Relevance to Neurological Damage
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Folate and Pterin Metabolism by Cancer Cells in Culture1
[CANCER RESEARCH 38, 2378-2384, August 1978) 0008-5472/78/0038-0000$02.00 Folate and Pterin Metabolism by Cancer Cells in Culture1 Baldassarre Stea, Peter S. Backlund, Jr., Phillip B. Berkey, Arthur K. Cho, Barbara C. Halpern, Richard M. Halpern, and Roberts A. Smith2 Departments of Chemistry (B. S., P. S. B., P. B. B., B. C. H.¡,Pharmacology ¡A.K. C.], Medicine, ¡Ft.M. H.]. and Chemistry [Ft. A. SJ and Molecular Biology Institute ¡R.M. H., R. A. S.], University of California, Los Angeles, California 90024 ABSTRACT cells, a significant peak of radioactivity was observed in the blue-fluorescent region. This peak of radioactivity was ab Malignant cells grown in culture excrete into their sent in chromatograms of growth media of normal cells growth medium a folate catabolite that can be seen as a grown under the same conditions. blue-fluorescent region on paper chromatograms of such We tentatively identified this blue-fluorescent compound media. This folate catabolite has now been identified by as Pt-6-CHO,3 primarily on the basis of its inhibitory power paper chromatography, thin-layer chromatography, and toward xanthine oxidase. However, we later found that Pt- combined gas chromatography-mass spectrometry as 6- 6-CH2OH also is a potent inhibitor of the same enzyme hydroxymethylpterin and not as pterin-6-carboxaldehyde system. This prompted us to identify by unequivocal means as previously reported. the fluorescent folate catabolite characteristic of cultured Moreover, when pterin-6-carboxaldehyde was added to malignant cells. the growth medium of logarithmically growing malignant Here we report the definitive identification of this blue- cells, it was primarily reduced to 6-hydroxymethylpterin. -
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. -
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. -
Natalis Information Sheet V03
Sema4 Natalis Clinical significance of panel Sema4 has designed and validated Natalis, a supplemental newborn screening panel offered for newborns, infants, and young children. This test may be offered to parents as an addition to the state mandated newborn screening that their child received at birth. This panel includes next-generation sequencing, targeting genotyping, and multiplex ligation-dependent probe amplification in a total of 166 genes to screen for 193 conditions that have onset in infancy or early childhood and for which there is treatment or medical management that, when administered early in an infant or child’s life, will significantly improve the clinical outcome. Conditions included in this panel were curated based on criteria such as: inclusion on current state mandated newborn screening panels, onset of symptoms occurring <10 years of age, evidence of high penetrance (>80%), and availability of a treatment or improvement in life due to early intervention. Sema4 has also designed and validated a pediatric pharmacogenetic (PGx) genotyping panel as an adjunct test to the Natalis assay. This panel includes 10 genes and 41 sequence variants involved in drug response variability. The genes and variants in the PGx genotyping panel inform on more than 40 medications that can be prescribed during childhood. Currently, there is evidence supporting the clinical utility of testing for certain PGx variants for which there are genotype-directed clinical practice recommendations for selected gene/drug pairs. Approximately 95% of all individuals will carry at least one clinically actionable variant in the PGx panel. Testing methods, sensitivity, and limitations A cheek swab, saliva sample, or blood sample is provided by the child and a biological parent. -
Downloaded from the App Store and Nucleobase, Nucleotide and Nucleic Acid Metabolism 7 Google Play
Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 https://doi.org/10.1186/s13023-021-01727-2 REVIEW Open Access Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app Eva M. M. Hoytema van Konijnenburg1†, Saskia B. Wortmann2,3,4†, Marina J. Koelewijn2, Laura A. Tseng1,4, Roderick Houben6, Sylvia Stöckler‑Ipsiroglu5, Carlos R. Ferreira7 and Clara D. M. van Karnebeek1,2,4,8* Abstract Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disabil‑ ity (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identifcation of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation. Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classifcation of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is avail‑ able. Data on clinical symptoms, diagnostic testing, treatment strategies, efects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features. Results: Our review identifed 116 treatable IDs (139 genes), of which 44 newly identifed, belonging to 17 ICIMD categories. -
An Ab Initio and Density Functional Theory Study on Neutral Pterin Radicals
Pteridines 2015; 26(4): 135–142 Gilbert Reibnegger* An ab initio and density functional theory study on neutral pterin radicals DOI 10.1515/pterid-2015-0008 responsible for a remarkably complex chemical behaviour Received May 8, 2015; accepted June 29, 2015; previously published of pteridine itself and also of the many derivatives thereof. online August 7, 2015 A large variety of pteridine derivatives occur in apparently all living organisms, exerting a multitude of different Abstract: The electronic structures of the five radicals biochemical/biological functions that are only partially resulting from homolytic elimination of one of the hydro- understood. In several investigations, pteridine radicals gen atoms from the most stable tautomeric form of neutral have been detected experimentally, or at least pteridine pterin were investigated in gas phase as well as in aque- derivatives were observed to modulate the reactivity of ous solution. Molecular wave functions obtained by den- other free radicals [1–18]. sity functional theory were analysed by quantum theory Recently, several studies were published reporting of atoms in molecules and electron localisation functions on the results of quantum chemical calculations of the (ELF). Spin densities of the radicals as well as electrostatic detailed electronic structures of pterin (2-amino-3H-pteri- potential functions were analysed. Radicals resulting from dine-4-on) and derivatives employing density functional elimination of N-bonded hydrogen atoms are more stable theory (DFT) with reasonably sized basis sets [19–22]. In in comparison with radicals obtained after abstraction of the present investigation, I report on such calculations C-bonded hydrogen atoms. N-centred radicals show strong extended to the five radicals derived from the most stable delocalisation of spin density over both heteroaromatic tautomeric form of neutral pterin by homolytic elimina- rings; in C-centred radicals delocalisation does not occur. -
Identification and Age-Dependance of Pteridines in the Head of Adult Mexican Fruit Fly, Anastrepha Ludens N
J. insect Phwol. Vol. 42, No. 4, pp 359-366, 1996 CopyrIght C lYY6 Elsewer Science Ltd Pergamon 0022-1910(95)00116-6 Printed III Great Bntaln. All rights reserved 0022-lYlOiY6 $15.00 + 0.00 Identification and Age-Dependance of Pteridines in the Head of Adult Mexican Fruit Fly, Anastrepha ludens N. TOMIC-CARRUTHERS,*t$ D. C. ROBACKER,? R. L. MANGAN? Received 16 May 1995: revised 21 August 1995 Pteridines from head capsules of adult Anastrepha ludens were identified and evaluated as a tool for age determination of flies. Pteridines were identified by a combination of TLC, HPLC and UV and fluorescence spectroscopy. Tentative identifications were obtained for one red pterine, neodrosopterin, and three orange pterines, drosopterin, isodrosopterin and aurodro- sopterin. Five pterines with blue or blue-green fluorescence were found and four were ident- ified: 7,8-dihydrobiopterin; biopterin; pterin; and pterind-carboxylic acid. An additional blue fluorescing non-pteridine compound was identified as kyurenine. Two pterines with yellow fluorescence were identified as sepiapterin and deoxysepiapterin. Titers of sepiapterin and deoxysepiapterin were age dependent based on TLC and HPLC analyses. HPLC demonstrated that only deoxysepiapterin accumulated sufficiently and over a sufficiently long period of adult life to be useful as a quantitative tool for determining age of adult flies. The HPLC method developed in this work specifically for separation of deoxysepiapterin from sepiapterin and other pteridines used reverse-phase (C18) with a mobile phase of 30% methanol in water and detection at 420 nm. Pteridines Sepiapterin Deoxysepiapterin Age Anastrepha ludens INTRODUCTION the main locations of accumulation, at least in adult Fluorescent compounds from insects have been the object insects, are the head and the integument. -
34Th International Winter Workshop Clinical, Chemical and Biochemical
DOI 10.1515/pterid-2015-0007 Pteridines 2015; 26(3): 113–133 Abstracts*) 34th International Winter Workshop Clinical, Chemical and Biochemical Aspects of Pteridines and Related Topics Society for Exploitation of Education and Research in Immunology and Infectious Diseases, Innsbruck, Austria in collaboration with The International Society of Pteridinology and The Austrian Society of Laboratory Medicine and Clinical Chemistry Held in Innsbruck, Tyrol, Austria, February 24th–27th, 2015 Scientific committee: Dietmar Fuchs (Innsbruck), Andrea Griesmacher (Innsbruck), Bohuslav Melichar (Olomouc), Gilbert Reibnegger (Graz), Barbara Strasser (Hall), Guenter Weiss (Innsbruck) and Ernst R. Werner (Innsbruck) Organization: Dietmar Fuchs, Sektion für Biologische Chemie, Biozentrum, Medizinische Universität Innsbruck, Innrain 80, 6020 Innsbruck, Austria, e-mail: [email protected] *)These abstracts have been reproduced directly from the material supplied by the authors, without editorial alteration by the staff of this Journal. Insufficiencies of preparation, grammar, spelling, style, syntax, and usage are the authors’ responsibility. 114 34th International Winter Workshop Circulating neopterin and citrulline concentrations Influence of carbon nanotubes, ZnO and in patients with germ-cell tumors during gold-doped TiO2 nanoparticles on human PBMC chemotherapy in vitro Bartoušková M, Študentová H, Pejpková I, Zezulová M, Adam T, Becker K, Herlin N, Bouhadoun S, Gostner JM, Ueberall F, Schennach Melichar B H, Fuchs D Palacký University Medical School and Teaching Hospital, Olomouc, Divisions of Biological Chemistry and of Medical Biochemistry, Czech Republic Biocenter, Medical University, and Central Institute of Blood ([email protected]) Transfusion and Immunology, University Hospital, Innsbruck, Austria; Au Service des Photons, Atomes et Molécules - Laboratoire Francis Germ-cell tumors are relatively rare neoplasms that affect mostly Perrin, Gif-sur Yvette, France young adults. -
Comparison of Pteridine Normalization Methods in Urine for Detection of Bladder Cancer
diagnostics Article Comparison of Pteridine Normalization Methods in Urine for Detection of Bladder Cancer Piotr Ko´sli´nski 1,* , Robert Pluskota 1, Katarzyna M ˛adra-Gackowska 2, Marcin Gackowski 1 , Michał J. Markuszewski 3 , Kornelia K˛edziora-Kornatowska 2 and Marcin Koba 1 1 Department of Toxicology and Bromatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru´n,dr. A. Jurasza 2, 85-089 Bydgoszcz, Poland; [email protected] (R.P.); [email protected] (M.G.); [email protected] (M.K.) 2 Department of Geriatrics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru´n, Poland, dr. A. Jurasza 2, 85-089 Bydgoszcz, Poland; [email protected] (K.M.-G.); [email protected] (K.K.-K.) 3 Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gda´nsk, al. Gen. J. Hallera 107, 80-416 Gda´nsk,Poland; [email protected] * Correspondence: [email protected] Received: 9 July 2020; Accepted: 18 August 2020; Published: 20 August 2020 Abstract: Pterin compounds belong to the group of biomarkers for which an increase in interest has been observed in recent years. Available literature data point to this group of compounds as potential biomarkers for cancer detection, although the biochemical justification for this claim is not yet fully understood. The aim of this study was to evaluate the usefulness of pterin compounds in the diagnosis of bladder cancer, with particular emphasis on the role of creatinine and the specific gravity of urine as factors for normalizing the concentration of pterin compounds in urine.