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  • 1. Bendsen, Nathalie T.
    et al.
    Stender, Steen
    Szecsi, Pal B.
    Pedersen, Steen B.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Hellgren, Lars I.
    Newman, John W.
    Larsen, Thomas M.
    Haugaard, Steen B.
    Astrup, Arne
    Effect of industrially produced trans fat on markers of systemic inflammation: evidence from a randomized trial in women2011Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 10, s. 1821-1828Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Consumption of industrially produced trans fatty acids (IP-TFA) has been positively associated with systemic markers of low-grade inflammation and endothelial dysfunction in cross-sectional studies, but results from intervention studies are inconclusive. Therefore, we conducted a 16 week double-blind parallel intervention study with the objective to examine the effect of IP-TFA intake on bio-markers of inflammation, oxidative stress, and endothelial dysfunction. Fifty-two healthy overweight postmenopausal women (49 completers) were randomly assigned to receive either partially hydrogenated soybean oil (15.7 g/day IP-TFA) or control oil without IP-TFA. After 16 weeks, IP-TFA intake increased baseline-adjusted serum tumor necrosis factor (TNF) alpha by 12% [95% confidence interval (CI): 5-20; P = 0.002] more in the IP-TFA group compared with controls. Plasma soluble TNF receptors 1 and 2 were also increased by IP-TFA [155 pg/ml (CI: 63-247); P < 0.001 and 480 pg/ml (CI: 72-887); P = 0.02, respectively]. Serum C-reactive protein, interleukin (IL) 6 and adiponectin and subcutaneous abdominal adipose tissue mRNA expression of IL6, IL8, TNF alpha, and adiponectin as well as ceramide content were not affected by IP-TFA, nor was urinary 8-iso-prostaglandin-F(2 alpha). In conclusion, this dietary trial indicates that the mechanisms linking dietary IP-TFA to cardiovascular disease may involve activation of the TNF alpha system.

  • 2.
    Bowden, John A.
    et al.
    NIST, Marine Biochem Sci Grp, Div Chem Sci, Hollings Marine Lab, Charleston, SC 29412 USA..
    Heckert, Alan
    NIST, Stat Engn Div, Gaithersburg, MD 20899 USA..
    Ulmer, Candice Z.
    NIST, Marine Biochem Sci Grp, Div Chem Sci, Hollings Marine Lab, Charleston, SC 29412 USA..
    Jones, Christina M.
    NIST, Marine Biochem Sci Grp, Div Chem Sci, Hollings Marine Lab, Charleston, SC 29412 USA..
    Koelmel, Jeremy P.
    Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA..
    Abdullah, Laila
    Roskamp Inst, Sarasota, FL USA..
    Ahonen, Linda
    Steno Diabet Ctr Copenhagen, Gentofte, Denmark..
    Alnouti, Yazen
    Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE USA..
    Armando, Aaron M.
    Univ Calif San Diego, Sch Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Asara, John M.
    Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Bamba, Takeshi
    Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Metabol,Higashi Ku, Fukuoka, Japan..
    Barr, John R.
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Borchers, Christoph H.
    Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC, Canada.;Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada.;McGill Univ, Jewish Gen Hosp, Gerald Bronfman Dept Oncol, Montreal, PQ, Canada.;McGill Univ, Jewish Gen Hosp, Prote Ctr, Segal Canc Ctr,Lady Davis Inst, Montreal, PQ, Canada..
    Brandsma, Joost
    Univ Southampton, Southampton Gen Hosp, Acad Unit Clin & Expt Sci, Fac Med, Southampton, Hants, England..
    Breitkopf, Susanne B.
    Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA..
    Cajka, Tomas
    Univ Calif Davis, Genome Ctr, Natl Inst Hlth West Coast Metabol Ctr, Davis, CA 95616 USA..
    Cazenave-Gassiot, Amaury
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Cinel, Michelle A.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Colas, Romain A.
    Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Cremers, Serge
    Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, Biomarker Core Lab, New York, NY USA..
    Dennis, Edward A.
    Univ Calif San Diego, Sch Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Evans, James E.
    Roskamp Inst, Sarasota, FL USA..
    Fauland, Alexander
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Fiehn, Oliver
    Univ Calif Davis, Genome Ctr, Natl Inst Hlth West Coast Metabol Ctr, Davis, CA 95616 USA.;King Abdulaziz Univ, Biochem Dept, Jeddah, Saudi Arabia..
    Gardner, Michael S.
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Garrett, Timothy J.
    Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA..
    Gotlinger, Katherine H.
    New York Med Coll, Sch Med, Dept Pharmacol, Valhalla, NY 10595 USA..
    Han, Jun
    Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC, Canada..
    Huang, Yingying
    Thermo Fisher Sci, San Jose, CA USA..
    Neo, Aveline Huipeng
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Hyotylainen, Tuulia
    Orebro Univ, Dept Chem, Orebro, Sweden..
    Izumi, Yoshihiro
    Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Metabol,Higashi Ku, Fukuoka, Japan..
    Jiang, Hongfeng
    Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, Biomarker Core Lab, New York, NY USA..
    Jiang, Houli
    New York Med Coll, Sch Med, Dept Pharmacol, Valhalla, NY 10595 USA..
    Jiang, Jiang
    Univ Calif San Diego, Sch Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Kachman, Maureen
    Univ Michigan, BRCF, Metabol Core, Ann Arbor, MI 48109 USA..
    Kiyonami, Reiko
    Thermo Fisher Sci, San Jose, CA USA..
    Klavins, Kristaps
    Biocrates Life Sci AG, Innsbruck, Austria..
    Klose, Christian
    Lipotype GmbH, Dresden, Germany..
    Kofeler, Harald C.
    Med Univ Graz, Core Facil Mass Spectrometry, Graz, Austria..
    Kolmert, Johan
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Koal, Therese
    Biocrates Life Sci AG, Innsbruck, Austria..
    Koster, Grielof
    Univ Southampton, Southampton Gen Hosp, Acad Unit Clin & Expt Sci, Fac Med, Southampton, Hants, England..
    Kuklenyik, Zsuzsanna
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Kurland, Irwin J.
    Albert Einstein Coll Med, Diabet Res Ctr, Stable Isotope & Metabol Core Facil, Bronx, NY 10467 USA..
    Leadley, Michael
    Hosp Sick Children, Res Inst, Analyt Facil Bioact Mol, Toronto, ON, Canada..
    Lin, Karen
    Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC, Canada..
    Maddipati, Krishna Rao
    Wayne State Univ, Lipid Core Facil, Detroit, MI USA.;Wayne State Univ, Dept Pathol, Detroit, MI USA..
    McDougall, Danielle
    Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA..
    Meikle, Peter J.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Mellett, Natalie A.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Monnin, Cian
    Concordia Univ, Dept Chem & Biochem, Montreal, PQ, Canada..
    Moseley, M. Arthur
    Duke Univ, Sch Med, Levine Sci Res Ctr, Prote & Metabol Shared Resource, Durham, NC USA..
    Nandakumar, Renu
    Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, Biomarker Core Lab, New York, NY USA.;Lipotype GmbH, Dresden, Germany..
    Oresic, Matej
    Univ Turku, Turku Ctr Biotechnol, Turku, Finland.;Abo Akad Univ, Turku, Finland..
    Patterson, Rainey
    Peake, David
    Pierce, Jason S.
    Post, Martin
    Hosp Sick Children, Res Inst, Analyt Facil Bioact Mol, Toronto, ON, Canada..
    Postle, Anthony D.
    Pugh, Rebecca
    NIST, Chem Sci Div, Environm Specimen Bank Grp, Hollings Marine Lab, Charleston, SC USA..
    Qiu, Yunping
    Albert Einstein Coll Med, Diabet Res Ctr, Stable Isotope & Metabol Core Facil, Bronx, NY 10467 USA..
    Quehenberger, Oswald
    Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Ramrup, Parsram
    Rees, Jon
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Rembiesa, Barbara
    Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC USA..
    Reynaud, Denis
    Hosp Sick Children, Res Inst, Analyt Facil Bioact Mol, Toronto, ON, Canada..
    Roth, Mary R.
    Kansas State Univ, Kansas Lipid Res Ctr, Div Biol, Manhattan, KS 66506 USA..
    Sales, Susanne
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Schuhmann, Kai
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Schwartzman, Michal Laniado
    New York Med Coll, Sch Med, Dept Pharmacol, Valhalla, NY 10595 USA..
    Serhan, Charles N.
    Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Shevchenko, Andrej
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Somerville, Stephen E.
    Med Univ South Carolina, Hollings Marine Lab, Charleston, SC USA..
    John-Williams, Lisa St.
    Duke Univ, Sch Med, Levine Sci Res Ctr, Prote & Metabol Shared Resource, Durham, NC USA..
    Surma, Michal A.
    Univ Michigan, BRCF, Metabol Core, Ann Arbor, MI 48109 USA..
    Takeda, Hiroaki
    Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Metabol,Higashi Ku, Fukuoka, Japan..
    Thakare, Rhishikesh
    Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE USA..
    Thompson, J. Will
    Duke Univ, Sch Med, Levine Sci Res Ctr, Prote & Metabol Shared Resource, Durham, NC USA..
    Torta, Federico
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Triebl, Alexander
    Med Univ Graz, Core Facil Mass Spectrometry, Graz, Austria..
    Troetzmueller, Martin
    Med Univ Graz, Core Facil Mass Spectrometry, Graz, Austria..
    Ubhayasekera, S. J. Kumari
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Vuckovic, Dajana
    Weir, Jacquelyn M.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Welti, Ruth
    Kansas State Univ, Kansas Lipid Res Ctr, Div Biol, Manhattan, KS 66506 USA..
    Wenk, Markus R.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Yao, Libin
    Kansas State Univ, Kansas Lipid Res Ctr, Div Biol, Manhattan, KS 66506 USA..
    Yuan, Min
    Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA..
    Zhao, Xueqing Heather
    Albert Einstein Coll Med, Diabet Res Ctr, Stable Isotope & Metabol Core Facil, Bronx, NY 10467 USA..
    Zhou, Senlin
    Wayne State Univ, Lipid Core Facil, Detroit, MI USA.;Wayne State Univ, Dept Pathol, Detroit, MI USA..
    Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma2017Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, nr 12, s. 2275-2288Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra-and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium.jlr While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

  • 3.
    Chen, Yang
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wennman, Anneli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karkehabadi, Saeid
    Swedish Univ Agr Sci, Dept Chem & Biotechnol, SE-75007 Uppsala, Sweden.
    Engström, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Oliw, Ernst H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Crystal structure of linoleate 13R-manganese lipoxygenase in complex with an adhesion protein.2016Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, nr 8, s. 1574-1588Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The crystal structure of 13R-manganese lipoxygenase (MnLOX) of Gaeumannomyces graminis (Gg) in complex with zonadhesin of Pichia pastoris was solved by molecular replacement. Zonadhesin contains β-strands in two subdomains. A comparison of Gg-MnLOX with the 9S-MnLOX of Magnaporthe oryzae (Mo) shows that the protein fold and the geometry of the metal ligands are conserved. The U-shaped active sites differ mainly due to hydrophobic residues of the substrate channel. The volumes and two hydrophobic side pockets near the catalytic base may sanction oxygenation at C-13 and C-9, respectively. Gly-332 of Gg-MnLOX is positioned in the substrate channel between the entrance and the metal center. Replacements with larger residues could restrict oxygen and substrate to reach the active site. C18 fatty acids are likely positioned with C-11 between Mn(2+)OH2 and Leu-336 for hydrogen abstraction and with one side of the 12Z double bond shielded by Phe-337 to prevent antarafacial oxygenation at C-13 and C-11. Phe-347 is positioned at the end of the substrate channel and replacement with smaller residues can position C18 fatty acids for oxygenation at C-9. Gg-MnLOX does not catalyze the sequential lipoxygenation of n-3 fatty acids in contrast to Mo-MnLOX, which illustrates the different configurations of their substrate channels.

  • 4.
    Cristea, Mirela
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oliw, Ernst H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    On the singular, dual, and multiple positional specificity of manganese lipoxygenase and its G316A mutant2007Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 48, nr 4, s. 890-903Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Manganese lipoxygenase (Mn-LO) oxygenates 18:3n-3 and 18:2n-6 to bis-allylic 11S-hydroperoxy fatty acids, which are converted to 13R-hydroperoxy fatty acids. Other unsaturated C16-C22 fatty acids, except 17:3n-3, are poor substrates, possibly due to ineffective enzyme activation (MnIIMnIII) by produced hydroperoxides. Our aim was to determine whether unsaturated C16-C22 fatty acids were oxidized by MnIII-LO. MnIII-LO oxidized C16, C19, C20, and C22 n-3 and n-6 fatty acids. The carbon chain length influenced the position of hydrogen abstraction (n-8, n-5) and oxygen insertion at the terminal or the penultimate 1Z,4Z-pentadienes. Dilinoleoyl¬glycero¬phosphatidyl¬¬choline was oxidized by Mn-LO in agreement with a “tail first” model. 16:3n-3 was oxidized at the bis-allylic n-5 carbon and at positions n-3, n-7, and n-6. Long fatty acids, 19:3n-3, 20:3n-3, 20:4n-6, 22:5n-3, and 22:5n-6, were mainly oxidized at the n-6 and the bis-allylic n-8 positions (in ratios of ~3:2). The bis-allylic hydroperoxides accumulated with one exception, 13-hydroperoxyeicosatetraenoic acid (13-HPETE). MnIII-LO oxidized 20:4n-6 to 15R-HPETE (~60%) and 13-HPETE (~37%) and converted 13-HPETE to 15R-HPETE. MnIII-LO G316A mainly oxygenated 16:3n-3 at positions n-7 and n-6, 19:3n-3 at n-10, n-8, and n-6, 20:3n-3 at n-10 and n-8. We conclude that Mn-LO likely binds fatty acids “tail first” and oxygenates many C16, C18, C20 and C22 fatty acids to significant amounts of bis-allylic hydroperoxides.

  • 5. Frank, J.
    et al.
    Budek, A.
    Lundh, T.
    Parker, R.S.
    Swanson, J.E.
    Lourenco, C.F.
    Gago, B.
    Laranjinha, J.
    Vessby, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kamal-Eldin, A.
    Dietary flavonoids with a catechol structure increase alpha-tocopherol in rats and protect the vitamin from oxidation in vitro2006Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 47, nr 12, s. 2718-2725Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To identify dietary phenolic compounds capable of improving vitamin E status, male Sprague-Dawleyrats were fed for 4 weeks either a basal diet ( control) with 2 g/kg cholesterol and an adequate content of vitamin E or the basal diet fortified with quercetin ( Q), (2)-epicatechin (EC), or (1)-catechin ( C) at concentrations of 2 g/kg. All three catechol derivatives substantially increased concentrations of alpha-tocopherol (alpha-T) in blood plasma and liver. To study potential mechanisms underlying the observed increase of alpha-T, the capacities of the Flavonoids to i) protect alpha-T from oxidation in LDL exposed to peroxyl radicals, ii) reduce alpha-tocopheroxyl radicals (alpha-T-.) in SDS micelles, and iii) inhibit the metabolism of tocopherols in HepG2 cells were determined. All flavonoids protected alpha-T from oxidation in human LDL ex vivo and dose-dependently reduced the concentrations of alpha-T-.. None of the test compounds affected vitamin E metabolism in the hepatocyte cultures. In conclusion, fortification of the diet of Sprague-Dawley rats with Q, EC, or C considerably improved their vitamin E status. The underlying mechanism does not appear to involve vitamin E metabolism but may involve direct quenching of free radicals or reduction of the alpha-T-. by the flavonoids.

  • 6.
    Hoffmann, Inga
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jernerén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oliw, Ernst H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Epoxy alcohol synthase of the rice blast fungus represents a novel subfamily of dioxygenase-cytochrome P450 fusion enzymes2014Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 55, nr 10, s. 2113-2123Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genome of the rice blast fungus Magnaporthe oryzae codes for two proteins with N-terminal dioxygenase (DOX) and C-terminal cytochrome P450 (CYP) domains, respectively. One of them, MGG_ 13239, was confirmed as 7,8-linoleate diol synthase by prokaryotic expression. The other recombinant protein (MGG_ 10859) possessed prominent 10R-DOX and epoxy alcohol synthase (EAS) activities. This enzyme, 10R-DOX-EAS, transformed 18:2n-6 sequentially to 10(R)-hydroperoxy-8(E), 12(Z)-octadecadienoic acid (10R-HPODE) and to 12S(13R)-epoxy-10(R)-hydroxy-8(E)octadecenoic acid as the end product. Oxygenation at C-10 occurred by retention of the pro-R hydrogen of C-8 of 18:2n-6, suggesting antarafacial hydrogen abstraction and oxygenation. Experiments with O-18(2) and O-16(2) gas confirmed that the epoxy alcohol was formed from 10R-HPODE, likely by heterolytic cleavage of the dioxygen bond with formation of P450 compound I, and subsequent intramolecular epoxidation of the 12(Z) double bond. Site-directed mutagenesis demonstrated that the cysteinyl heme ligand of the P450 domain was required for the EAS activity. Replacement of Asn(965) with Val in the conserved AsnGlnXaaGln sequence revealed that Asn965 supported formation of the epoxy alcohol. 10R-DOX-EAS is the first member of a novel subfamily of DOX-CYP fusion proteins of devastating plant pathogens.

  • 7.
    Hoffmann, Inga
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oliw, Ernst H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Discovery of a linoleate 9S-dioxygenase and an allene oxide synthase in a fusion protein of Fusarium oxysporum2013Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 54, nr 12, s. 3417-3480Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fusarium oxysporum is a devastating plant pathogen that oxidizes C-18 fatty acids sequentially to jasmonates. The genome codes for putative dioxygenase (DOX)-cytochrome P450 (CYP) fusion proteins homologous to linoleate diol synthases (LDSs) and the allene oxide synthase (AOS) of Aspergillus terreus, e. g., FOXB_01332. Recombinant FOXB_01332 oxidized 18:2n-6 to 9S-hydroperoxy-10(E), 12(Z)-octadecadienoic acid by hydrogen abstraction and antarafacial insertion of molecular oxygen and sequentially to an allene oxide, 9S(10)-epoxy-10,12(Z)-octadecadienoic acid, as judged from nonenzymatic hydrolysis products (alpha- and gamma-ketols). The enzyme was therefore designated 9S-DOX-AOS. The 9S-DOX activity oxidized C-18 and C-20 fatty acids of the n-6 and n-3 series to hydroperoxides at the n-9 and n-7 positions, and the n-9 hydroperoxides could be sequentially transformed to allene oxides with only a few exceptions. The AOS activity was stereospecific for 9- and 11-hydroperoxides with S configurations. FOXB_01332 has acidic and alcoholic residues, Glu(946)-Val-Leu-Ser(949), at positions of crucial Asn and Gln residues (Asn-Xaa-Xaa-Gln) of the AOS and LDS. Site-directed mutagenesis studies revealed that FOXB_01332 and AOS of A. terreus differ in catalytically important residues suggesting that AOS of A. terreus and F. oxysporum belong to different subfamilies. FOXB_01332 is the first linoleate 9-DOX with homology to animal heme peroxidases and the first 9-DOX-AOS fusion protein.

  • 8. Kallin, Anders
    et al.
    Johannessen, Lene E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Cani, Patrice D.
    Marbehant, Catherine Y.
    Essaghir, Ahmed
    Foufelle, Fabienne
    Ferré, Pascal
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Delzenne, Nathalie M.
    Demoulin, Jean-Baptiste
    SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55 gamma2007Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 48, nr 7, s. 1628-1636Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sterol-regulatory element binding proteins (SREBPs) control the expression of genes involved in fatty acid and cholesterol biosynthesis. Using microarrays, we observed that mature SREBP-1 also induced the expression of genes unrelated to lipid metabolism, such as heme oxygenase 1 (HMOX1), plasma glutathione peroxidase, the phosphatidylinositol-3 kinase regulatory subunit p55 gamma, synaptic vesicle glycoprotein 2A, and COTE1. The expression of these genes was repressed upon addition of sterols, which block endogenous SREBP cleavage, and was induced by the statin drug mevinolin. Stimulation of fibroblasts with platelet-derived growth factor, which activates SREBP-1, had a similar effect. Fasted mice that were refed with a high-carbohydrate diet presented an increased expression of HMOX1 and p55 gamma in the liver. Overall, the transcriptional signature of SREBP-1 in fibroblasts stimulated by growth factors was very similar to that described in liver cells. We analyzed the HMOX1 promoter and found one SREBP binding site of the E-box type, which was required for regulation by SREBP-1a and SREBP-1c but was insensitive to SREBP-2. In conclusion, our data suggest that SREBP-1 regulates the expression of stress response and signaling genes, which could contribute to the metabolic response to insulin and growth factors in various tissues.

  • 9. Kast, Heidi Rachelle
    et al.
    Nguyen, Catherine M.
    Anisfeld, Andrew M.
    Ericsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Edwards, Peter A.
    CTP: phosphocholine cytidylyltransferase, a new sterol- and SREBP-responsive gene2001Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 42, nr 8, s. 1266-1272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The CTP:phosphocholine cytidylyltransferase (CT) gene encodes the rate-controlling enzyme in the phosphatidylcholine biosynthesis pathway. CTalpha mRNA levels, like farnesyl diphosphate synthase and the LDL receptor, are repressed when human or rodent cells are incubated with exogenous sterols and induced when cells are incubated in lipid-depleted medium. A putative sterol response element (SRE) was identified 156 bp upstream of the transcription start site of the CTalpha gene. Electrophoretic mobility shift assays demonstrate that recombinant SREBP-1a binds to the wild-type SRE identified in the CTalpha promoter but not to oligonucleotides containing two mutations in the SRE. In other studies, a luciferase reporter construct under the control of the murine CTalpha proximal promoter was transiently transfected into cells. The activity of the reporter was repressed after addition of sterols to the medium and induced when the cells were incubated in lipid-depleted medium. The activity of the CTalpha-luciferase reporter was also induced when cells were cotransfected with plasmids encoding either SREBP-1a or SREBP-2. In contrast, no induction was observed under the same conditions when the CTalpha promoter-reporter gene contained two mutations in the SRE. In addition, the induction of the wild-type CTalpha promoter-reporter gene that occurs in cells incubated in lipid-depleted medium is attenuated when dominant-negative SREBP is cotransfected into the cells. These studies demonstrate that transcription of the CTalpha gene is inhibited by sterols and activated by mature forms of SREBP. We conclude that SREBP-regulated genes are involved not only in the synthesis of cholesterol, fatty acids, triglycerides, and NADPH, but also, as shown here, in the synthesis of phospholipids.

  • 10. Liu, Li
    et al.
    Yu, Shuiqing
    Khan, Raffay S
    Ables, Gene P
    Bharadwaj, Kalyani G
    Hu, Yunying
    Huggins, Lesley A
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Buckett, Linda K
    Turnbull, Andrew V
    Ginsberg, Henry N
    Blaner, William S
    Huang, Li-Shin
    Goldberg, Ira J
    DGAT1 deficiency decreases PPAR expression and does not lead to lipotoxicity in cardiac and skeletal muscle2011Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 4, s. 732-744Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diacylglycerol (DAG) acyl transferase 1 (Dgat1) knockout (−/−) mice are resistant to high-fat-induced obesity and insulin resistance, but the reasons are unclear. Dgat1−/− mice had reduced mRNA levels of all three Ppar genes and genes involved in fatty acid oxidation in the myocardium of Dgat1−/− mice. Although DGAT1 converts DAG to triglyceride (TG), tissue levels of DAG were not increased in Dgat1−/− mice. Hearts of chow-diet Dgat1−/− mice were larger than those of wild-type (WT) mice, but cardiac function was normal. Skeletal muscles from Dgat1−/− mice were also larger. Muscle hypertrophy factors phospho-AKT and phospho-mTOR were increased in Dgat1−/− cardiac and skeletal muscle. In contrast to muscle, liver from Dgat1−/− mice had no reduction in mRNA levels of genes mediating fatty acid oxidation. Glucose uptake was increased in cardiac and skeletal muscle in Dgat1−/− mice. Treatment with an inhibitor specific for DGAT1 led to similarly striking reductions in mRNA levels of genes mediating fatty acid oxidation in cardiac and skeletal muscle. These changes were reproduced in cultured myocytes with the DGAT1 inhibitor, which also blocked the increase in mRNA levels of Ppar genes and their targets induced by palmitic acid. Thus, loss of DGAT1 activity in muscles decreases mRNA levels of genes involved in lipid uptake and oxidation.

  • 11.
    Love-Gregory, Latisha
    et al.
    Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA..
    Kraja, Aldi T.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Allum, Fiona
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada..
    Aslibekyan, Stella
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA..
    Hedman, Åsa K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Duan, Yanan
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Arnett, Donna K.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7JU, England.;Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7JU, England..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, London EC1M 6BQ, England..
    Ordovas, Jose M.
    Tufts Univ, JM USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA..
    Hopkins, Paul N.
    Univ Utah, Cardiovasc Genet Res, Salt Lake City, UT 84132 USA..
    Grundberg, Elin
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0G1, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada..
    Abumrad, Nada A.
    Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA..
    Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD362016Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, nr 12, s. 2176-2184Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a approximate to 410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPAR, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids.

  • 12.
    Norlin, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Toll, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bjorkhem, Ingemar
    Wikvall, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    24-Hydroxycholesterol is a substrate for hepatic cholesterol 7 alpha-hydroxylase (CYP7A)2000Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 41, nr 10, s. 1629-1639Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    (24S)-Hydroxycholesterol is formed from cholesterol in the brain and is important for cholesterol homeostasis in this organ. Elimination of (24S)-hydroxycholesterol has been suggested to occur in the liver but little is known about the metabolism of this oxysterol. In the present investigation, we report formation of 7alpha, 24-dihydroxycholesterol in pig and human liver. 7alpha-hydroxylase activity toward both isomers of 24-hydroxycholesterol [(24S) and (24R)] was found in a partially purified and reconstituted cholesterol 7alpha-hydroxylase (CYP7A) enzyme fraction from pig liver microsomes. In contrast, a purified enzyme fraction of pig liver oxysterol 7alpha-hydroxylase with high activity toward 27-hydroxycholesterol did not show any detectable activity toward 24-hydroxycholesterol. 7alpha-Hydroxylation of 24-hydroxycholesterol was strongly inhibited by 7-oxocholesterol, a known inhibitor of CYP7A. Human CYP7A, recombinantly expressed in Escherichia coli and in simian COS cells, showed 7alpha-hydroxylase activity toward both cholesterol and the two isomers of 24-hydroxycholesterol, with a preference for the (24S)-isomer. Our results show that 24-hydroxycholesterol is metabolized by CYP7A, an enzyme previously considered to be specific for cholesterol and cholestanol and not active toward oxysterols. Because CYP7A is the rate-limiting enzyme in the major pathway of bile acid biosynthesis, the possibility is discussed that at least part of the 24-hydroxycholesterol is converted into 7alpha-hydroxylated bile acids by the enzymes involved in the normal biosynthesis of bile acids.

  • 13.
    Norlin, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    von Bahr, Sara
    Björkhem, Ingemar
    Wikvall, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    On the substrate specificity of human CYP27A1: implications for bile acid and cholestanol formation2003Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 44, nr 8, s. 1515-1522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mitochondrial sterol 27-hydroxylase (CYP27A1) is required for degradation of the C27-sterol side chain in bile acid biosynthesis. CYP27A1 seems, however, to have roles beyond this, as illustrated by patients with a deficient sterol 27-hydroxylase due to mutations of the CYP27A1 gene [cerebrotendinous xanthomatosis (CTX)]. These subjects have symptoms ranging from accumulation of bile alcohols and cholestanol to accelerated atherosclerosis and progressive neurologic impairment. The present work describes a detailed investigation on the substrate specificity of recombinant human CYP27A1. In accordance with some previous work with rat liver mitochondria, the activity in general increased with the polarity of the substrate. An obvious example was the finding that cholesterol was 27-hydroxylated more efficiently than cholesterol oleate but less efficiently than cholesterol sulfate. The oxysterols 24S-hydroxycholesterol and 25-hydroxycholesterol were 27-hydroxylated less efficiently than cholesterol, possibly due to steric hindrance. Surprisingly, sterols with a 3-oxo-Delta4 structure were found to be hydroxylated at a much higher rate than the corresponding sterols with a 3beta-hydroxy-Delta5 structure. The rates of hydroxylation of the sterols were: 7alpha-hydroxy-4-cholesten-3-one>4-cholesten-3-one>7alpha-hydroxycholesterol>24-hydroxy-4-cholesten-3-one> cholesterol>25-hydroxy-4-cholesten-3-one>24-hydroxycholesterol>or=25-hydroxycholesterol. The possibility is discussed that the findings may have implications for oxysterol-mediated regulation of gene expression. The very high activity of CYP27A1 towards the cholestanol precursor 4-cholesten-3-one may be of importance in connection with the accumulation of cholestanol in patients with CTX.

  • 14.
    Oliw, E
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hamberg, Mats
    Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    An allene oxide and 12-oxophytodienoic acid are key intermediates in jasmonic acid biosynthesis by Fusarium oxysporum2017Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, nr 8, s. 1670-1680Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fungi can produce jasmonic acid (JA) and its isoleucine conjugate in large quantities, but little is known about the biosynthesis. Plants form JA from 18: 3n-3 by 13S-lipoxygenase (LOX), allene oxide synthase, and allene oxide cyclase. Shaking cultures of Fusarium oxysporum f.sp. tulipae released over 200 mg of jasmonates per liter. Nitrogen powder of the mycelia expressed 10R-dioxygenase-epoxy alcohol synthase activities, which was confirmed by comparison with the recombinant enzyme. The 13S-LOX of F. oxysporum could not be detected in the cell-free preparations. Incubation of mycelia in phosphate buffer with [17,17,18,18,18-2 H5] 18: 3n-3 led to biosynthesis of a [H-2(5)] 12-oxo-13-hydroxy-9Z, 15Z-octadecadienoic acid (. -ketol), [H-2(5)] 12-oxo-10,15Z-phytodienoic acid (12-OPDA), and [H-2(5)] 13-keto-and [H-2(5)] 13S-hydroxyoctadecatrienoic acids. The. -ketol consisted of 90% of the 13R stereoisomer, suggesting its formation by nonenzymatic hydrolysis of an allene oxide with 13S configuration. Labeled and unlabeled 12-OPDA were observed following incubation with 0.1 mM [H-2(5)] 18: 3n-3 in a ratio from 0.4: 1 up to 47: 1 by mycelia of liquid cultures of different ages, whereas 10 times higher concentration of [H-2(5)] 13S-hydroperoxyoctadecatrienoic acid was required to detect biosynthesis of [H-2(5)] 12-OPDA. The allene oxide is likely formed by a cytochrome P450 or catalase-related hydroperoxidase. We conclude that F. oxysporum, like plants, forms jasmonates with an allene oxide and 12-OPDA as intermediates.

  • 15.
    Oliw, Ernst H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Factors influencing the rearrangement of bis-allylic hydroperoxides by manganese lipoxygenase2008Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 49, nr 2, s. 420-428Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Manganese lipoxygenase (Mn-LOX) catalyzes the rearrangement of bis-allylic S-hydroperoxides to allylic R-hydroperoxides, but little is known about the reaction mechanism. 1-Linoleoyl-lysoglycerophosphatidylcholine was oxidized in analogy with 18:2n-6 at the bis-allylic carbon with rearrangement to C-13 at the end of lipoxygenation, suggesting a "tail-first" model. The rearrangement of bis-allylic hydroperoxides was influenced by double bond configuration and the chain length of fatty acids. The Gly316Ala mutant changed the position of lipoxygenation toward the carboxyl group of 20:2n-6 and 20:3n-3 and prevented the bis-allylic hydroperoxide of 20:3n-3 but not 20:2n-6 to interact with the catalytic metal. The oxidized form, Mn-III-LOX, likely accepts an electron from the bis-allylic hydroperoxide anion with the formation of the peroxyl radical, but rearrangement of 11-hydroperoxyoctadecatrienoic acid by Mn-LOX was not reduced in D2O(pD7.5), and aqueous Fe3+ did not transfer 11S-hydroperoxy-9Z,12Z,15Z-octadecatrienoic acid to allylic hydroperoxides. Mutants in the vicinity of the catalytic metal, Asn466Leu and Ser469Ala, had little influence on bis-allylic hydroperoxide rearrangement. In conclusion, Mn-LOX transforms bis-allylic hydroperoxides to allylic by a reaction likely based on the positioning of the hydroperoxide close to Mn3+ and electron transfer to the metal, with the formation of a bis-allylic peroxyl radical, beta-fragmentation, and oxygenation under steric control by the protein.

  • 16.
    Oliw, Ernst H
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Aragó, Marc
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Chen, Yang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jernerén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A new class of fatty acid allene oxide formed by the DOX-P450 fusion proteins of human and plant pathogenic fungi, C. immitis and Z. tritici.2016Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, nr 8, s. 1518-1528Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Linoleate dioxygenase-cytochrome P450 (DOX-CYP) fusion enzymes are common in pathogenic fungi. The DOX domains form hydroperoxy metabolites of 18:2n-6, which can be transformed by the CYP domains to 1,2- or 1,4-diols, epoxy alcohols, or to allene oxides. We have characterized two novel allene oxide synthases (AOSs), namely, recombinant 8R-DOX-AOS of Coccidioides immitis (causing valley fever) and 8S-DOX-AOS of Zymoseptoria tritici (causing septoria tritici blotch of wheat). The 8R-DOX-AOS oxidized 18:2n-6 sequentially to 8R-hydroperoxy-9Z,12Z-octadecadienoic acid (8R-HPODE) and to an allene oxide, 8R(9)-epoxy-9,12Z-octadecadienoic acid, as judged from the accumulation of the α-ketol, 8S-hydroxy-9-oxo-12Z-octadecenoic acid. The 8S-DOX-AOS of Z. tritici transformed 18:2n-6 sequentially to 8S-HPODE and to an α-ketol, 8R-hydroxy-9-oxo-12Z-octadecenoic acid, likely formed by hydrolysis of 8S(9)-epoxy-9,12Z-octadecadienoic acid. The 8S-DOX-AOS oxidized [8R-(2)H]18:2n-6 to 8S-HPODE with retention of the (2)H-label, suggesting suprafacial hydrogen abstraction and oxygenation in contrast to 8R-DOX-AOS. Both enzymes oxidized 18:1n-9 and 18:3n-3 to α-ketols, but the catalysis of the 8R- and 8S-AOS domains differed. 8R-DOX-AOS transformed 9R-HPODE to epoxy alcohols, but 8S-DOX-AOS converted 9S-HPODE to an α-ketol (9-hydroxy-10-oxo-12Z-octadecenoic acid) and epoxy alcohols in a ratio of ∼1:2. Whereas all fatty acid allene oxides described so far have a conjugated diene impinging on the epoxide, the allene oxides formed by 8-DOX-AOS are unconjugated.

  • 17.
    Oliw, Ernst H.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wennman, Anneli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hoffmann, Inga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Garscha, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hamberg, Mats
    Jernerén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Stereoselective oxidation of regioisomeric octadecenoic acids by fatty acid dioxygenases2011Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 11, s. 1995-2004Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Seven Z-octadecenoic acids having the double bond located in positions 6Z to 13Z were photooxidized. The resulting hydroperoxy-E-octadecenoic acids [HpOME(E)] were resolved by chiral phase-HPLC-MS, and the absolute configurations of the enantiomers were determined by gas chromatographic analysis of diastereoisomeric derivatives. The MS/MS/MS spectra showed characteristic fragments, which were influenced by the distance between the hydroperoxide and carboxyl groups. These fatty acids were then investigated as substrates of cyclooxygenase-1 (COX-1), manganese lipoxygenase (MnLOX), and the (8R)-dioxygenase (8R-DOX) activities of two linoleate diol synthases (LDS) and 10R-DOX. COX-1 and MnLOX abstracted hydrogen at C-11 of (12Z)-18:1 and C-12 of (13Z)-18:1. (11Z)-18:1 was subject to hydrogen abstraction at C-10 by MnLOX and at both allylic positions by COX-1. Both allylic hydrogens of (8Z)-18:1 were also abstracted by 8R-DOX activities of LDS and 10R-DOX, but only the allylic hydrogens close to the carboxyl groups of (11Z)-18:1 and (12Z)-18:1. 8R-DOX also oxidized monoenoic C(14)-C(20) fatty acids with double bonds at the (9Z) position, suggesting that the length of the omega end has little influence on positioning for oxygenation. We conclude that COX-1 and MnLOX can readily abstract allylic hydrogens of octadecenoic fatty acids from C-10 to C-12 and 8R-DOX from C-7 and C-12.

  • 18.
    Persson, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Löfgren, Lars
    Hansson, Göran
    Abrahamsson, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nilsson, Ralf
    Simultaneous assessment of lipid classes and bile acids in human intestinal fluid by solid-phase extraction and HPLC methods2007Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 48, nr 1, s. 242-251Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of the study reported here was to develop a method for the determination of lipid classes in intestinal fluids, including bile acids (BAs). A solid-phase extraction (SPE) method using C18 and silica columns for the separation of BAs, phospholipids (PLs), and neutral lipids (NLs), including free fatty acids, has been developed and validated. Fed-state small intestinal fluid collected from humans was treated with orlistat to inhibit lipolysis and mixed with acetic acid and methanol before SPE to maximize lipid recoveries. BAs, PLs, and NLs were isolated using lipophilic and polar solvents to promote elution from the SPE columns. The different lipid classes were subsequently analyzed using three separately optimized HPLC methods with evaporative light-scattering detectors. High recoveries (>90%) of all lipids evaluated were observed, with low coefficients of variation (<5%). The HPLC methods developed were highly reproducible and allowed baseline separation of nearly all lipid classes investigated. In conclusion, these methods provide a means of lipid class analysis of NLs, PLs, and BAs in human fed-state small intestinal fluid, with potential use in other fluids from the intestinal tract and animals.

  • 19. Phillips, Catherine M
    et al.
    Goumidi, Louisa
    Bertrais, Sandrine
    Field, Martyn R
    Cupples, L Adrienne
    Ordovas, Jose M
    Defoort, Catherine
    Lovegrove, Julie A
    Drevon, Christian A
    Gibney, Michael J
    Blaak, Ellen E
    Kiec-Wilk, Beata
    Karlström, Brita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Lopez-Miranda, Jose
    McManus, Ross
    Hercberg, Serge
    Lairon, Denis
    Planells, Richard
    Roche, Helen M
    Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome2010Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 51, nr 7, s. 1793-1800Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.

  • 20. Phillips, Catherine M.
    et al.
    Goumidi, Louisa
    Bertrais, Sandrine
    Field, Martyn R.
    Cupples, L. Adrienne
    Ordovas, Jose M.
    McMonagle, Jolene
    Defoort, Catherine
    Lovegrove, Julie A.
    Drevon, Christian A.
    Blaak, Ellen E.
    Kiec-Wilk, Beata
    Riserus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Lopez-Miranda, Jose
    McManus, Ross
    Hercberg, Serge
    Lairon, Denis
    Planells, Richard
    Roche, Helen M.
    ACC2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat2010Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 51, nr 12, s. 3500-3507Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acetyl-CoA carboxylase beta (ACC2) plays a key role in fatty acid synthesis and oxidation pathways. Disturbance of these pathways is associated with impaired insulin responsiveness and metabolic syndrome (MetS). Gene-nutrient interactions may affect MetS risk. This study determined the relationship between ACC2 polymorphisms (rs2075263, rs2268387, rs2284685, rs2284689, rs2300453, rs3742023, rs3742026, rs4766587, and rs6606697) and MetS risk, and whether dietary fatty acids modulate this in the LIPGENE-SU. VI.MAX study of MetS cases and matched controls (n = 1754). Minor A allele carriers of rs4766587 had increased MetS risk (OR 1.29 [CI 1.08, 1.58], P = 0.0064) compared with the GG homozygotes, which may in part be explained by their increased body mass index (BMI), abdominal obesity, and impaired insulin sensitivity (P < 0.05). MetS risk was modulated by dietary fat intake (P = 0.04 for gene-nutrient interaction), where risk conferred by the A allele was exacerbated among individuals with a high-fat intake (>35% energy) (OR 1.62 [CI 1.05, 2.50], P = 0.027), particularly a high intake (>5.5% energy) of n-6 polyunsaturated fat (PUFA) (OR 1.82 [CI 1.14, 2.94], P = 0.01; P = 0.05 for gene-nutrient interaction). Saturated and monounsaturated fat intake did not modulate MetS risk. Importantly, we replicated some of these findings in an independent cohort.jlr In conclusion, the ACC2 rs4766587 polymorphism influences MetS risk, which was modulated by dietary fat, suggesting novel gene-nutrient interactions.-Phillips, C. M., L. Goumidi, S. Bertrais, M. R. Field, L. Adrienne Cupples, J. M. Ordovas, J. McMonagle, C. Defoort, J. A. Lovegrove, C. A. Drevon, E. E. Blaak, B. Kiec-Wilk, U. Riserus, J. Lopez-Miranda, R. McManus, S. Hercberg, D. Lairon, R. Planells, and H. M. Roche. ACC2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat.

  • 21. Singer, J.B.
    et al.
    Holdaas, Hallvard
    Jardine, Alan G.
    Fellström, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Os, Ingrid
    Meyer, Joanne M.
    Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients2007Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 48, nr 9, s. 2072-2078Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Assessment of Lescol in Renal Transplantation clinical trial demonstrated the efficacy of fluvastatin in reducing cardiovascular (CV) disease in renal transplant recipients. The study included a voluntary pharmacogenetic component, enrolling 1,404 patients, which allowed association testing of baseline measures and longitudinal analysis of the 707 fluvastatin-treated and 697 placebo-treated individuals. A candidate gene approach, examining 42 polymorphisms in 18 genes, was used to test for association between selected polymorphisms and major adverse cardiac events, graft failure, change in LDL and HDL cholesterol, and baseline LDL and HDL cholesterol. Reported associations between cholesteryl ester transfer protein (CETP) and baseline HDL cholesterol were replicated, with four previously implicated single nucleotide polymorphisms significantly associated in males and one in females; tests of reported associations between CETP and CV disease yielded varying results. We found no evidence for genetic factors affecting fluvastatin response. Polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) previously reported to affect the efficacy of pravastatin did not show a similar effect on the reduction of LDL cholesterol by fluvastatin.

  • 22. Stålberg, Kjell
    et al.
    Neal, Andrea C.
    Ronne, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ståhl, Ulf
    Identification of a novel GPCAT activity and a new pathway for phosphatidylcholine biosynthesis in S. cerevisiae2008Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 49, nr 8, s. 1794-1806Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Turnover of phospholipids in the yeast Saccharomyces cerevisiae generates intracellular glycerophosphocholine (GPC). Here we show that GPC can be reacylated in an acyl-CoA-dependent reaction by yeast microsomal membranes. The lysophosphatidylcholine that is formed in this reaction is efficiently further acylated to phosphatidylcholine (PC) by yeast microsomes, thus providing a new pathway for PC biosynthesis that can either recycle endogenously generated GPC or utilize externally provided GPC. Genetic and biochemical evidence suggests that this new enzymatic activity, which we call GPC acyltransferase (GPCAT), is not mediated by any of the previously known acyltransferases in yeast. The GPCAT activity has an apparent V(max) of 8.7 nmol/min/mg protein and an apparent K(m) of 2.5 mM. It has a neutral pH optimum, similar to yeast glycerol-3-phosphate acyltransferase, but differs from the latter in being more heat stable. The GPCAT activity is sensitive to N-ethylmaleimide, phenanthroline, and Zn(2+) ions. In vivo experiments showed that PC is efficiently labeled when yeast cells are fed with [(3)H]choline-GPC, and that this reaction occurs also in pct1 knockout strains, where de novo synthesis of PC by the CDP-choline pathway is blocked. This suggests that GPCAT can provide an alternative pathway for PC biosynthesis in vivo.

  • 23. Vedin, Inger
    et al.
    Cederholm, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Freund-Levi, Yvonne
    Basun, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Hjorth, Erik
    Irving, Gerd Faxén
    Eriksdotter-Jönhagen, Maria
    Schultzberg, Marianne
    Wahlund, Lars-Olof
    Palmblad, Jan
    Reduced prostaglandin F release from blood mononuclear leukocytes after oral supplementation of ω3 fatty acids: the OmegAD study2010Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 51, nr 5, s. 1179-1185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Omega-3 fatty acids, e.g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary supplementation with a DHA-rich fish oil influenced the release of PGF(2alpha) from peripheral blood mononuclear cells (PBMC). In the OmegAD study, 174 Alzheimer disease patients received either 1.7 g DHA plus 0.6 g EPA or a placebo daily for six months. PBMCs from the 21 (9 on fish oil and 12 on placebo) first-randomized patients were stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) before and after 6 months. Our results showed that plasma concentrations of DHA and EPA increased significantly at 6 months in the omega-3 group. PGF(2alpha) release from LPS- (but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF(2alpha) changes correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1(beta) levels correlated with decreased PGF(2alpha) levels. The stimulus-specific PGF(2alpha) release from PBMC after 6 months of oral supplementation with the DHA-rich fish oil might be one event related to reduced inflammatory reactions associated with omega-3 fatty acid intake.

  • 24. Wang, Xiuzhe
    et al.
    Hjorth, Erik
    Vedin, Inger
    Eriksdotter, Maria
    Freund-Levi, Yvonne
    Wahlund, Lars-Olof
    Cederholm, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Palmblad, Jan
    Schultzberg, Marianne
    Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study2015Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 56, nr 3, s. 674-681Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer's disease (AD) is associated with brain inflammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-beta 1-40 showed unchanged levels of the SPMs lipoxin A 4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.

  • 25.
    Wennman, Anneli
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Magnuson, Ann
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Hamberg, Mats
    Oliw, Ernst H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Manganese lipoxygenase of F. oxysporum and the structural basis for biosynthesis of distinct 11-hydroperoxy stereoisomers2015Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 56, nr 8, s. 1606-1615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The biosynthesis of jasmonates in plants is initiated by 13S-lipoxygenase (LOX), but details of jasmonate biosynthesis by fungi, including Fusarium oxysporum, are unknown. The genome of F. oxysporum codes for linoleate 13S-LOX (Fox-LOX) and for F. oxysporum manganese LOX (Fo-MnLOX), an uncharacterized homolog of 13R-MnLOX of Gaeumannomyces graminis. We expressed Fo-MnLOX and compared its properties to Cg-MnLOX from Colletotrichum gloeosporioides. Electron paramagnetic resonance and metal analysis showed that Fo-MnLOX contained catalytic Mn. Fo-MnLOX oxidized 18:2n-6 mainly to 11 R-hydroperoxyoctadecadienoic acid (HPODE), 13S-HPODE, and 9(S/R)-HPODE, whereas Cg-MnLOX produced 9S-, 11S-, and 13R-HPODE with high stereoselectivity. The 11-hydroperoxides did not undergo the rapid beta-fragmentation earlier observed with 13R-MnLOX. Oxidation of [11S-H-2] 18:2n-6 by Cg-MnLOX was accompanied by loss of deuterium and a large kinetic isotope effect (>30). The Fo-MnLOX-catalyzed oxidation occurred with retention of the H-2-label. Fo-MnLOX also oxidized 1-lineoyl-2-hydroxy-glycero3- phosphatidylcholine. The predicted active site of all MnLOXs contains Phe except for Ser(348) in this position of Fo-MnLOX. The Ser348Phe mutant of Fo-MnLOX oxidized 18: 2n-6 to the same major products as Cg-MnLOX.Jlr Our results suggest that Fo-MnLOX, with support of Ser(348), binds 18:2n-6 so that the pro R rather than the proShydrogen at C-11 interacts with the metal center, but retains the suprafacial oxygenation mechanism observed in other MnLOXs.

  • 26.
    Wennman, Anneli
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oliw, Ernst H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Secretion of two novel enzymes, manganese 9S-Lipoxygenase and epoxy alcohol synthase, by the rice pathogen Magnaporthe salvinii2013Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 54, nr 3, s. 762-775Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mycelium of the rice stem pathogen, Magnaporthe salvinii, secreted linoleate 9S-lipoxygenase (9S-LOX) and epoxy alcohol synthase (EAS). The EAS rapidly transformed 9S-hydroperoxy-octadeca-10E,12Z-dienoic acid (9S-HPODE) to threo 10(11)-epoxy-9S-hydroxy-12Z-octadecenoic acid, but other hydroperoxy fatty acids were poor substrates. 9S-LOX was expressed in Pichia pastoris. Recombinant 9S-LOX oxidized 18:2n-6 directly to 9S-HPODE, the end product, and also to two intermediates, 11S-hydroperoxy-9Z,12Z-octadecenoic acid (11S-HPODE; ~5%) and 13R-hydroperoxy-9Z,11E-octadecenoic acid (13R-HPODE; ~1%). 11S- and 13R-HPODE were isomerized to 9S-HPODE, likely after oxidation to peroxyl radicals, β-fragmentation, and oxygen insertion at C-9. 18:3n-3 was oxidized at C-9, C-11, and C-13, and to 9,16-dihydroxy-10E,12,14E-octadecatrienoic acid. 9S-LOX contained catalytic manganese (Mn:protein ≥ 0.2:1; Mn/Fe, 1:0.05), and its sequence could be aligned with 77% identity to 13R-LOX with catalytic manganese (13R-MnLOX) of the Take-all fungus. The Leu350Met mutant of 9S-LOX shifted oxidation of 18:2n-6 from C-9 to C-13, and the Phe347Leu, Phe347Val, and Phe347Ala mutants of 13R-MnLOX from C-13 to C-9. In conclusion, M. salvinii secretes 9S-LOX with catalytic manganese along with a specific EAS. Alterations in the Sloane determinant of 9S-LOX and 13R-MnLOX with larger and smaller hydrophobic residues interconverted the regiospecific oxidation of 18:2n-6, presumably by altering the substrate position in relation to oxygen insertion.

  • 27.
    Zhou, Yitian
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, Stockholm, Sweden.
    Mägi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Milani, Lili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Lauschke, Volker M.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, Stockholm, Sweden.
    Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk2018Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, nr 10, s. 1987-2000Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identify further 6,875 genetic variants, 33% of which are novel and 98.7% of which are rare with minor allele frequencies <1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM (Coronary Artery Disease Genomewide Replication and Meta-analysis) and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits, and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.

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