Microsomal Epoxide Hydrolase Polymorphisms
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Functional Properties and Molecular Architecture of Leukotriene A4 Hydrolase, a Pivotal Catalyst of Chemotactic Leukotriene Formation
Review Article TheScientificWorldJOURNAL (2002) 2, 1734–1749 ISSN 1537-744X; DOI 10.1100/tsw.2002.810 Functional Properties and Molecular Architecture of Leukotriene A4 Hydrolase, a Pivotal Catalyst of Chemotactic Leukotriene Formation Jesper Z. Haeggström1,*, Pär Nordlund2, and Marjolein M.G.M. Thunnissen2 1Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, S-171 77 Stockholm, Sweden; 2Department of Biochemistry, University of Stockholm, Arrhenius Laboratories A4, S-106 91 Stockholm, Sweden E-mail: [email protected]; [email protected]; [email protected] Received March 25, 2002; Accepted April 26, 2002; Published June 26, 2002 The leukotrienes are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4 is a classical chemoattractant, which triggers adherence and aggregation of leukocytes to the endothelium at only nM concentrations. In addition, leukotriene B4 modulates immune responses, participates in the host defense against infections, and is a key mediator of PAF-induced lethal shock. Because of these powerful biological effects, leukotriene B4 is implicated in a variety of acute and chronic inflammatory diseases, e.g., nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease. The final step in the biosynthesis of leukotriene B4 is catalyzed by leukotriene A4 hydrolase, a unique bifunctional zinc metalloenzyme with an anion-dependent aminopeptidase activity. Here we describe the most recent developments regarding our understanding -
Role of Epoxide Hydrolases in Lipid Metabolism
Biochimie 95 (2013) 91e95 Contents lists available at SciVerse ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi Mini-review Role of epoxide hydrolases in lipid metabolism Christophe Morisseau* Department of Entomology and U.C.D. Comprehensive Cancer Center, One Shields Avenue, University of California, Davis, CA 95616, USA article info abstract Article history: Epoxide hydrolases (EH), enzymes present in all living organisms, transform epoxide-containing lipids to Received 29 March 2012 1,2-diols by the addition of a molecule of water. Many of these oxygenated lipid substrates have potent Accepted 8 June 2012 biological activities: host defense, control of development, regulation of blood pressure, inflammation, Available online 18 June 2012 and pain. In general, the bioactivity of these natural epoxides is significantly reduced upon metabolism to diols. Thus, through the regulation of the titer of lipid epoxides, EHs have important and diverse bio- Keywords: logical roles with profound effects on the physiological state of the host organism. This review will Epoxide hydrolase discuss the biological activity of key lipid epoxides in mammals. In addition, the use of EH specific Epoxy-fatty acids Cholesterol epoxide inhibitors will be highlighted as possible therapeutic disease interventions. Ó Juvenile hormone 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction hydrolyzed by a water molecule [8]. Based on this mechanism, transition-state inhibitors of EHs have been designed (Fig. 1B). Epoxides are three atom cyclic ethers formed by the oxidation of These ureas and amides are tight-binding competitive inhibitors olefins. Because of their highly polarized oxygen-carbon bonds and with low nanomolar dissociation constants (KI) [9] [10]. -
Quantum Chemical Studies of Epoxide- Transforming Enzymes
Quantum Chemical Studies of Epoxide- Transforming Enzymes Kathrin H. Hopmann Department of Theoretical Chemistry Royal Institute of Technology Stockholm, Sweden, 2007 ii © Kathrin H. Hopmann, 2007 ISBN 978-91-7178-640-1 ISSN 1654-2312 TRITA-BIO-Report 2007:3 Printed by Universitetsservice US-AB, Stockholm, Sweden. iii Abstract Density functional theory is employed to study the reaction mechanisms of different epoxide-transforming enzymes. Calculations are based on quantum chemical active site models, which are build from X-ray crystal structures. The models are used to study conversion of various epoxides into their corresponding diols or substituted alcohols. Epoxide-transforming enzymes from three different families are studied. The human soluble epoxide hydrolase (sEH) belongs to the α/β-hydrolase fold family. sEH employs a covalent mechanism to hydrolyze various epoxides into vicinal diols. The Rhodococcus erythrobacter limonene epoxide hydrolase (LEH) constitutes a novel epoxide hydrolase, which is considered the founding member of a new family of enzymes. LEH mediates transformation of limone-1,2-epoxide into the corresponding vicinal diol by employing a general acid/general base-mediated mechanism. The Agrobacterium radiobacter AD1 haloalcohol dehalogenase HheC is related to the short-chain dehydrogenase/reductases. HheC is able to convert epoxides using various nucleophiles such as azide, cyanide, and nitrite. Reaction mechanisms of these three enzymes are analyzed in depth and the role of different active site residues is studied through in silico mutations. Steric and electronic factors influencing the regioselectivity of epoxide opening are identified. The computed energetics help to explain preferred reaction pathways and experimentally observed regioselectivities. Our results confirm the usefulness of the employed computational methodology for investigating enzymatic reactions. -
Multi-Omic Understanding of the Evolution of Xenobiotic Tolerance in Bacterial Isolates and Communities
Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Summer 8-15-2019 Multi-omic Understanding of the Evolution of Xenobiotic Tolerance in Bacterial Isolates and Communities Tayte Paul Campbell Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Bioinformatics Commons, Biology Commons, and the Microbiology Commons Recommended Citation Campbell, Tayte Paul, "Multi-omic Understanding of the Evolution of Xenobiotic Tolerance in Bacterial Isolates and Communities" (2019). Arts & Sciences Electronic Theses and Dissertations. 1888. https://openscholarship.wustl.edu/art_sci_etds/1888 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Plant and Microbial Biosciences Dissertation Examination Committee: Gautam Dantas, Chair Arpita Bose Andrew Kau Audrey Odom-John Himadri Pakrasi Fuzhong Zhang Multi-omic Understanding of the Evolution of Xenobiotic Tolerance in Bacterial Isolates and Communities by Tayte P. Campbell A dissertation presented to The Graduate School of Washington University in partial fulfillment -
Polychlorinated Biphenyls in Pigments
doi: 10.1111/cote.12167 Polychlorinated biphenyls in pigments: inadvertent production and environmental Coloration significance Technology Lisa Rodenburg,a Jia Guoa and Robert Christieb,* aDepartment of Environmental Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA bSchool of Textiles and Design, Heriot-Watt University, Scottish Borders Campus, Netherdale, Galashiels, TD1 3HF, UK Feature article Email: [email protected] Society of Dyers and Colourists Received: 18 December 2014; Accepted: 26 June 2015 Polychlorobiphenyls are toxic, bioaccumulative, and persistent chemicals whose intentional manufacture has been banned throughout the developed world. Polychlorobiphenyls may be generated inadvertently during the production of certain pigments, including diarylides. This inadvertent production is allowed under various regulatory schemes, such as the Toxic Substances Control Act in the United States and the Stockholm Convention on Persistent Organic Pollutants. Generally, these regulations require polychlorobiphenyl levels in batches of pigment to be less than certain regulatory limits, usually 50 ppm. A growing body of evidence suggests that the use of pigments is dispersing polychlorobiphenyls throughout the environment. Polychlorobiphenyl congeners associated with pigments have been found throughout the United States in sediments and in surface waters at levels exceeding the prevailing water quality standards. A recent Japanese government study reported measured polychlorobiphenyl concentrations well -
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Enzyme and Microbial Technology 139 (2020) 109592 Contents lists available at ScienceDirect Enzyme and Microbial Technology journal homepage: www.elsevier.com/locate/enzmictec Identification and catalytic properties of new epoxide hydrolases fromthe T genomic data of soil bacteria Gorjan Stojanovskia, Dragana Dobrijevica, Helen C. Hailesb, John M. Warda,* a Department of Biochemical Engineering, University College London, Bernard Katz, London WC1E 6BT, UK b Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK ARTICLE INFO ABSTRACT Keywords: Epoxide hydrolases (EHs) catalyse the conversion of epoxides into vicinal diols. These enzymes have extensive Epoxide hydrolase value in biocatalysis as they can generate enantiopure epoxides and diols which are important and versatile Limonene epoxide hydrolase synthetic intermediates for the fine chemical and pharmaceutical industries. Despite these benefits, theyhave Genome mining seen limited use in the bioindustry and novel EHs continue to be reported in the literature. Biotransformation We identified twenty-nine putative EHs within the genomes of soil bacteria. Eight of these EHs wereexplored in terms of their activity. Two limonene epoxide hydrolases (LEHs) and one ⍺/β EH were active on a model compound styrene oxide and its ring-substituted derivatives, with low to good percentage conversions of 18–86%. Further exploration of the substrate scope with enantiopure (R)-styrene oxide and (S)-styrene oxide, showed different epoxide ring opening regioselectivities. Two enzymes, expressed from plasmids pQR1984and pQR1990 de-symmetrised the meso-epoxide cyclohexene oxide, forming the (R,R)-diol with high enantioselec- tivity. Two LEHs, from plasmids pQR1980 and pQR1982 catalysed the hydrolysis of (+) and (−) limonene oxide, with diastereomeric preference for the (1S,2S,4R)- and (1R,2R,4S)-diol products, respectively. -
Coordination of T Cell Activation and Migration Through Formation of the Immunological Synapse
Coordination of T Cell Activation and Migration through Formation of the Immunological Synapse MICHAEL L. DUSTIN Program in Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine and the Department of Pathology, New York University School of Medicine, New York, New York 10016, USA ABSTRACT: T cell activation is based on interactions of T cell antigen receptors with MHC-peptide complexes in a specialized cell–cell junction between the T cell and antigen-presenting cell—the immunological synapse. The immunolog- ical synapse coordinates naïve T cell activation and migration by stopping T cell migration with antigen-presenting cells bearing appropriate major histo- compatibility complex (MHC) peptide complexes. At the same time, the immu- nological synapse allows full T cell activation through sustained signaling over a period of several hours. The immunological synapse supports activation in the absence of continued T cell migration, which is required for T cell activa- tion through serial encounters. Src and Syk family kinases are activated early in immunological synapse formation, but this signaling process returns to the basal level after 30 min; at the same time, the interactions between T cell re- ceptors (TCRs) and MHC peptides are stabilized within the immunological synapse. The molecular pattern of the mature synapse in helper T cells is a self- stabilized structure that is correlated with cytokine production and prolifera- tion. I propose that this molecular pattern and its specific biochemical constit- uents are necessary -
The New Aspects of Aminoacyl-Trna Synthetases
Vol. 47 No. 3/2000 821–834 QUARTERLY Review The new aspects of aminoacyl-tRNA synthetases. Maciej Szymañski, Marzanna Deniziak and Jan Barciszewski½ Institute of Bioorganic Chemistry of the Polish Academy of Sciences, 60-704 Poznañ, Poland Received: 29 December, 1999; revised: 24 May, 2000; accepted: 02 June, 2000 Key words: aminoacylation, aminoacyl-tRNA synthetases, protein biosynthesis, tRNA Aminoacyl-tRNA synthetases (AARS) are essential proteins found in all living organ- isms. They form a diverse group of enzymes that ensure the fidelity of transfer of ge- netic information from the DNA into the protein. AARS catalyse the attachment of amino acids to transfer RNAs and thereby establish the rules of the genetic code by virtue of matching the nucleotide triplet of the anticodon with its cognate amino acid. Here we summarise the effects of recent studies on this interesting family of multifunctional enzymes. The universal genetic code is established in a only components of the gene expression appa- single aminoacylation reaction of transfer ri- ratus that function at the interface between bonucleic acids (tRNAs). The reaction is nucleic acids and proteins. This leads to three catalysed by the family of aminoacyl-tRNA interesting aspects of studies on amino- synthetases (AARS) each of which activates acyl-tRNA synthetases: (i) the mechanism of an amino acid by binding to ATP and trans- amino acid recognition and chemical activa- fers it to the 3¢ end of the cognate tRNA. The tion, (ii) the specificity of tRNA recognition, conservation of the genetic code suggests that and (iii) the origin and evolution of AARS [3]. -
Lymphocyte-Activation Gene 3 (LAG-3) Immune Pathway
Lymphocyte-Activation Gene 3 (LAG-3) About LAG-3 LAG-3 Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth.1 TCR T cells are a type of white blood cell that are part of the immune system. Activation of cytotoxic T cells by antigens enables them to 1 kill unhealthy or foreign cells. Inactive T cell Antigen MHC Dendritic cell (APC) LAG-3 and LAG-3 and LAG-3 and Immune Function T Cell Exhaustion Cancer • After a T cell is activated to kill its • However, in certain situations where T • Because of its critical role in regulating target cell, LAG-3 expression is cells experience prolonged exposure to an exhaustion of cytotoxic T cells and Treg increased to turn off the immune antigen, such as cancer or chronic function, LAG-3 has become a target of response, so that the T cell does not go infection, the T cells become desensitized study in the cancer field. on to attack healthy cells.2 and lose their ability to activate and multiply in the presence of the antigen.4 • In cancer, LAG-3 expressing exhausted • Inhibition of the immune response is cytotoxic T cells and Tregs expressing accomplished through activation of • The desensitized T cell will also LAG-3 gather at tumor sites.5,6 the LAG-3 pathway, which can occur progressively fail to produce cytokines via binding of LAG-3 to a type of (proteins that assist in the immune • Preclinical studies suggest that inhibiting antigen-presenting complex called response) and kill the target cells.4 LAG-3 allows T cells to regain their MHC II. -
Development of a Transplantable Liver Graft from a Tiny Partial Liver( Dissertation 全文 )
Auxiliary xenotransplantation as an in vivo bioreactor - Title Development of a transplantable liver graft from a tiny partial liver( Dissertation_全文 ) Author(s) Masano, Yuki Citation 京都大学 Issue Date 2020-03-23 URL https://doi.org/10.14989/doctor.r13329 Right https://onlinelibrary.wiley.com/journal/13993089 Type Thesis or Dissertation Textversion ETD Kyoto University Received: 27 November 2018 | Revised: 25 May 2019 | Accepted: 27 June 2019 DOI: 10.1111/xen.12545 ORIGINAL ARTICLE Auxiliary xenotransplantation as an in vivo bioreactor— Development of a transplantable liver graft from a tiny partial liver Yuki Masano1 | Shintaro Yagi1 | Yosuke Miyachi1 | Shinya Okumura1 | Toshimi Kaido1 | Hironori Haga2 | Eiji Kobayashi3 | Shinji Uemoto1 1Division of Hepato‐Biliary‐Pancreatic and Transplant Surgery, Department of Surgery, Abstract Graduate School of Medicine, Kyoto Background: We established a completely novel method of auxiliary xenogeneic University, Kyoto, Japan partial liver transplantation and examined whether liver grafts procured from Syrian 2Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan hamsters regenerated in nude rats, which were used as in vivo bioreactors. 3Department of Organ Fabrication, Keio Methods: The hamsters and the rats were all males (n = 10). Partial liver grafts from University School of Medicine, Tokyo, Japan hamsters were transplanted into nude rats in an auxiliary manner. We evaluated liver Correspondence graft injury, rejection, and regeneration during 7 days after auxiliary xenogeneic par- Shintaro Yagi, 54 Kawahara‐cho, Shogoin, Sakyo‐ku, Kyoto, 606‐8507, Japan. tial liver transplantation. Email: [email protected]‐u.ac.jp Results: All rats survived until sacrifice on post‐operative day (POD) 1, 3, and 7. HE‐ Funding information staining showed normal at POD1, mild periportal edema, and slight bile duct and Japan Society for the Promotion of Science, venous endothelial inflammation at POD3, and moderate acute cellular rejection at Grant/Award Number: 17H06814 POD7 without parenchymal necrosis. -
Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters
pharmaceuticals Review Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters Teresa Iannaccone 1, Carmine Sellitto 1,2,* , Valentina Manzo 1,2 , Francesca Colucci 1, Valentina Giudice 1 , Berenice Stefanelli 1 , Antonio Iuliano 1, Giulio Corrivetti 3 and Amelia Filippelli 1,2 1 Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; [email protected] (T.I.); [email protected] (V.M.); [email protected] (F.C.); [email protected] (V.G.); [email protected] (B.S.); [email protected] (A.I.); afi[email protected] (A.F.) 2 Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy 3 European Biomedical Research Institute of Salerno (EBRIS), 84125 Salerno, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-089673848 Abstract: Pharmacogenomics can identify polymorphisms in genes involved in drug pharma- cokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient’s genotype, also in psychiatric and neurological settings. Citation: Iannaccone, T.; Sellitto, C.; However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagno- Manzo, V.; Colucci, F.; Giudice, V.; Stefanelli, B.; Iuliano, A.; Corrivetti, sis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, G.; Filippelli, A. Pharmacogenetics of because their benefit in clinical practice is still controversial. In this review, we summarize the current Carbamazepine and Valproate: Focus knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs. -
NST110: Advanced Toxicology Lecture 4: Phase I Metabolism
Absorption, Distribution, Metabolism and Excretion (ADME): NST110: Advanced Toxicology Lecture 4: Phase I Metabolism NST110, Toxicology Department of Nutritional Sciences and Toxicology University of California, Berkeley Biotransformation The elimination of xenobiotics often depends on their conversion to water-soluble chemicals through biotransformation, catalyzed by multiple enzymes primarily in the liver with contributions from other tissues. Biotransformation changes the properties of a xenobiotic usually from a lipophilic form (that favors absorption) to a hydrophilic form (favoring excretion in the urine or bile). The main evolutionary goal of biotransformation is to increase the rate of excretion of xenobiotics or drugs. Biotransformation can detoxify or bioactivate xenobiotics to more toxic forms that can cause tumorigenicity or other toxicity. Phase I and Phase II Biotransformation Reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups: Phase I and phase II. 1. Phase I reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group (-OH, -NH2, -SH or –COOH) to increase reactivity and slightly increase hydrophilicity. O R1 - O S O sulfation O R2 OH Phase II Phase I R1 R2 R1 R2 - hydroxylation COO R1 O O glucuronidation OH R2 HO excretion OH O COO- HN H -NH2 R R1 R1 S N 1 Phase I Phase II COO O O oxidation glutathione R2 OH R2 R2 conjugation 2. Phase II reactions include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids (glycine, taurine and glutamic acid) that strongly increase hydrophilicity. Phase I and II Biotransformation • With the exception of lipid storage sites and the MDR transporter system, organisms have little anatomical defense against lipid soluble toxins.