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169 ALLOPUBINOL-INDUCED OROTICACIDURIA 172 in a NEW DUTCH PATIENT with PNP-DEFICIENCY and CELLULAR ITNODEFICIENCY Sebastian Beiter
URINABY OXIPURINOL-1-RIBOSIDE EXCRETION AND RESIDUAL PURINE NUCLEOSIDE PHOSPHORYLASE ACTIVITY 169 ALLOPUBINOL-INDUCED OROTICACIDURIA 172 IN A NEW DUTCH PATIENT WITH PNP-DEFICIENCY AND CELLULAR ITNODEFICIENCY Sebastian Beiter. Werner Loffler, Wolfgang 2 Grobner and Nepomnk Zollner. Medizinische Poliklinik der G.R~ 'ksenl, J.M.Ze ers , lL. J.M. S aa en , W.~uis~,M.Duran , Universitat Miinchen, W-Germany. B.S.:oorbrooc?, G.E.2Staal and S.E.zdman2. 1 Dept. Hematology, Div. Med.Enzymology, University Hospital, Allopurinol-induced oroticaciduria which is due to inhi- Utrecht, The Netherlands. 2 University Children's Hospital "Het bition of OW-decarboxylase by oxipurinol-1- and -7-riboti- Wilhelmina Kinderziekenhuis", Utrecht, The Netherlands. 3 Juli- de is markedly reduced by dietary purines. The underlying ana Ziekenhuis, Dept. of Pediatrics, Rhenen, The Netherlands. mechanism possibly is an influence of dietary purines on A deficiency of purine nucleoside phosphorylase (PNP) was the formation of oxipurinol-ribotides. The latter being ex- detected in a three-year-old boy who was admitted for the creted as their corresponding aucleosides we first measured investigation of behaviour disorders and spastic diplegia. The the urinary excretion of oxipnrinol-7-riboside which was urinary excretion profile of oxypurines, analyzed by liquid found not to be altered by dietary purines. Therefore we chromatography, showed the presence of large amounts of searched for oxipurinol-1-riboside which had not yet been (deoxytinosine and (deoxy)guanosine together with a low uric detected in human urine. By HPM: we were able to demonstra- acid. The PNP activity in red blood cells and peripheral blood te the presence of this metabolite. -
IVPAIRED RENAL EXCRETION of HYPOXANTHINE Ihx) and Clinical
IVPAIRED RENAL EXCRETION OF HYPOXANTHINE IHx) AND RED BLOOD CELL MORPHOLOGY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): EFFECT OF OXYGEN THERAPY 122 VERSUS ALLOPURINOL. A MichBn, J Puig. P Crespo*. F Maccas", A GonzBlez, and J Ortiz. 'La Paz' Hospital, Clinical Biochemistry, Universidad Autbnoma, Madrid, Department of Internal Medicine, Universidad Aut6nomq Spain. Madrid, and 'Department of Histology, Granada, Spain. Most patients with primary gout show normal uric acid (UA) production rates and a relative underexcretion of UA. To examine Morphologic abnormalities in red blood cells depend on dlverse if the renal dysfunction for UA excretion in primary gout also factors which may include the intracellular centent of oxygen. affects the excretion of UA precursors, we compared the plasma Hypoxemia increases adenine nucleotide turnover and may influence concentrations and 24 hour urinary excretion of Hx and X in 10 erythrocyte morphology. To test this hypothesis in 7 patients normal srlojects, 15 patients with primary gout and UA under- with cliilically stable COPD we measured red cell ATP (iATP) excretioli and 10 patients with diverse enzyme deficiencies known levels by HPLC and observed erythrocyte morphology by scanning to overproduce UA. All subjects showed a creatinine clearance electron microscopy. Studies were carried out in 3 situations: above 80 ml/min/1.73 m2. Results (mean+SEM) were as follows basal state (mean+SEM; Pa02, 5823 mm Hg), after 7 days on oxygen therapy (Pa02, 79~4mm Hg; Pc0.01) and following a 7 day course PW URINE on allopurinol (300 mg/24 h; Pa02, 58+3 mm Hg). iATP concentra- UAHxX UA Hx X tions were similar in the 3 expermental conditions. -
Relevance to Neurological Damage
Postgrad Med J: first published as 10.1136/pgmj.62.724.113 on 1 February 1986. Downloaded from Postgraduate Medical Journal (1986) 62, 113-123 Pteridines and mono-amines: relevance to neurological damage I. Smith, D.W. Howells and K. Hyland Institute ofChildHealth (University ofLondon), 30 Guilford Street, London WCIN2NR, UK. Summary: Patients with phenylalanine hydroxylase deficiency show increased concentrations of biopterins and neopterins, and reduced concentrations ofserotonin and catecholamines, when phenylalan- ine concentrations are raised. The pterin rise reflects increased synthesis of dihydroneopterin and tetrahydrobiopterin, and the amine fall a reduction in amine synthesis due to inhibition by phenylalanine of tyrosine and typtophan transport into neurones. The pterin and amine changes appear to be independent of each other and are present in the central nervous system as well as the periphery; they disappear when phenylalanine concentrations are reduced to normal. Patients with arginase deficiency show a similar amine disturbance but have normal pterin levels. The amine changes probably contribute neurological symptoms but pterin disturbance is not known to affect brain function. Patients with defective biopterin metabolism exhibit severely impaired amine synthesis due to tetrahydrobiopterin deficiency. Pterin concentrations vary with the site of the defect. Symptoms include profound hypokiesis and other features of basal ganglia disease. Neither symptoms nor amine changes are relieved by controlling phenylalanine concentrations. Patients with dihydropteridine reductase (DHPR) deficiency accumulate dihydrobiopterins and develop secondary folate deficiency which resembles that occurring in patients with defective 5,10-methylene tetrahydrofolate reductase activity. The latter disorder is also associated writh Parkinsonisn and defective amine and pterin turnover in the and a occurs in In central nervous system, demyelinating illness both disorders. -
Massive Parallel Sequencing As a New Diagnostic Approach For
Chaiyasap et al. BMC Medical Genetics (2017) 18:102 DOI 10.1186/s12881-017-0464-x RESEARCH ARTICLE Open Access Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand Pongsathorn Chaiyasap1, Chupong Ittiwut1,2, Chalurmpon Srichomthong1,2, Apiruk Sangsin3, Kanya Suphapeetiporn1,2,4* and Vorasuk Shotelersuk1,2 Abstract Background: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. Method: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. Result: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. Conclusion: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand. Keywords: Next generation sequencing, Exome, Hyperphenylalaninemia, Phenylketonuria, Tetrahydrobiopterin deficiency, Newborn screening Background 120 μmol/l (2 mg/dl), the individual is considered to be Phenylketonuria (PKU) is an autosomal recessive metabolic hyperphenylalaninemia (HPA) and needs further diagnosis disorder, characterized by progressive intellectual disability, [4]. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Gene Transfer As a Potential Treatment for Tetralujdrobiopterin Deficient States
Gene Transfer as a Potential Treatment for Tetralujdrobiopterin Deficient States Rickard F oxton Division of Neurochemistry Department of Molecular Neuroscience Institute of Neurology University College London Submitted November 2006 Funded by Brain Research Trust Thesis submitted for the degree of Doctor of Philosophy, University of London. I, Richard Hartas Foxton, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' 1 UMI Number: U592813 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592813 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine (DA), noradrenaline (NA), serotonin and nitric oxide (NO) synthesis in the brain. Inborn errors of BH4 metabolism including GTP cyclohydrolase 1 (GTP-CH) deficiency are debilitating diseases in which BH4, DA, 5-HT and NO metabolism are impaired. Current treatment for these disorders is typically monoamine replacement +/- BH4. Whilst correction of the primary defect is the ideal, BH4 treatment is problematic as it is expensive and inefficacious. -
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Application Guide Ultra Fast HPLC Food & Beverages YMC UltraHT HPLC Columns for Ultra Fast LC Nowadays the need for Ultra Fast LC and Rapid Resolution is still growing, especially in the pharmaceutical industry, due to the continuous demand for high throughput analysis in research & development and quality control. As a column and bulk media supplier with many years of practical chromato- graphic experience, YMC found it unacceptable that the use of novel sepa- ration media is often restricted to dedicated equipment and not applicable to the large installed base of “conventional” HPLC systems with a standard operating pressure rating of less than 400 bar. For this reason, specifications for YMC-UltraHT columns were designed to provide powerful chromatographic improvements, in terms of velocity and resolution, with conventional operating conditions as well as ultra-high pressure systems. Since YMC-UltraHT columns provides a substantially lower pressure drop than most competitive 2 µm or sub-2 µm media, high flow rates can be achieved without generating excessive back pressure and without the need for specialised equipment. For effective high throughput separations, YMC offer a wide range of high per- formance HPLC columns, which allow Ultra Fast analytical HPLC separations using conventional equipment. Due to the down-scalability of the majority of YMC’s stationary phases, the time needed for a single analysis can be reduced to less than 60 seconds, depending on the sample conditions. YMC-UltraHT Pro C18 (2μm, 12nm) 50 x 2.0mm ID �� 1. -
Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells
Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells William N. Kelley, James B. Wyngaarden J Clin Invest. 1970;49(3):602-609. https://doi.org/10.1172/JCI106271. Research Article In the present study we have examined the effects of allopurinol and oxipurinol on thed e novo synthesis of purines in cultured human fibroblasts. Allopurinol inhibits de novo purine synthesis in the absence of xanthine oxidase. Inhibition at lower concentrations of the drug requires the presence of hypoxanthine-guanine phosphoribosyltransferase as it does in vivo. Although this suggests that the inhibitory effect of allopurinol at least at the lower concentrations tested is a consequence of its conversion to the ribonucleotide form in human cells, the nucleotide derivative could not be demonstrated. Several possible indirect consequences of such a conversion were also sought. There was no evidence that allopurinol was further utilized in the synthesis of nucleic acids in these cultured human cells and no effect of either allopurinol or oxipurinol on the long-term survival of human cells in vitro could be demonstrated. At higher concentrations, both allopurinol and oxipurinol inhibit the early steps ofd e novo purine synthesis in the absence of either xanthine oxidase or hypoxanthine-guanine phosphoribosyltransferase. This indicates that at higher drug concentrations, inhibition is occurring by some mechanism other than those previously postulated. Find the latest version: https://jci.me/106271/pdf Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells WILLIAM N. KELLEY and JAMES B. WYNGAARDEN From the Division of Metabolic and Genetic Diseases, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27706 A B S TR A C T In the present study we have examined the de novo synthesis of purines in many patients. -
Isolation and Expression of Rat Liver Sepiapterin Reductase Cdna
Proc. Nat!. Acad. Sci. USA Vol. 87, pp. 6436-6440, August 1990 Genetics Isolation and expression of rat liver sepiapterin reductase cDNA (tetrahydrobiopterin/biopterin/pyruvoyltetrahydropterin/aromatic amino acid hydroxylase/molecular cloning) BRUCE A. CITRON*, SHELDON MILSTIEN*, JOANNE C. GUTIERREZt, ROBERT A. LEVINE, BRENDA L. YANAK*§, AND SEYMOUR KAUFMAN*¶ *Laboratory of Neurochemistry, Room 3D30, Building 36, and tLaboratory of Cell Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; and tLaboratory of Molecular Neurobiology, Lafayette Clinic, 951 East Lafayette, Detroit, MI 48207 Contributed by Seymour Kaufman, June 7, 1990 ABSTRACT Sepiapterin reductase (7,8-dihydrobiopterin: either case, the final carbonyl reduction to form tetrahydro- NADP+ oxidoreductase, EC 1.1.1.153) catalyzes the terminal biopterin must be catalyzed by sepiapterin reductase. step in the biosynthetic pathway for tetrahydrobiopterin, the In the present study, we have screened a rat liver cDNA cofactor necessary for aromatic amino acid hydroxylation. We library with a specific antibody that reacts positively to the report here the isolation of a cDNA clone for rat liver sepia- enzyme band on Western blots (19). These clones were used pterin reductase. The cDNA has been excised from a lambda to further characterize the enzyme and to begin to elucidate vector and the DNA sequence was determined. The insert the functional sites ofthe enzymes in the tetrahydrobiopterin contains the coding sequence for at least 95% of the rat enzyme biosynthetic pathway. 11 and is fused to the Escherichia coli (3-galactosidase N-terminal segment and the lac promoter. The N-terminal region of the clone contains an extraordinarily high G+C content. -
Biosynthesis of Tetrahydrobiopterin in Man
J. tnher. Metab. Dis. 8 Suppl. 1 (I985) 28-33 Biosynthesis of Tetrahydrobiopterin in Man H.-CH. CURTIUS, D. HEINTEL, S. GHISLA1, TH. KUSTER, W. LEIMBACHER and A. NIEDERWIESER Division of Clinical Chemistry, Department of Pediatrics, University of Zurich, Switzerland t Department of Biology, University of Constance, POB 5560, D-7750 Constance, FRG The biosynthesis oftetrahydrobiopterin (BH4) from dihydroneopterin triphosphate (NHzP3) was studied in human liver extract. The phosphate-eliminating enzyme (PEE) was purified ~ 750-fold. The conversion of NH2P3 to BH~ was catalyzed by this enzyme in the presence of partially purified sepiapterin reductase, Mg z ÷ and NADPH. The PEE is heat stable when heated at 80 °C for 5 min. It has a molecular weight of 63 000 daltons. One possible intermediate 6-(l'-hydroxy-2'-oxopropyl)5,6,7,8-tetrahydropterin(2'-oxo-tetrahydro- pterin) was formed upon incubation of BH4 in the presence of sepiapterin reductase and NADP ÷ at pH 9.0. Reduction of this compound with NaBD4 yielded monodeutero threo and erythro-BH4, the deuterium was incorporated at the 2' position. This and the UV spectra were consistent with a 2'-oxo-tetrahydropterin structure. Dihydrofolate reductase (DHFR) catalyzed the reduction of BH2 to BH4 and was found to be specific for the pro-R-NADPH side. The sepiapterin reductase catalyzed the transfer of the pro-S hydrogen of NADPH during the reduction of sepiapterin to BHa. In the presence of crude liver extracts the conversion of NHzP3 to BH4 requires NADPH. Two deuterium atoms were incorporated from (4S-2H)NADHP in the 1' and 2' position of the BH4 side chain. -
Allopurinol Metabolism in a Patient with Xanthine Oxidase Deficiency
Ann Rheum Dis: first published as 10.1136/ard.42.6.684 on 1 December 1983. Downloaded from Annals ofthe Rheumatic Diseases, 1983, 42, 684-686 Allopurinol metabolism in a patient with xanthine oxidase deficiency HISASHI YAMANAKA, KUSUKI NISHIOKA, TAKEHIKO SUZUKI,* AND KEIICHI KOHNO* From the Rheumatology Department, Clinical Research Centre, Tokyo Women's Medical College, 2-4-1, NS BLD, Nishishinjuku, Shinjukuku, Tokyo, Japan SUMMARY A patient with complete deficiency of xanthine oxidise would not be expected to oxidase allopurinol to oxipurinol if allopurinol did not have any alternative metabolic pathway. 400 mg of allopurinol was administered to a patient with xanthine oxidase deficiency, and plasma allopurinol, oxipurinol, hypoxanthine, and xanthine levels were determined serially by the use of high-perfornman9e liquid chromatography (HPLC). Plasma oxipurinol as well as allopurinol was increased after the administration of allopurinol, and oxipurinol reached a maximum level of 13 1 ,u.g/ml at 6 hours after the administration. This was the same pattern as that of normal controls. This result demonstrated the existence of some other oxidising enzyme of allopurinol than xanthine oxidase. Allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine) free diet. Creatinine clearance was 73 3 m/min, and is known as a potent inhibitor of xanthine oxidase no calculus was found in her urinary tract by abdomi- copyright. (EC 1.2.3.2). In addition allopurinol itself is nal plain x-ray film and drip infusion pyelography. metabolised in vivo by xanthine oxidase to oxipurinol The xanthine oxidase activity of the duodenal (4,6-dihydroxypyrazolo[ 3,4-d]pyrimidine, which mucosa, which was obtained by gastrofibroscopy, also inhibits xanthine oxidase. -
University of Huddersfield Repository
University of Huddersfield Repository Aburas, Omaro A Emhmed Investigation of aldehyde oxidase and xanthine oxidoreductase in rainbow trout (Oncorhynchus mykiss) Original Citation Aburas, Omaro A Emhmed (2014) Investigation of aldehyde oxidase and xanthine oxidoreductase in rainbow trout (Oncorhynchus mykiss). Doctoral thesis, University of Huddersfield. This version is available at http://eprints.hud.ac.uk/23543/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. Users may access full items free of charge; copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational or not-for-profit purposes without prior permission or charge, provided: • The authors, title and full bibliographic details is credited in any copy; • A hyperlink and/or URL is included for the original metadata page; and • The content is not changed in any way. For more information, including our policy and submission procedure, please contact the Repository Team at: [email protected]. http://eprints.hud.ac.uk/ Investigation of aldehyde oxidase and xanthine oxidoreductase in rainbow trout (Oncorhynchus mykiss) Omaro Aburas B.Sc., M.Sc. Department of Chemical and Biological Science University of Huddersfield United Kingdom Thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy July 2014 Abstract Molybdo-flavoenzymes (MFEs), aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR) are involved in the oxidation of N-heterocyclic compounds and aldehydes, many of which are environmental pollutants, drugs and vitamins.