Unexpected Sequence Similarity Between Nucleosidases and Phosphoribosyltransferases of Different Specificity
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35 Disorders of Purine and Pyrimidine Metabolism
35 Disorders of Purine and Pyrimidine Metabolism Georges van den Berghe, M.- Françoise Vincent, Sandrine Marie 35.1 Inborn Errors of Purine Metabolism – 435 35.1.1 Phosphoribosyl Pyrophosphate Synthetase Superactivity – 435 35.1.2 Adenylosuccinase Deficiency – 436 35.1.3 AICA-Ribosiduria – 437 35.1.4 Muscle AMP Deaminase Deficiency – 437 35.1.5 Adenosine Deaminase Deficiency – 438 35.1.6 Adenosine Deaminase Superactivity – 439 35.1.7 Purine Nucleoside Phosphorylase Deficiency – 440 35.1.8 Xanthine Oxidase Deficiency – 440 35.1.9 Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency – 441 35.1.10 Adenine Phosphoribosyltransferase Deficiency – 442 35.1.11 Deoxyguanosine Kinase Deficiency – 442 35.2 Inborn Errors of Pyrimidine Metabolism – 445 35.2.1 UMP Synthase Deficiency (Hereditary Orotic Aciduria) – 445 35.2.2 Dihydropyrimidine Dehydrogenase Deficiency – 445 35.2.3 Dihydropyrimidinase Deficiency – 446 35.2.4 Ureidopropionase Deficiency – 446 35.2.5 Pyrimidine 5’-Nucleotidase Deficiency – 446 35.2.6 Cytosolic 5’-Nucleotidase Superactivity – 447 35.2.7 Thymidine Phosphorylase Deficiency – 447 35.2.8 Thymidine Kinase Deficiency – 447 References – 447 434 Chapter 35 · Disorders of Purine and Pyrimidine Metabolism Purine Metabolism Purine nucleotides are essential cellular constituents 4 The catabolic pathway starts from GMP, IMP and which intervene in energy transfer, metabolic regula- AMP, and produces uric acid, a poorly soluble tion, and synthesis of DNA and RNA. Purine metabo- compound, which tends to crystallize once its lism can be divided into three pathways: plasma concentration surpasses 6.5–7 mg/dl (0.38– 4 The biosynthetic pathway, often termed de novo, 0.47 mmol/l). starts with the formation of phosphoribosyl pyro- 4 The salvage pathway utilizes the purine bases, gua- phosphate (PRPP) and leads to the synthesis of nine, hypoxanthine and adenine, which are pro- inosine monophosphate (IMP). -
Metabolism of Nucleotides
METABOLISM OF NUCLEOTIDES Tomáš Kuˇcera Ústav lékaˇrské chemie a klinické biochemie 2. lékaˇrská fakulta, Univerzita Karlova v Praze 2013 NUKLEOTIDY rocy t e c l e e − − − h O O O N −O P O P O P O O O O O O H H H H OH OH heterocycle = nucleobase the name is historic pyrimidine purine nicotinamide, flavine PYRIMIDINE BASES AND NUCLEOSIDES PURINE BASES AND NUCLEOSIDES SOME LESS USUAL BASES AND NUCLEOSIDES 5-formylcytosine 6-methyladenine 4-methylcytosine FUNCTION OF NUCLEOTIDES precursors of DNA and RNA ATP, GTP, CTP, UTP, dATP, dGTP, dCTP, dTTP components of enzyme cofactors NAD(P), FAD, FMN, CoA [(P)APS – (phospho)adenosylphosphosulphate] macroergic “energy quanta” carriers ATP, GTP activated intermediates in biosyntheses UDP-sugars, CDP-diacylglycerols, S-adenosylmethionine second messengers in signal transduction cAMP, cGMP allosteric regulators ATP, ADP, AMP GAINING NUCLEOTIDES pancreatic (deoxy)ribonucleases and intestinal polynucleotidases: NA ! nucleotides nucleotidase of epithelial cells of the intestine: nucleotides ! nucleosides in the intestinal epithelial cells, nucleosides are used intact hydrolyzed by nucleoside (phosphoryl)ases: nucleoside ! base + pentose(-1-phosphate) + [phosphate] — salvage for the cells own need — transport to the blood about 5 % of digested nucleotides into the blood as bases and nucleosides low dietary uptake ) need of biosynthesis PYRIMIDINE NUCLEOSIDES BIOSYNTHESIS 1 PYRIMIDINE NUCLEOSIDES BIOSYNTHESIS 2 UTP SYNTHESIS nucleosidmonophosphate- UMP + ATP kinase UDP + ADP nucleosiddiphosphate- UDP + ATP -
(12) Patent Application Publication (10) Pub. No.: US 2002/0179493 A1 Etter (43) Pub
US 2002O179493A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0179493 A1 Etter (43) Pub. Date: Dec. 5, 2002 (54) PRODUCTION AND USE OF A PREMIUM (52) U.S. Cl. .................... 208/131; 208/108; 208/111.01; FUEL GRADE PETROLEUM COKE 208/142; 208/143; 208/144; 208/145 (75) Inventor: Roger G. Etter, Cardington, OH (US) Correspondence Address: (57) ABSTRACT STANDLEY & GLCREST LLP 495 METRO PLACE SOUTH A premium "fuel-grade' petroleum coke is produced by SUTE 210 modifying petroleum coking technology. Coking process DUBLIN, OH 43017 (US) parameters are controlled to consistently produce petroleum coke within a predetermined range for Volatile combustible (73) Assignee: Environmental & Energy Enterprises, material (VCM) content. The invention includes a process of LLC producing a coke fuel, the method comprising Steps: (a) obtaining a coke precursor material derived from crude oil (21) Appl. No.: 10/027,677 and having a volatile organic component; and (b) Subjecting the coke precursor material to a thermal cracking proceSS for (22) Filed: Dec. 20, 2001 Sufficient time and at Sufficient temperature and under Suf ficient preSSure So as to produce a coke product having Related U.S. Application Data volatile combustible materials (VCMs) present in an amount (63) Continuation-in-part of application No. 09/556,132, in the range of from about 13% to about 50% by weight. filed on Apr. 21, 2000. Continuation-in-part of appli Most preferably, the volatile combustible materials in the coke product typically may be in the range of from about cation No. 09/763,282, filed on Feb. -
Glucan Phosphorylase-Catalyzed Enzymatic Reactions Using Analog Substrates to Synthesize Non-Natural Oligo- and Polysaccharides
catalysts Review α-Glucan Phosphorylase-Catalyzed Enzymatic Reactions Using Analog Substrates to Synthesize Non-Natural Oligo- and Polysaccharides Jun-ichi Kadokawa Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 860-0065, Japan; [email protected]; Tel.: +81-99-285-7743 Received: 9 October 2018; Accepted: 16 October 2018; Published: 19 October 2018 Abstract: As natural oligo- and polysaccharides are important biomass resources and exhibit vital biological functions, non-natural oligo- and polysaccharides with a well-defined structure can be expected to act as new functional materials with specific natures and properties. α-Glucan phosphorylase (GP) is one of the enzymes that have been used as catalysts for practical synthesis of oligo- and polysaccharides. By means of weak specificity for the recognition of substrates by GP, non-natural oligo- and polysaccharides has precisely been synthesized. GP-catalyzed enzymatic glycosylations using several analog substrates as glycosyl donors have been carried out to produce oligosaccharides having different monosaccharide residues at the non-reducing end. Glycogen, a highly branched natural polysaccharide, has been used as the polymeric glycosyl acceptor and primer for the GP-catalyzed glycosylation and polymerization to obtain glycogen-based non-natural polysaccharide materials. Under the conditions of removal of inorganic phosphate, thermostable GP-catalyzed enzymatic polymerization of analog monomers occurred to give amylose analog polysaccharides. Keywords: analog substrate; α-glucan phosphorylase; non-natural oligo- and polysaccharides 1. Introduction Oligo- and polysaccharides are widely distributed in nature and enact specific important biological functions in accordance with their chemical structures [1]. -
Defective Galactose Oxidation in a Patient with Glycogen Storage Disease and Fanconi Syndrome
Pediatr. Res. 17: 157-161 (1983) Defective Galactose Oxidation in a Patient with Glycogen Storage Disease and Fanconi Syndrome M. BRIVET,"" N. MOATTI, A. CORRIAT, A. LEMONNIER, AND M. ODIEVRE Laboratoire Central de Biochimie du Centre Hospitalier de Bichre, 94270 Kremlin-Bicetre, France [M. B., A. C.]; Faculte des Sciences Pharmaceutiques et Biologiques de I'Universite Paris-Sud, 92290 Chatenay-Malabry, France [N. M., A. L.]; and Faculte de Midecine de I'Universiti Paris-Sud et Unite de Recherches d'Hepatologie Infantile, INSERM U 56, 94270 Kremlin-Bicetre. France [M. 0.1 Summary The patient's diet was supplemented with 25-OH-cholecalci- ferol, phosphorus, calcium, and bicarbonate. With this treatment, Carbohydrate metabolism was studied in a child with atypical the serum phosphate concentration increased, but remained be- glycogen storage disease and Fanconi syndrome. Massive gluco- tween 0.8 and 1.0 mmole/liter, whereas the plasma carbon dioxide suria, partial resistance to glucagon and abnormal responses to level returned to normal (18-22 mmole/liter). Rickets was only carbohydrate loads, mainly in the form of major impairment of partially controlled. galactose utilization were found, as reported in previous cases. Increased blood lactate to pyruvate ratios, observed in a few cases of idiopathic Fanconi syndrome, were not present. [l-14ClGalac- METHODS tose oxidation was normal in erythrocytes, but reduced in fresh All studies of the patient and of the subjects who served as minced liver tissue, despite normal activities of hepatic galactoki- controls were undertaken after obtaining parental or personal nase, uridyltransferase, and UDP-glucose 4epirnerase in hornog- consent. enates of frozen liver. -
Curriculum Vitae Vern Lee Schramm
September 2011 CURRICULUM VITAE VERN LEE SCHRAMM Department of Biochemistry Albert Einstein College of Medicine of Yeshiva University 1300 Morris Park Avenue Bronx, New York 10461 Phone: (718) 430-2813 Fax: (718) 430-8565 E-mail: [email protected] Personal Information: Date of Birth: November 9, 1941 Place of Birth: Howard, South Dakota Citizenship: U.S.A. Home Address: 68 Hampton Oval New Rochelle, NY 10805 Home Telephone: (914) 576-2578 Education: Sept 1959 – June 1963 B.S. in Bacteriology (chemistry emphasis), South Dakota State College Sept 1963 – June 1965 Masters Degree in Nutrition (biochemistry emphasis), Harvard University Research Advisor, Dr. R.P. Geyer Oct 1965 – April 1969 Ph.D. in Mechanism of Enzyme Action, Department of Biochemistry, Australian National University Research Advisor, Dr. John Morrison Postdoctoral Experience: Aug 1969 – Aug 1971 NRC-NSF Postdoctoral Research Associate at NASA Ames Research Center, Biological Adaptation Branch Appointments: July 1999 – Present University Professor of the Albert Einstein College of Medicine July 1995 – Present Ruth Merns Endowed Chair of Biochemistry Aug 1987 – Present Professor and Chairman, Department of Biochemistry, Albert Einstein College of Medicine July 1981 - July 1987 Professor of Biochemistry, Temple University School of Medicine July 1976 - June 1981 Associate Professor of Biochemistry, Temple University School of Medicine Aug 1971 - July 1976 Assistant Professor of Biochemistry, Temple University School of Medicine Vern L. Schramm 2 Fields of Interest: Enzymatic -
Letters to Nature
letters to nature Received 7 July; accepted 21 September 1998. 26. Tronrud, D. E. Conjugate-direction minimization: an improved method for the re®nement of macromolecules. Acta Crystallogr. A 48, 912±916 (1992). 1. Dalbey, R. E., Lively, M. O., Bron, S. & van Dijl, J. M. The chemistry and enzymology of the type 1 27. Wolfe, P. B., Wickner, W. & Goodman, J. M. Sequence of the leader peptidase gene of Escherichia coli signal peptidases. Protein Sci. 6, 1129±1138 (1997). and the orientation of leader peptidase in the bacterial envelope. J. Biol. Chem. 258, 12073±12080 2. Kuo, D. W. et al. Escherichia coli leader peptidase: production of an active form lacking a requirement (1983). for detergent and development of peptide substrates. Arch. Biochem. Biophys. 303, 274±280 (1993). 28. Kraulis, P.G. Molscript: a program to produce both detailed and schematic plots of protein structures. 3. Tschantz, W. R. et al. Characterization of a soluble, catalytically active form of Escherichia coli leader J. Appl. Crystallogr. 24, 946±950 (1991). peptidase: requirement of detergent or phospholipid for optimal activity. Biochemistry 34, 3935±3941 29. Nicholls, A., Sharp, K. A. & Honig, B. Protein folding and association: insights from the interfacial and (1995). the thermodynamic properties of hydrocarbons. Proteins Struct. Funct. Genet. 11, 281±296 (1991). 4. Allsop, A. E. et al.inAnti-Infectives, Recent Advances in Chemistry and Structure-Activity Relationships 30. Meritt, E. A. & Bacon, D. J. Raster3D: photorealistic molecular graphics. Methods Enzymol. 277, 505± (eds Bently, P. H. & O'Hanlon, P. J.) 61±72 (R. Soc. Chem., Cambridge, 1997). -
Molecular Basis for the Involvement of Thymidine Phosphorylase in Cancer Invasion
1085-1091 2/5/06 14:03 Page 1085 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 17: 1085-1091, 2006 Molecular basis for the involvement of thymidine phosphorylase in cancer invasion TAKENARI GOTANDA1,2, MISAKO HARAGUCHI2, TOKUSHI TACHIWADA1,2, REIKO SHINKURA3, CHIHAYA KORIYAMA3, SUMINORI AKIBA3, MOTOSHI KAWAHARA1, KENRYU NISHIYAMA1, TOMOYUKI SUMIZAWA2, TATSUHIKO FURUKAWA2, HIROMITSU MIMATA4, YOSHIO NOMURA4, SHIN-ICHI AKIYAMA2 and MASAYUKI NAKAGAWA1 Departments of 1Urology, 2Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics; 3Department of Epidemiology and Preventive Medicine, Field of Human and Environmental Sciences, Course of Health Research, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520; 4Department of Urology, School of Medicine, Oita University, Oita 879-5593, Japan Received November 28, 2005; Accepted January 17, 2006 Abstract. Thymidine phosphorylase (TP), also known as Introduction platelet-derived endothelial cell growth factor (PD-ECGF), has been implicated in bladder cancer angiogenesis and invasion. Cancer invasion is a complicated process involving the activity However, the molecular basis of its role in invasion remains of multiple genes. As cancer cells undergo invasion, they must unclear. We investigated the expression of TP and 10 invasion- first attach to the target tissue's basal matrix and then degrade related genes in bladder cancers from 72 randomly selected the basement membrane. Degradation of the extracellular patients by real-time two-step RT-PCR assay. We found that matrix, or components of the basement membrane, is carried the expression levels of TP, MMP-9, uPA, and MMP-2 were out mainly by proteases belonging to the matrix metallo- significantly higher in invasive tumors than those in proteinase family (MMPs) (1,2). -
The Microbiota-Produced N-Formyl Peptide Fmlf Promotes Obesity-Induced Glucose
Page 1 of 230 Diabetes Title: The microbiota-produced N-formyl peptide fMLF promotes obesity-induced glucose intolerance Joshua Wollam1, Matthew Riopel1, Yong-Jiang Xu1,2, Andrew M. F. Johnson1, Jachelle M. Ofrecio1, Wei Ying1, Dalila El Ouarrat1, Luisa S. Chan3, Andrew W. Han3, Nadir A. Mahmood3, Caitlin N. Ryan3, Yun Sok Lee1, Jeramie D. Watrous1,2, Mahendra D. Chordia4, Dongfeng Pan4, Mohit Jain1,2, Jerrold M. Olefsky1 * Affiliations: 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. 2 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. 3 Second Genome, Inc., South San Francisco, California, USA. 4 Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. * Correspondence to: 858-534-2230, [email protected] Word Count: 4749 Figures: 6 Supplemental Figures: 11 Supplemental Tables: 5 1 Diabetes Publish Ahead of Print, published online April 22, 2019 Diabetes Page 2 of 230 ABSTRACT The composition of the gastrointestinal (GI) microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine (fMLF), are elevated in high fat diet (HFD)- induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon- like peptide-1 (GLP-1). Obese Fpr1-knockout (Fpr1-KO) mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. -
Four Novel Thymidine Phosphorylase Gene Mutations in Mitochondrial Neurogastrointestinal Encephalomyopathy Syndrome (MNGIE) Patients
European Journal of Human Genetics (2003) 11, 102 – 104 ª 2003 Nature Publishing Group All rights reserved 1018 – 4813/03 $25.00 www.nature.com/ejhg SHORT REPORT Four novel thymidine phosphorylase gene mutations in mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) patients YC¸ etin Kocaefe1, Sevim Erdem2, Meral O¨ zgu¨c¸*,1,3 and Ersin Tan2 1Department of Medical Biology, Faculty of Medicine, Hacettepe University Ankara, Turkey; 2Department of Neurology, Faculty of Medicine, Hacettepe University Ankara, Turkey; 3TU¨BITAK DNA/Cell Bank, Hacettepe University Ankara, Turkey Mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) is a rare autosomal recessive neurologic disorder characterised by multiple mitochondrial DNA deletions. In this study, five Turkish MNGIE patients are investigated for mtDNA deletions and TP gene mutations. The probands presented all the clinical criteria of the typical MNGIE phenotype; the muscle biopsy specimens also confirmed the diagnosis with ragged red fibres and cytochrome C oxidase (COX) negative fibres. The mitochondrial DNA analysis revealed no deletions in the probands’ skeletal muscle samples. We have identified four novel mutations in the TP gene while one of the patients also harboured a nucleotide change, which was previously reported as a mutation. European Journal of Human Genetics (2003) 11, 102 – 104. doi:10.1038/sj.ejhg.5200908 Keywords: Mitochondrial myopathy; MNGIE; mtDNA deletions; thymidine phosphorylase; gliostatin Introduction cyte TP activity to less than 5% of normal controls.1 In Mitochondrial diseases are a group of heterogeneous and this study we investigated five Turkish MNGIE patients complex disorders. The pathology may reside in the mito- for mutations in the TP gene. We have identified four chondrial DNA (mtDNA) or the nuclear genome. -
Chem331 Glycogen Metabolism
Glycogen metabolism Glycogen review - 1,4 and 1,6 α-glycosidic links ~ every 10 sugars are branched - open helix with many non-reducing ends. Effective storage of glucose Glucose storage Liver glycogen 4.0% 72 g Muscle glycogen 0.7% 245 g Blood Glucose 0.1% 10 g Large amount of water associated with glycogen - 0.5% of total weight Glycogen stored in granules in cytosol w/proteins for synthesis, degradation and control There are very different means of control of glycogen metabolism between liver and muscle Glycogen biosynthetic and degradative cycle Two different pathways - which do not share enzymes like glycolysis and gluconeogenesis glucose -> glycogen glycogenesis - biosynthetic glycogen -> glucose 1-P glycogenolysis - breakdown Evidence for two paths - Patients lacking phosphorylase can still synthesize glycogen - hormonal regulation of both directions Glycogenolysis (glycogen breakdown)- Glycogen Phosphorylase glycogen (n) + Pi -> glucose 1-p + glycogen (n-1) • Enzyme binds and cleaves glycogen into monomers at the end of the polymer (reducing ends of glycogen) • Dimmer interacting at the N-terminus. • rate limiting - controlled step in glycogen breakdown • glycogen phosphorylase - cleavage of 1,4 α glycosidic bond by Pi NOT H2O • Energy of phosphorolysis vs. hydrolysis -low standard state free energy change -transfer potential -driven by Pi concentration -Hydrolysis would require additional step s/ cost of ATP - Think of the difference between adding a phosphate group with hydrolysis • phosphorylation locks glucose in cell (imp. for muscle) • Phosphorylase binds glycogen at storage site and the catalytic site is 4 to 5 glucose residues away from the catalytic site. • Phosphorylase removes 1 residue at a time from glycogen until 4 glucose residues away on either side of 1,6 branch point – stericaly hindered by glycogen storage site • Cleaves without releasing at storage site • general acid/base catalysts • Inorganic phosphate attacks the terminal glucose residue passing through an oxonium ion intermediate. -
The Origins of Protein Phosphorylation
historical perspective The origins of protein phosphorylation Philip Cohen The reversible phosphorylation of proteins is central to the regulation of most aspects of cell func- tion but, even after the first protein kinase was identified, the general significance of this discovery was slow to be appreciated. Here I review the discovery of protein phosphorylation and give a per- sonal view of the key findings that have helped to shape the field as we know it today. he days when protein phosphorylation was an abstruse backwater, best talked Tabout between consenting adults in private, are over. My colleagues no longer cringe on hearing that “phosphorylase kinase phosphorylates phosphorylase” and their eyes no longer glaze over when a “”kinase kinase kinase” is mentioned. This is because protein phosphorylation has gradu- ally become an integral part of all the sys- tems they are studying themselves. Indeed it would be difficult to find anyone today who would disagree with the statement that “the reversible phosphorylation of proteins regu- lates nearly every aspect of cell life”. Phosphorylation and dephosphorylation, catalysed by protein kinases and protein phosphatases, can modify the function of a protein in almost every conceivable way; for Carl and Gerty Cori, the 1947 Nobel Laureates. Picture: Science Photo Library. example by increasing or decreasing its bio- logical activity, by stabilizing it or marking it for destruction, by facilitating or inhibiting movement between subcellular compart- so long before its general significance liver enzyme that catalysed the phosphory- ments, or by initiating or disrupting pro- was appreciated? lation of casein3. Soon after, Fischer and tein–protein interactions.