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Enzymatic Encoding Methods for Efficient Synthesis Of
(19) TZZ__T (11) EP 1 957 644 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/10 (2006.01) C12Q 1/68 (2006.01) 01.12.2010 Bulletin 2010/48 C40B 40/06 (2006.01) C40B 50/06 (2006.01) (21) Application number: 06818144.5 (86) International application number: PCT/DK2006/000685 (22) Date of filing: 01.12.2006 (87) International publication number: WO 2007/062664 (07.06.2007 Gazette 2007/23) (54) ENZYMATIC ENCODING METHODS FOR EFFICIENT SYNTHESIS OF LARGE LIBRARIES ENZYMVERMITTELNDE KODIERUNGSMETHODEN FÜR EINE EFFIZIENTE SYNTHESE VON GROSSEN BIBLIOTHEKEN PROCEDES DE CODAGE ENZYMATIQUE DESTINES A LA SYNTHESE EFFICACE DE BIBLIOTHEQUES IMPORTANTES (84) Designated Contracting States: • GOLDBECH, Anne AT BE BG CH CY CZ DE DK EE ES FI FR GB GR DK-2200 Copenhagen N (DK) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • DE LEON, Daen SK TR DK-2300 Copenhagen S (DK) Designated Extension States: • KALDOR, Ditte Kievsmose AL BA HR MK RS DK-2880 Bagsvaerd (DK) • SLØK, Frank Abilgaard (30) Priority: 01.12.2005 DK 200501704 DK-3450 Allerød (DK) 02.12.2005 US 741490 P • HUSEMOEN, Birgitte Nystrup DK-2500 Valby (DK) (43) Date of publication of application: • DOLBERG, Johannes 20.08.2008 Bulletin 2008/34 DK-1674 Copenhagen V (DK) • JENSEN, Kim Birkebæk (73) Proprietor: Nuevolution A/S DK-2610 Rødovre (DK) 2100 Copenhagen 0 (DK) • PETERSEN, Lene DK-2100 Copenhagen Ø (DK) (72) Inventors: • NØRREGAARD-MADSEN, Mads • FRANCH, Thomas DK-3460 Birkerød (DK) DK-3070 Snekkersten (DK) • GODSKESEN, -
Hyperbilirubinemia
Porphyrins Porphyrins (Porphins) are cyclic tetrapyrol compounds formed by the linkage )). of four pyrrole rings through methenyl bridges (( HC In the reduced porphyrins (Porphyrinogens) the linkage of four pyrrole rings (tetrapyrol) through methylene bridges (( CH2 )) The characteristic property of porphyrins is the formation of complexes with the metal ion bound to nitrogen atoms of the pyrrole rings. e.g. Heme (iron porphyrin). Proteins which contain heme ((hemoproteins)) are widely distributed e.g. Hemoglobin, Myoglobin, Cytochromes, Catalase & Tryptophan pyrrolase. Natural porphyrins have substituent side chains on the eight hydrogen atoms numbered on the pyrrole rings. These side chains are: CH 1-Methyl-group (M)… (( 3 )) 2-Acetate-group (A)… (( CH2COOH )) 3-Propionate-group (P)… (( CH2CH2COOH )) 4-Vinyl-group (V)… (( CH CH2 )) Porphyrins with asymmetric arrangement of the side chains are classified as type III porphyrins while those with symmetric arrangement of the side chains are classified as type I porphyrins. Only types I & III are present in nature & type III series is more important because it includes heme. 1 Heme Biosynthesis Heme biosynthesis occurs through the following steps: 1-The starting reaction is the condensation between succinyl-CoA ((derived from citric acid cycle in the mitochondria)) & glycine, this reaction is a rate limiting reaction in the hepatic heme synthesis, it occurs in the mitochondria & is catalyzed by ALA synthase (Aminolevulinate synthase) enzyme in the presence of pyridoxal phosphate as a cofactor. The product of this reaction is α-amino-β-ketoadipate which is rapidly decarboxylated to form δ-aminolevulinate (ALA). 2-In the cytoplasm condensation reaction between two molecules of ALA is catalyzed by ALA dehydratase enzyme to form two molecules of water & one 2 molecule of porphobilinogen (PBG) which is a precursor of pyrrole. -
Characterisation of Bilirubin Metabolic Pathway in Hepatic Mitochondria Siti Nur Fadzilah Muhsain M.Sc
Characterisation of Bilirubin Metabolic Pathway in Hepatic Mitochondria Siti Nur Fadzilah Muhsain M.Sc. (Medical Research) 2005 Universiti Sains Malaysia Postgrad. Dip. (Toxicology) 2003 University of Surrey B.Sc.(Biomed. Sc.) 2000 Universiti Putra Malaysia A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2014 School of Medicine ABSTRACT Bilirubin (BR), a toxic waste product of degraded haem, is a potent antioxidant at physiological concentrations. To achieve the maximum benefit of BR, its intracellular level needs to be carefully regulated. A system comprising of two enzymes, haem oxygenase-1 (HMOX1) and cytochrome P450 2A5 (CYP2A5) exists in the endoplasmic reticulum (ER), responsible for regulating BR homeostasis. This system is induced in response to oxidative stress. In this thesis, oxidative stress caused accumulation of these enzymes in mitochondria — major producers and targets of reactive oxygen species (ROS) — is demonstrated. To understand the significance of this intracellular targeting, properties of microsomal and mitochondrial BR metabolising enzymes were compared and the capacity of mitochondrial CYP2A5 to oxidise BR in response to oxidative stress is reported. Microsomes and mitochondrial fractions were isolated from liver homogenates of DBA/2J mice, administered with sub-toxic dose of pyrazole, an oxidant stressor. The purity of extracted organelles was determined by analysing the expressions and activities of their respective marker enzymes. HMOX1 and CYP2A5 were significantly increased in microsomes and even more so in mitochondria in response to pyrazole-induced oxidative stress. By contrast, the treatment did not increase either microsomes or mitochondrial Uridine-diphosphate-glucuronosyltransferase 1A1 (UGT1A1), the sole enzyme that catalyses BR elimination through glucuronidation. -
An Efficient Synthesis of Porphyrins with Different Meso Substituents That Avoids Scrambling in Aqueous Media
An Efficient Synthesis of Porphyrins with Different meso Substituents that Avoids Scrambling in Aqueous Media Agnieszka Nowak-Krol, Rémi Plamont, Gabriel Canard, J.A. Edzang, Daniel T. Gryko, Teodor Silviu Balaban To cite this version: Agnieszka Nowak-Krol, Rémi Plamont, Gabriel Canard, J.A. Edzang, Daniel T. Gryko, et al.. An Efficient Synthesis of Porphyrins with Different meso Substituents that Avoids Scrambling inAque- ous Media. Chemistry - A European Journal, Wiley-VCH Verlag, 2015, 21 (4), pp.1488-1498. 10.1002/chem.201403677. hal-01130057 HAL Id: hal-01130057 https://hal.archives-ouvertes.fr/hal-01130057 Submitted on 7 Feb 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. An Efficient Synthesis of Porphyrins with Different Meso Substituents that Avoids Scrambling in Aqueous Media Agnieszka Nowak-Król,a,† Rémi Plamont,b,† Gabriel Canard,b,c Judicaelle Andeme Edzang,b,c Daniel T. Grykoa,* and Teodor Silviu Balabanb,* To the memory of Alan Roy Katritzky, magister of heterocyclic chemistry [a] Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland E-mail: [email protected] [b] Aix Marseille Université, Centrale Marseille, CNRS, Institut des Sciences Moléculaires de Marseille (iSm2), UMR 7313, Chirosciences, Avenue Escadrille Normandie Niemen, St. -
Characterisation, Classification and Conformational Variability Of
Characterisation, Classification and Conformational Variability of Organic Enzyme Cofactors Julia D. Fischer European Bioinformatics Institute Clare Hall College University of Cambridge A thesis submitted for the degree of Doctor of Philosophy 11 April 2011 This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except where specifically indicated in the text. This dissertation does not exceed the word limit of 60,000 words. Acknowledgements I would like to thank all the members of the Thornton research group for their constant interest in my work, their continuous willingness to answer my academic questions, and for their company during my time at the EBI. This includes Saumya Kumar, Sergio Martinez Cuesta, Matthias Ziehm, Dr. Daniela Wieser, Dr. Xun Li, Dr. Irene Pa- patheodorou, Dr. Pedro Ballester, Dr. Abdullah Kahraman, Dr. Rafael Najmanovich, Dr. Tjaart de Beer, Dr. Syed Asad Rahman, Dr. Nicholas Furnham, Dr. Roman Laskowski and Dr. Gemma Holli- day. Special thanks to Asad for allowing me to use early development versions of his SMSD software and for help and advice with the KEGG API installation, to Roman for knowing where to find all kinds of data, to Dani for help with R scripts, to Nick for letting me use his E.C. tree program, to Tjaart for python advice and especially to Gemma for her constant advice and feedback on my work in all aspects, in particular the chemistry side. Most importantly, I would like to thank Prof. Janet Thornton for giving me the chance to work on this project, for all the time she spent in meetings with me and reading my work, for sharing her seemingly limitless knowledge and enthusiasm about the fascinating world of enzymes, and for being such an experienced and motivational advisor. -
About Wales' Pathology Handbook
Aneurin Bevan University Health Board About Wales' Pathology Handbook Wales Pathology Handbook (WPH) is a knowledge service within the Welsh national information architecture. It provides national and local catalogues of requestable tests, rules and guidance for electronic requesting (via the Welsh Clinical Portal (WCP) and GP systems) and a web-based knowledge resource for all clinical staff. The introduction of the new national Laboratory Information Management System (LIMS) for Wales means that the operational WPH needs to be reviewed and updated to ensure that it is fit for purpose in the future environment. Page 1 of 697 Date Created - Monday, September 27, 2021 Aneurin Bevan University Health Board Departments Andrology Blood Sciences Cytology Histopathology Microbiology Mortuary Services Transfusion Page 2 of 697 Date Created - Monday, September 27, 2021 Aneurin Bevan University Health Board Andrology Department Information PLEASE NOTE: THE PATHOLOGY HANDBOOK INFORMATION BELOW IS ONLY VALID AT THE TIME OF ACCESS, PRINTED COPIES MUST NOT BE USED Andrology services available are: Semen analysis for fertility investigations. Semen analysis following a vasectomy. Retrograde Ejaculation Investigation. Andrology work is carried out within the Andrology Department, Pathology at Nevill Hall Hospital. Lead Andrologist: Mrs Karen Llewelyn (01873 733062). Deputy Lead: Mrs Ruth Lancaster (01873 733062). Department Manager: Mr Julian Bendle (01633 234502). Please Scroll or Page Down for additional information relating to telephone numbers, sample requesting and collection. ROUTINE OPENING TIMES Nevill Hall site: Andrology Service Monday to Friday: 9:00am - 5:00pm Semen samples for Fertility analysis, Vasectomy analysis or Retrograde Ejaculation Investigation are processed by appointment only. Any sample booked without an appointment will not be tested. -
OPNF Hyperbilirubinemia Presentation
OPNF Hyperbilirubinemia Presentation 1) Definitions: a) Jaundice: _____________ discoloration of the skin and sclera caused by an elevated _________ level. b) Bilirubin: Metabolic end product of ____ breakdown. c) Always assess for jaundice in good lighting. Jaundice is not a reliable indicator for bilirubin level. 2) Bilirubin Physiology: a) Synthesis: Red blood cell breakdown Heme Biliverdin Bilirubin b) Bilirubin is _____ soluble. c) Transport: Bilirubin Free floating OR binds to Albumin and transports directly to the liver Taken up into the hepatocytes d) Metabolism (conjugation): Bilirubin is converted and becomes _____ soluble and secreted into bile and excreted then into the digestive track. e) Clearance/Excretion: i) Conjugated bilirubin changes into urobilinogen and excretes in urine. ii) Urobilinogen converts into stercobilinogen and excreted in the stool f) Enterohepatic circulation: Beta-glucuronidase from the lining of the small intestine deconjugates the bilirubin allowing it to be reabsorbed into circulation 3) Basics of Hyperbilirubinemia: a) Hyperbilirubinemia: _________ ___________ _________________ b) Physiologic Pathologic Jaundice after 24-48hr Jaundice within the first 24hr Requires no treatment Requires evaluation & treatment Peak: Day 3 in term, Day 5-6 in preterm Bili increases > 5mg/dL each day Resolved by 14 days of life Jaundice lasting longer than 14 days Normal infant appearance Can be anemic, discolored stools/urine Normal physiology of increased RBC Cause varies, any process that is destruction, reduced hepatic uptake, exaggerated enterohepatic reabsorption & decreased clearance c) Causes of Hyperbilirubinemia: i) Increased bilirubin production ii) Increased enterohepatic circulation iii) Decreased clearance of unconjugated bilirubin iv) Metabolic conditions v) Inborn errors of metabolism 4) Diagnosis a) Gold standard is the ___________________ which is the plasma level of bilirubin bound to albumin. -
Functional Group Manipulation Usin Organoselenium Reagents
22 Reich Accounts of Chemical Research (25), bound covalently or by physical forces to the possibilities. One is that cosynthetase alters the con- enzyme system, is then converted into uro’gen-I11 (1) formation of the deaminase-bilane complex to direct by an intramolecular rearrangement which directly cyclization of 25 at C-16. There are indication^",^^ that affects only ring D and the two carbons which become deaminase associates with cosynthetase, and it has been C-15 and C-20. The nature of the intermediate between ~uggested”~,~~that cosynthetase acts as a “specifier the bilane and uro’gen-111 remains to be established, protein” in the way lactoalbumiri works during the and this leads to the concluding section. biosynthesis of lactose. The other possibility is that the Prospect. In the presence of deaminase alone, and bilane (25) is the product from deaminase but is then also nonenzymically, the cyclization of bilane (25) occurs the substrate for cosynthetase which brings about ring at C-19 to produce 26, leading to uro’gen-I (11). We closure with rearrangement to produce uro’gen-I11 suggest that in the presence of cosynthetase cyclization specifically. occurs at C-16 rather than at (2-19 (Scheme XIII). The Work is in hand on these aspects and on the problem postulated attack at C-16 would produce the spiro of the structure of the intermediate5’ between the bilane intermediate 27; the labeling arising from 25b and 25c and uro‘gen-111. It will be good to have the answers to is shown. Fragmentation and cyclization again as il- the few remaining questions. -
Porphyrins and Bile Pigments: Metabolism and Disorders Dr
Porphyrins and bile pigments: metabolism and disorders Dr. Jaya Chaturvedi Porphyrins • Porphyrins are cyclic compounds formed by the linkage of four pyrrole rings through methyne (ÓHC—) bridges.In the naturally occurring porphyrins, various side chains replace the eight numbered hydrogen atoms of the pyrroles. • Porphyrins have had different structures depend on side chains that are attached to each of the four pyrrole rings. For example; Uroporphyrin, coporporphyyrin and protoporphyrin IX (heme). • The most prevalent metalloporphyrin in humans is heme, which consists of one ferrous (Fe2+) iron ion coordinated at the center of the tetrapyrrole ring of protoporphyrin IX. What is bilirubin? •Bilirubin is a yellowish pigment found in bile, a fluid made by the liver. •The breakdown product of Hgb from injured RBCs and other heme containing proteins. •Produced by reticuloendothelial system •Released to plasma bound to albumin •Hepatocytes conjugate it and excrete through bile channels into small intestine. Bilirubin di-glucoronid Structure of heme: • Heme structure: a porphyrin ring coordinated with an atom of iron side chains: methyl, vinyl, propionyl • Heme is complexed with proteins to form: • Hemoglobin, myoglobin and cytochromes Pathway of Heme Biosynthesis. Heme biosynthesis begins in the mitochondria from glycine and succinyl- CoA, continues in the cytosol, and ultimately is completed within the mitochondria. The heme that it produced by this biosynthetic pathway is identified as heme b. PBG: porphobilinogen; ALA: δ- aminolevulinic -
Recent Studies Ofthe Urobilin Problem1
J Clin Pathol: first published as 10.1136/jcp.16.1.1 on 1 January 1963. Downloaded from J. clin. Path. (1963), 16, 1 --Recent studies of the urobilin problem1 C. J. WATSON2 From the Department of Medicine, University of Minnesota Hospital, Minneapolis, Minn. It is now almost a century since Jaffe (1868, 1869) 1961). Sjostrand (1949) demonstrated that this is described urobilin. It would manifestly be an imposi- lost as CO, an important observation not yet tion on your patience if I were to attempt any com- exploited to any extent by clinical investigators. It is prehensive treatment of the ensuing history of this intriguing that the opening of the porphyrin ring to topic, but I shall strive to bring together for you a form bile pigment involves only the ix bridge carbon. few of what seem to me the more important mile- A number of years ago Schwartz and I (Watson and stones in their relation to recent studies. For reasons Schwartz, 1942) converted the bilirubins from each that will become apparent, the term urobilin, both of a series of human fistula biles to urobilinogen, on historical and clinical chemical grounds, is best thence to a crystalline urobilin, which was shown to applied to a group of closely related substances. be the same in all instances, i.e., 9, ax in type. Gray, Under ordinary circumstances the urobilin group is Nicholson, and Nicolaus (1958) at King's College related mainly to destruction of the haemoglobin of Hospital, using a much more elegant and precise circulating red cells. Other possible sources will be method depending on oxidation to monopyrrolic referred to later. -
7 Bilirubin Metabolism
#7 Bilirubin metabolism Objectives : ● Definition of bilirubin ● The normal plasma concentration of total bilirubin ● Bilirubin metabolism : - Bilirubin formation - Transport of bilirubin in plasma - Hepatic bilirubin transport - Excretion through intestine ● Other substances conjugated by glucuronyl transferase. ● Differentiation between conjugated & unconjugated bilirubin ● Other substances excreted in the bile ● Definition of Jaundice ● Classification of jaundice ( Prehepatic / Hepatic / poat-hepatic ). Doctors’ notes Extra Important Resources: 435 Boys’ & Girls’ slides | Guyton and Hall 12th & 13th edition Editing file [email protected] 1 Overview- mind map Porphyrin Metabolism (Boys’ slides) : ● Porphyrins are cyclic compounds that readily bind metal ions usually Fe2+ or +3 Fe which can carry O2. ● Porphyrins are heterocyclic macrocycles composed of four modified pyrrole (a colorless, toxic, liquid, five-membered ring compound, C4 H5 N) subunits interconnected at their α carbon atoms via methine bridges (=CH-). ● The most prevalent porphyrin in the human is heme, which consists of one ferrous (Fe2+ ) iron ion coordinated in the center of tetrapyrrole ring of protoporphyrin IX. ● Structure of Hemoglobin showing the polypeptides backbone that are composed of four subunits: 2 α and 2 β subunits. Every subunit is consisted of one ferrous (Fe2+ ) iron ion coordinated in the center porphyrin compound. The most prevalent porphyrin in the human is heme Definition of bilirubin : ● Bilirubin is the end product of heme degradation derived from breakdown senescent (aging) erythrocytes by mononuclear phagocytes system specially in the spleen, liver and bone marrow. (It is the water insoluble breakdown product of normal heme catabolism). ● Bilirubin is the greenish yellow pigment excreted in bile, urine and feces. ● The major pigment present in bile is the orange compound bilirubin. -
Bile Pigments Porphyrins
ÚSTAV LÉKAŘSKÉ BIOCH EMIE A LABORATORNÍ DIAGNO STIKY 1. LF UK Bile pigments Porphyrins General Medicine Lenka Fialová & Martin Vejražka translated and edited by Jan Pláteník 2020/2021 Bile pigments, porphyrins 1 Bile pigments Bile pigments are compounds that contain four pyrrole rings in linear arrangement , and originate from degradation of heme. They encompass bilirubin , urobilinogen , stercobilinogen , and their oxidation products urobilin and stercobilin . 1.1 Origin of bile pigments Majority of bilirubin originates from degradation of hemoglobin released from red blood cells (75%); the rest comes from catabolism of other hemoproteins (cytochromes, catalase, peroxidase, myoglobin, etc.) There are two mechanisms of hemoglobin breakdown, according to where degradation of erythrocytes is localized: • extravascular – outside the blood vessels in the reticuloendothelial system or tissue macrophages • intravascular – inside the blood vessels The extravascular breakdown of red blood cells takes place in the macrophages of spleen, liver, and bone marrow. Under normal condition more than 90 % of hemoglobin is degraded in this way. Bilirubin formation proceeds in several steps: • Removal of iron and globin from the hemoglobin molecule together with opening of the porphyrin ring between pyrrole I and II and release of carbon monoxide gives rise to a linear tetrapyrrole, green pigment biliverdin . • Reduction of the central methenyl bridge between pyrrole III and IV in the biliverdin molecule by action of biliverdin reductase produces yellow bilirubin . This form of bilirubin is denoted as unconjugated bilirubin . It is insoluble in water , and rather easily passes biomembranes and enters the cells, where it is strongly toxic. That is why bilirubin, following release from its site of origin, is transported in circulation bound to albumin .