extensive colitis. Moreover, the expression of mouse GST A4-4 was elevated with time when germ-free mice were exposed to normal bacteria flora. In contrast, Mu and Pi class GSTs showed decreased expression in the colon of germ-free mice associated with commensal flora. The Alpha, Mu and Pi class GST levels in mouse colon were increased when germ-free mice received Lactobacillus strain GG.

    The distribution of Alpha, Mu and Pi class GST in the intestinal tissues of patients with Crohn’s disease was investigated using immunohistochemistry. All the three classes were consistently expressed in the intestinal epithelium as well as in macrophage-like cells and smooth muscle tissue. The mucus secreting goblet cells, however, did not express Alpha class GST.

  • 45. Edalat, Maryam H
    et al.
    Mannervik, Bengt
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Peptide phage display for probing GST-protein interactions.2005In: Methods Enzymol, ISSN 0076-6879, Vol. 401, p. 354-67Article in journal (Refereed)
    Abstract [en]

    Phage display is a powerful strategy for identifying protein-peptide interactions. Glutathione transferases (GSTs) play prominent roles in the cellular protection against oxidative stress by catalyzing detoxication reactions. In addition, GSTs seem to act in signaling pathways by means of interaction with other macromolecules such as protein kinases. This chapter describes how the technique of peptide phage display can be used to identify possible partners in GST-protein complexes.

  • 46.
    Edalat, Maryam
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Mannervik, Bengt
    Technology, Department of Materials Science. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Axelsson, Lars-Göran
    Selective expression of detoxifying glutathione transferases in mouse colon: effect of experimental colitis and the presence of bacteria.2004In: Histochem Cell Biol, ISSN 0948-6143, Vol. 122, no 2, p. 151-9Article in journal (Refereed)
  • 47.
    Edalat, Maryam
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Persson, Mats A.A.
    Mannervik, Bengt
    Selective recognition of peptide sequences by glutathione transferases: a possible mechanism for modulation of cellular stress-induced signaling pathways2003In: Biological Chemistry, Vol. 384, p. 645-651Article in j