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Molecular Analysis of the Aldolase B Gene in Patients with Hereditary
1of8 J Med Genet: first published as 10.1136/jmg.39.9.e56 on 1 September 2002. Downloaded from ONLINE MUTATION REPORT Molecular analysis of the aldolase B gene in patients with hereditary fructose intolerance from Spain J C Sánchez-Gutiérrez, T Benlloch, M A Leal, B Samper, I García-Ripoll, J E Felíu ............................................................................................................................. J Med Genet 2002;39:e56 (http://www.jmedgenet.com/cgi/content/full/39/9/e56) ereditary fructose intolerance (HFI) is an autosomal resident in the following regions: Madrid (11 families), Anda- recessive metabolic disorder caused by aldolase (fructo- lusia (4), Galicia (3), Estremadura (1), Valencia (1), and Hsediphosphate aldolase, EC 4.1.2.13) B deficiency.1 The Spanish possessions in North Africa (1). HFI diagnosis was B isoform of aldolase is critical for the metabolism of based on enzymatic studies (deficient aldolase B activity in exogenous fructose by the liver, kidney, and intestine, since it hepatic biopsies from 16 patients) or clinical symptoms (six can use fructose-1-phosphate as substrate at physiological patients). Another six subjects were suspected to suffer from concentrations, unlike aldolases A and C. Affected subjects HFI on the basis of dietary intolerance with episodes sugges- suffer abdominal pain, vomiting, and hypoglycaemia after the tive of hypoglycaemia and occurrence of the disease in their ingestion of fructose, sucrose, or sorbitol. Continued ingestion first degree relatives. of noxious sugars causes hepatic and renal injury, which eventually leads to liver cirrhosis and sometimes death, Reagents particularly in small infants.1 Treatment consists of strict Thermostable DNA polymerase, deoxynucleotides, and gen- elimination of fructose, sucrose, and sorbitol from the diet eral PCR products were from Biotools (Madrid, Spain). -
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Research Article Glutathione Transferase P Plays a Critical Role in the Development of Lung Carcinogenesis following Exposure to Tobacco-Related Carcinogens and Urethane Kenneth J. Ritchie,1 Colin J. Henderson,1 Xiu Jun Wang,1 Olga Vassieva,1 Dianne Carrie,1 Peter B. Farmer,2 Margaret Gaskell,2 Kevin Park,3 and C. Roland Wolf1 1Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom; 2Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, Leicester, United Kingdom;and 3Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom Abstract family of dimeric enzymes (EC 2.5.1.18;GST a, A, k, u, j, ~, n, and N) Human cancer is controlled by a complex interaction between identified on the basis of their amino acid sequence and substrate genetic and environmental factors. Such environmental specificity (4). GSTs are regarded as being important detoxification factors are well defined for smoking-induced lung cancer; enzymes due to their capacity to catalyze the addition of reduced however, the roles of specific genes have still to be elucidated. glutathione (GSH) to reactive electrophiles produced by cyto- Glutathione transferase P (GSTP) catalyzes the detoxification chrome P450 metabolism. As a consequence, there has been a of electrophilic diol epoxides produced by the metabolism of significant interest in elucidating the relationship between GSTP polycyclic aromatic hydrocarbons such as benzo[a]pyrene function and resistance to cancer chemotherapeutic agents and the development of cancer (5–7). In a genetic approach to study GST (BaP), a common constituent of tobacco smoke. Activity- altering polymorphisms in Gstp have therefore been speculated functions, we have generated mice nulled at the Gstp gene locus to be potential risk modifiers in lung cancer development. -
ASPA Gene Aspartoacylase
ASPA gene aspartoacylase Normal Function The ASPA gene provides instructions for making an enzyme called aspartoacylase. In the brain, this enzyme breaks down a compound called N-acetyl-L-aspartic acid (NAA) into aspartic acid (an amino acid that is a building block of many proteins) and another molecule called acetic acid. The production and breakdown of NAA appears to be critical for maintaining the brain's white matter, which consists of nerve fibers surrounded by a myelin sheath. The myelin sheath is the covering that protects nerve fibers and promotes the efficient transmission of nerve impulses. The precise function of NAA is unclear. Researchers had suspected that it played a role in the production of the myelin sheath, but recent studies suggest that NAA does not have this function. The enzyme may instead be involved in the transport of water molecules out of nerve cells (neurons). Health Conditions Related to Genetic Changes Canavan disease More than 80 mutations in the ASPA gene are known to cause Canavan disease, which is a rare inherited disorder that affects brain development. Researchers have described two major forms of this condition: neonatal/infantile Canavan disease, which is the most common and most severe form, and mild/juvenile Canavan disease. The ASPA gene mutations that cause the neonatal/infantile form severely impair the activity of aspartoacylase, preventing the breakdown of NAA and allowing this substance to build up to high levels in the brain. The mutations that cause the mild/juvenile form have milder effects on the enzyme's activity, leading to less accumulation of NAA. -
Isolation and Characterization of a Mutant Liver Aldolase in Adult Hereditary Fructose Intolerance
Isolation and characterization of a mutant liver aldolase in adult hereditary fructose intolerance. Identification of the enzyme variant by radioassay in tissue biopsy specimens Timothy M. Cox, … , Michael Camilleri, Arthur H. Burghes J Clin Invest. 1983;72(1):201-213. https://doi.org/10.1172/JCI110958. Hereditary fructose intolerance (HFI) is a metabolic disorder caused by enzymic deficiency of aldolase B, a genetically distinct cytosolic isoenzyme expressed exclusively in liver, kidney, and intestine. The molecular basis of this enzyme defect has been investigated in three affected individuals from a nonconsanguineous kindred, in whom fructose-l- phosphate aldolase activities in liver or intestinal biopsy samples were reduced to 2-6% of mean control values. To identify a putative enzyme mutant in tissue extracts, aldolase B was purified from human liver by affinity chromatography and monospecific antibodies were prepared from antiserum raised in sheep. Immunodiffusion gels showed a single precipitin line common to pure enzyme and extracts of normal liver and intestine, but no reaction with extracts of brain, muscle, or HFI liver. However, weak positive staining for aldolase in hepatocyte and enterocyte cytosol was demonstrated by indirect immunofluorescence of HFI tissues. This was abolished by pretreatment with pure enzyme protein. Accordingly, a specific radioimmunoassay (detection limit 7.5 ng) was established to quantify immunoreactive aldolase B in human biopsy specimens. Extracts of tissue from affected patients gave 10-25% immunoreactive enzyme in control samples; immunoreactive aldolase in intestinal extracts from four heterozygotes was reduced (to 55%) when compared with seven samples from normal control subjects (P < 0.05). In extracts of HFI tissues, there was a sevenfold reduction in apparent absolute specific […] Find the latest version: https://jci.me/110958/pdf Isolation and Characterization of a Mutant Liver Aldolase in Adult Hereditary Fructose Intolerance IDENTIFICATION OF THE ENZYME VARIANT BY RADIOASSAY IN TISSUE BIOPSY SPECIMENS TIMOTHY M. -
Global Histone Modification Fingerprinting in Human Cells Using
OPEN Citation: Cell Death Discovery (2017) 3, 16077; doi:10.1038/cddiscovery.2016.77 Official journal of the Cell Death Differentiation Association www.nature.com/cddiscovery ARTICLE Global histone modification fingerprinting in human cells using epigenetic reverse phase protein array Marina Partolina1,HazelCThoms1, Kenneth G MacLeod2, Giovanny Rodriguez-Blanco1,MatthewNClarke1, Anuroop V Venkatasubramani1,3, Rima Beesoo4, Vladimir Larionov5, Vidushi S Neergheen-Bhujun4, Bryan Serrels2, Hiroshi Kimura6, Neil O Carragher2 and Alexander Kagansky1,7 The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear. For example, enzymes controlling histone modifications utilize key cellular metabolites associated with intra- and extracellular feedback loops, adding a further layer of complexity to this process. Meanwhile, it has become increasingly evident that new assay technologies which provide robust and precise measurement of global histone modifications are required, -
Generated by SRI International Pathway Tools Version 25.0, Authors S
Authors: Pallavi Subhraveti Ron Caspi Quang Ong Peter D Karp An online version of this diagram is available at BioCyc.org. Biosynthetic pathways are positioned in the left of the cytoplasm, degradative pathways on the right, and reactions not assigned to any pathway are in the far right of the cytoplasm. Transporters and membrane proteins are shown on the membrane. Ingrid Keseler Periplasmic (where appropriate) and extracellular reactions and proteins may also be shown. Pathways are colored according to their cellular function. Gcf_000725805Cyc: Streptomyces xanthophaeus Cellular Overview Connections between pathways are omitted for legibility. -
Identification of Proteins Differentially Expressed in the Conventional Renal Cell Carcinoma by Proteomic Analysis
J Korean Med Sci 2005; 20: 450-5 Copyright � The Korean Academy ISSN 1011-8934 of Medical Sciences Identification of Proteins Differentially Expressed in the Conventional Renal Cell Carcinoma by Proteomic Analysis Renal cell carcinoma (RCC) is one of the most malignant tumors in urology, and Jeong Seok Hwa, Hyo Jin Park*, due to its insidious onset patients frequently have advanced disease at the time of Jae Hun Jung, Sung Chul Kam, clinical presentation. Thus, early detection is crucial in management of RCC. To Hyung Chul Park, Choong Won Kim*, identify tumor specific proteins of RCC, we employed proteomic analysis. We pre- Kee Ryeon Kang*, Jea Seog Hyun, Ky Hyun Chung pared proteins from conventional RCC and the corresponding normal kidney tis- sues from seven patients with conventional RCC. The expression of proteins was Department of Urology and Biochemistry*, College of determined by silver stain after two-dimensional polyacrylamide gel electrophore- Medicine and Institute of Health Science, sis (2D-PAGE). The overall protein expression patterns in the RCC and the normal Gyeongsang National University, Jinju, Korea kidney tissues were quite similar except some areas. Of 66 differentially expressed Received : 29 December 2004 protein spots (p<0.05 by Student t-test), 8 different proteins from 11 spots were Accepted : 13 January 2005 identified by MALDI-TOF-MS. The expression of the following proteins was repress- ed (p<0.05); aminoacylase-1, enoyl-CoA hydratase, aldehyde reductase, tropo- Address for correspondence myosin -4 chain, agmatinase and ketohexokinase. Two proteins, vimentin and -1 Jeong Seok Hwa, M.D. Department of Urology, College of Medicine, antitrypsin precursor, were dominantly expressed in RCC (p<0.05). -
CUMMINGS-DISSERTATION.Pdf (4.094Mb)
D-AMINOACYLASES AND DIPEPTIDASES WITHIN THE AMIDOHYDROLASE SUPERFAMILY: RELATIONSHIP BETWEEN ENZYME STRUCTURE AND SUBSTRATE SPECIFICITY A Dissertation by JENNIFER ANN CUMMINGS Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2010 Major Subject: Chemistry D-AMINOACYLASES AND DIPEPTIDASES WITHIN THE AMIDOHYDROLASE SUPERFAMILY: RELATIONSHIP BETWEEN ENZYME STRUCTURE AND SUBSTRATE SPECIFICITY A Dissertation by JENNIFER ANN CUMMINGS Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, Frank Raushel Committee Members, Paul Lindahl David Barondeau Gregory Reinhart Head of Department, David Russell December 2010 Major Subject: Chemistry iii ABSTRACT D-Aminoacylases and Dipeptidases within the Amidohydrolase Superfamily: Relationship Between Enzyme Structure and Substrate Specificity. (December 2010) Jennifer Ann Cummings, B.S., Southern Oregon University; M.S., Texas A&M University Chair of Advisory Committee: Dr. Frank Raushel Approximately one third of the genes for the completely sequenced bacterial genomes have an unknown, uncertain, or incorrect functional annotation. Approximately 11,000 putative proteins identified from the fully-sequenced microbial genomes are members of the catalytically diverse Amidohydrolase Superfamily. Members of the Amidohydrolase Superfamily separate into 24 Clusters of Orthologous Groups (cogs). Cog3653 includes proteins annotated as N-acyl-D-amino acid deacetylases (DAAs), and proteins within cog2355 are homologues to the human renal dipeptidase. The substrate profiles of three DAAs (Bb3285, Gox1177 and Sco4986) and six microbial dipeptidase (Sco3058, Gox2272, Cc2746, LmoDP, Rsp0802 and Bh2271) were examined with N-acyl-L-, N-acyl-D-, L-Xaa-L-Xaa, L-Xaa-D-Xaa and D-Xaa-L-Xaa substrate libraries. -
WO2019226953A1.Pdf
) ( 2 (51) International Patent Classification: Street, Brookline, MA 02446 (US). WILSON, Christo¬ C12N 9/22 (2006.01) pher, Gerard; 696 Main Street, Apartment 311, Waltham, MA 0245 1(US). DOMAN, Jordan, Leigh; 25 Avon Street, (21) International Application Number: Somverville, MA 02143 (US). PCT/US20 19/033 848 (74) Agent: HEBERT, Alan, M. et al. ;Wolf, Greenfield, Sacks, (22) International Filing Date: P.C., 600 Atlanitc Avenue, Boston, MA 02210-2206 (US). 23 May 2019 (23.05.2019) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection av ailable) . AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (30) Priority Data: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 62/675,726 23 May 2018 (23.05.2018) US HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 62/677,658 29 May 2018 (29.05.2018) US KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 415 Main Street, Cambridge, MA 02142 (US). PRESI¬ OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, DENT AND FELLOWS OF HARVARD COLLEGE SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, [US/US]; 17 Quincy Street, Cambridge, MA 02138 (US). -
Antenatal Diagnosis of Inborn Errors Ofmetabolism
816 ArchivesofDiseaseinChildhood 1991;66: 816-822 CURRENT PRACTICE Arch Dis Child: first published as 10.1136/adc.66.7_Spec_No.816 on 1 July 1991. Downloaded from Antenatal diagnosis of inborn errors of metabolism M A Cleary, J E Wraith The introduction of experimental treatment for Sample requirement and techniques used in lysosomal storage disorders and the increasing prenatal diagnosis understanding of the molecular defects behind By far the majority of antenatal diagnoses are many inborn errors have overshadowed the fact performed on samples obtained by either that for many affected families the best that can amniocentesis or chorion villus biopsy. For be offered is a rapid, accurate prenatal diag- some disorders, however, the defect is not nostic service. Many conditions remain at best detectable in this material and more invasive only partially treatable and as a consequence the methods have been applied to obtain a diagnos- majority of parents seek antenatal diagnosis in tic sample. subsequent pregnancies, particularly for those disorders resulting in a poor prognosis in terms of either life expectancy or normal neurological FETAL LIVER BIOPSY development. Fetal liver biopsy has been performed to The majority of inborn errors result from a diagnose ornithine carbamoyl transferase defi- specific enzyme deficiency, but in some the ciency and primary hyperoxaluria type 1. primary defect is in a transport system or Glucose-6-phosphatase deficiency (glycogen enzyme cofactor. In some conditions the storage disease type I) could also be detected by biochemical defect is limited to specific tissues this method. The technique, however, is inva- only and this serves to restrict the material avail- sive and can be performed by only a few highly able for antenatal diagnosis for these disorders. -
Inhibition of N-Acetylglutamate Synthase by Various Monocarboxylic and Dicarboxylic Short-Chain Coenzyme a Esters and the Production of Alternative Glutamate Esters☆
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1842 (2014) 2510–2516 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters☆ M. Dercksen a,b,⁎, L. IJlst a, M. Duran a, L.J. Mienie b, A. van Cruchten a, F.H. van der Westhuizen b, R.J.A. Wanders a a Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands b Centre for Human Metabonomics, North-West University (Potchefstroom Campus), Hoffman street 11, Potchefstroom, South Africa, 2520 article info abstract Article history: Hyperammonemia is a frequent finding in various organic acidemias. One possible mechanism involves the Received 11 December 2012 inhibition of the enzyme N-acetylglutamate synthase (NAGS), by short-chain acyl-CoAs which accumulate due Received in revised form 9 April 2013 to defective catabolism of amino acids and/or fatty acids in the cell. The aim of this study was to investigate the Accepted 29 April 2013 effect of various acyl-CoAs on the activity of NAGS in conjunction with the formation of glutamate esters. NAGS Available online 2 May 2013 activity was measured in vitro using a sensitive enzyme assay with ultraperformance liquid chromatography– – Keywords: tandem mass spectrometry (UPLC MS/MS) product analysis. Propionyl-CoA and butyryl-CoA proved to be the N-acetylglutamate synthase most powerful inhibitors of N-acetylglutamate (NAG) formation. -
N-Acetylglutamate Content in Liver and Gut of Normal and Fasted Mice, Normal Human Livers, and Livers of Individuals with Carbam
003 I -3998/90/2704-0408$02.00/0 PEDIATRIC RESEARCH Vol. 27, No. 4, 1990 Copyright O 1990 International Pediatric Research Foundation, Inc Printed in U.S. A. N-Acetylglutamate Content in Liver and Gut of Normal and Fasted Mice, Normal Human Livers, and Livers of Individuals with Carbamyl Phosphate Synthetase or Ornithine Transcarbamylase Deficiency MENDEL TUCHMAN AND ROBERT A. HOLZKNECHT Division ofMetabolism, Depurtmmt.~ofPediatrics and Laboratory Medicine and Pulhology, Universifyu/ Minnesota, Minneapolis, Minnesota 55455 ABSTRACT. N-acetylglutamate (NAG) content was CPS I, carbamyl phosphate synthetase I measured in homogenates of liver and small intestine ob- OTC, ornithine transcarbamylase tained from normal and 24-h starved syngeneic mice. Sub- GC-MS, gas chromatography-mass spectrometry sequently, NAG was determined in normal, and in car- MSD, mass selective detector bamyl phosphate synthetase I and ornithine transcarbam- SIM, selected ion monitoring ylase enzyme-deficient human liver tissue homogenates. TMS, trimethylsilyl The method used in this study, which is direct and highly specific, used anion exchange extraction, gas chromato- graphic separation, and mass spectrometric detection and quantitation. Hepatic NAG content in the fed animals was In 1953, Grisolia and Cohen (1) discovered that a derivative 94.8 + 19.8 nmoljg tissue or 602.5 + 168.4 nmol/g protein n of L-glutamic acid enhanced the biosynthesis of L-citrulline by (mean + SD, = 5), whereas it was much lower in the preparation of mammalian liver. This naturally occumng com- fasted mice (49.4 + 13.0 nmol/g tissue or 330.1 + 113.9 n pound was isolated and identified as NAG, which is the cofactor nmol/g protein, mean + SD, = 5).