DOCSLIB.ORG

Intestinal Uptake of 6(R)-L-Ery¿/?Ro-Tetrahydrobiopterin Is Distinct from the Liver-Type MTX-Sensitive Accumulation Process

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Intestinal Uptake of 6(R)-L-Ery¿/?Ro-Tetrahydrobiopterin Is Distinct from the Liver-Type MTX-Sensitive Accumulation Process 6 Sawabe Κ. et ai.·. Intestinal Uptake of Tetrahydrobiopterin Pteridines Vol. 16, 2005, pp. 6-10 Intestinal Uptake of 6(R)-L-ery¿/?ro-Tetrahydrobiopterin is Distinct from the Liver-Type MTX-Sensitive Accumulation Process Keiko Sawabe2, Yasuko Suetake1, Kazunori Osuke Wakasugi\ Hiroyuki Hasegawa1 2 'Department of Biosciences and JBiotechnology Research Center, Teikyo University of Science and Technology. Ucnohara, Yamanashi 409-0193, 'Internal Medicine Clinical Immunohaematology, Hachioji Medical Center, Tokyo Medical University, Hachioji, Tokyo 193-0944 Abstract In order to increase the tissue level of tetrahydrobiopterin (BH4), supplementation with 6R-tetrahydrobiopterin (6RBH4) has been widely employed. In this work, the profile of BH4 accumulation was compared between the liver and the small intestine after feeding with 10mg/kg of 6RBH4 or 7,8-dihydrobiopterin (7,8BH2 ). Endogenous BH4 was 7.20 ± 0.28 and 1.59 ± 0.13 nmol/g in the liver and the intestine, respectively. BH4 levels rose to 12.5 ± 1.35 (1.7-fold) and 53.0 + 19.6 nmol/g (40-fold) in the liver and the intestine within 30 min, respectively. Administration of 7,8BH2 caused an even higher rise in BH4 (14.4 ± 2.79 nmol/g) in the liver, while it led to a considerable increase in tissue BH2 in the intestine. When dihydrofolate reductase inhibitor MTX was adminis- tered before the pterin feeding, BH4 did not increase in the liver, while it increased 20-fold in the intestine, although the rise was 45% less than that in the absence of MTX. These results suggest that 1) the liver was scarcely able to uptake BH4 in its reduced form; 2) accumulation of BH4 in the liver was achieved through the MTX-sensitive pathway presumably driven by dihydrofolate reductase; 3) a large concentration of BH4 accumu- lated in the intestine, bypassing the MTX-sensitive pathway, that is, it was taken up directly as the fully reduced form, BH4; 4) the other BH4 accumulated in the intestine seemed to have been converted from BH2 through the MTX-sensitive pathway, as in the liver. Key words: tetrahydrobiopterin. dihydrobiopterin, methotrexate Introduction cultured cells and in vivo in mouse. In our in vitro w ork using cultured RBL2H3 and PC 12 cells, uptake 6-(R)-L-erv7/7/O-5,6,7,8-Tetrahydrobiopterin of BH4 was shown to be hampered by some cellular (6RBH4) is an essential cofactor of aromatic amino processes resulting in poor incorporation, while sepia- acid hydroxylases, phenylalanine- (1), tyrosine- (2) pterin and 7.8BH2 were incorporated and converted and tryptophan-hydroxylase (3, 4). The biosynthesis of into BH4 in an efficient manner ( 12-16). We observed classic monoamines such as dopamine, noradrenaline, in mice that orally administered BH4 resulted in an adrenaline as well as serotonin is dependent on the appreciable elevation of tissue BII4 levels in organs cofactor BH4. Furthermore, BH4 is also the cofactor of such as the liver and kidney (17). Remarkably, the NO-synlhase (NOS) (5, 6). An insufficient supply of increased portion of BH4 was revealed to have been BH4 results in a lowered production of monoamines converted from BH by a MTX-sensitive manner in and an uncontrolled release of active oxygen concomi- 2 tant with inadequate NO production, which might lead most organs examined, presumably by the enzymatic to various disorders regarding neural function and action of dihydrofolate reductase (18). In the same work, we noticed a very steep rise in BH2 levels in the blood circulation, respectively (7, 8). Regarding BH4 blood circulation following oral administration of therapy for patients with BH4 insufficiency, however, the efficiency of BH4 uptake has not been appreciated 6RBH4. In this study, we examined biopterin accumu- (9-11 ). We have been working on permeability and the lation (BH4 and BH2) in intestinal mucosa and the liver metabolic fate of exogenously administered BH4 with after feeding 6RBH4 to mice. We analyzed whether the Correspondence to: Dr. Keiko Sawabe, Department of Biosciences, Teikyo University of Science and Technology. Uenohara, Yamanashi 409-0193, Japan, Phone: +(81 (-554-63-441 1, Fax: +(81 (-554-63-443 1, e-mail: k-sawabe(í¿st.ntu.ae.jp Pteridines/Vol. 16/No. 1 Sawabe Κ. et aì.\ Intestinal Uptake of Tetrahydrobiopterin 7 BH4 was directly incorporated in its fully reduced form acid-l2 oxidation was taken as the "total biopterin". or produced in situ from acquired BH2, the oxidation The diffcrcncc between the biopterin quantity after product of exogenous BH4. acid-oxidation and that after alkaline-oxidation was In this work, we report the results that intestinal tis- termed "BH4" throughout this paper. Since the amount sue can uptake BH4 in its reduced form, by passing the of fully oxidized biopterin detected in fresh tissue MTX-sensitive route, while the liver uptakes BH4 extracts was insignificant, the biopterin calculated through the MTX-sensitive pathway. from the "total biopterin" minus "BH4" was termed "BH:". When 6-(R)-L-erv?/7ro-tetrahydrobioptcrin was specified as a reagent, "6RBH4" was used instead Materials and Methods of "BH4". For example, a working solution of the reagent BH, for administration to mice was termed 6-( R )-L-erythro-5,6,7,8-Tetrahydrobiopterin "6RBH4". (6RBH4) was donated by Daiich Suntory (Tokyo) and 7,8-dihydrobiopterin (7.8BH2) was purchased from Schirks Laboratories (Jona, Switzerland). Results and Discussion Methotrexate (MTX) was purchased from Wako (Osaka, Japan). CM-cellulose (medium viscosity, In order to measure intestinal absorption of orally sodium salt) was obtained from Fluka (Buchs, administered BH4, we gave 6RB114 at a dose of 10 Switzerland). C57BL/6J mice were from Japan SLC mg/kg to mice (C57BL/6J 10 week, male), then (Hamamatsu, Japan) and adult males 10 weeks of age biopterin uptake (BH4 and BH2) was measured in the were used in the present experiments. The animals liver and intestine after administration. were maintained on an ordinary laboratory chow and Increase in biopterin (BH4 and BH2) in the liver was tap water ad libidunu under a constant 1 2-h light-dark first examined after administration. The liver con- cycle. The experiments were conducted in accordance tained endogenous biopterin at a level of 7.64 ± 0.32, with the ethical guidelines of the Teikyo University of of which 94.2% was the fully reduced form, BH4. Science and Technology Animal Experimentation When 6RBH4 was given orally, biopterin content Committee. increased to about 2-fold within 30 min. continued to Pterins were given to animals at a dose of 10mg/kg increase, and reached more than 5-fold at 120 min, body weight. The pterin compounds were dissolved in then decreased gradually. As mentioned previously 0.05 Ν HCl just prior to oral administration (p.o.). (18), a steep BH2 surge appeared in the blood 30-60 When MTX was given, the reagent was suspended in min after 6RBH4 administration. Since liver cells con- aqueous 2% CM-cellulose and was administered 90 tain dihydrofolate reductase DHFR which converts min before the pterins. The liver and small intestine 7.8BH2 to BH4. some portion of the BH4 might be were dissected under anaesthesia. The proximal third derived from 7,8BH2. In order to analyze the contribu- of the small intestine was taken and opened longitudi- tion of the DHFR-pathway, an inhibitor, MTX, was nally, washed with cold saline, blotted three times with administered 90 min prior to 6RBH4 administration, filter paper to remove the mucus coat, weighed, frozen then incorporation of biopterin in the liver was meas- ured, as shown in Fig. I b. MTX administration did not immediately in liquid N2. and then stored at -80°C until determination. alter the endogenous content of total biopterin but sig- Frozen tissues were partially thawed and homoge- nificantly lowered the percentage of BH4 (designated as "%BH ") to 76.6%, suggesting that the MTX-sensi- nized immediately in a 5 vol of 0.1 Ν HCl. An aliquot 4 tive pathway was involved to a considerable extent in ( 100 μι.) of the homogenate was mixed with a 0.5 vol maintaining the endogenous level. When 6RBH4 was of an acid-iodine solution (2% I2. 3% KI in 0.1 Ν HCl), given to the animals in the absence of MTX, liver BH or with alkaline-iodine (2% l , 3% KI in 0.2 Ν NaOH) 4 2 rose up to 1.7-fold with a constant %BH (95.4%). In for oxidation under acid or alkaline conditions, respec- 4 the presence of MTX, total biopterin also increased up tively ( 19). The oxidation reaction was allowed to pro- to 1.58-fold, however. BH scarcely rose and conse- ceed for 1 h at room temperature. After addition of a 4 quent %BH decreased to 57.7%, therefore, a large 0.5 vol of ascorbic acid (2.5%) dissolved in perchloric 4 quantity of 7,8BH2 appeared. The large quantity of acid (0.4 M), a clear solution was obtained by cen- BH2 might otherwise be converted to BH4 by an trifugation at 1 (),()()() χ g for 10 min. Biopterin and MTX-sensitive pathway. 7,8BH2 administration at the pterin were determined by HPLC equipped with a flu- same dose raised the liver BH4 level 1.97-fold (%BH4 orescence detector (Ex=350 and Em=450 nm). The - 95.4) within 30 min in the absence of MTX. The solid phase was Fine-SIL C18T-5 and the mobile increase in BH4 caused by BH2 administration was phase was 7% methanol. Biopterin measured after Pteridincs/Vol. 16/No. 1 8 Sawabe Κ. et αι.: Intestinal Uptake of Tetrahydrobiopterin 10 (a) 8 Pterin Non BH4 7,8BH2 Pterin Non BH4 7,8BH2 MTX - + - + - + MTX -+-+-+ Figure 1.
Load more

Recommended publications
  • Malignant Hyperphenylalaninemia Tetrahydrobiopterin (BH4) Phenylalanine
    Pediat. Res. 13: 1 150-1 155 (1979) Dihydropterine reductase (DHPR) phenylketonuria malignant hyperphenylalaninemia tetrahydrobiopterin (BH4) phenylalanine Malignant Hyperphenylalaninemia-Clinical Features, Biochemical Findings, and Experience with Administration of Biopterins D. M. DANKS, P. SCHLESINGER, F. FIRGAIRA, R. G. H. COTTON. B. M. WATSON, H. REMBOLD. AND G. HENNINGS Genetics Research Unit, Royal Children S Hospital Research Foundation, and Department of Paediatrics, Universi1.y of Melbourne, Parkville, Australia (D. M. D., P. S., F. F.. R. G. H. C., B. M. W.) and Max Planck Institutfur Biochemie. Germany (H. R., G. H.) Summary has been attributed to defective production of neurotransmitters derived from hydroxylation of tyrosine and of tryptophan (3, 4). Four cases of malignant hyperphenylalaninemia (MHPA) are The results of treatment with L-dopa and 5-hydroxytryptophan described. Pretreatment serum phenylalanine levels were 1.5, 3.0, support this contention (2, 3. 7). 2.4, and 0.9 mmoles/l. Dihydropteridine reductase (DHPR) defi- Four patients with MHPA seen in Melbourne since 1963 are ciency was proven in one patient by assays on cultured fibroblastic presented. One patient has been shown to have DHPR deficiency cells and was presumed in her sibling and in another deceased and her sister is presumed to have died of this defect. Both parents patient whose parents' fibroblastic cells show approximately 50% of another baby had DHPR levels in the heterozygote range of normal enzyme activity. DHPR and phenylalanine hydroxylase suggesting DHPR deficiency as the cause of her death. The 4th deficiency were excluded by assays on liver obtained at autopsy in baby had neither PH or DHPR deficiency and defective BH4 the 4th patient.
    [Show full text]
  • Epithelial Cell Line Derived from Endometriotic Lesion Mimics Macrophage Nervous Mechanism of Pain Generation on Proteome and Metabolome Levels
    biomolecules Article Epithelial Cell Line Derived from Endometriotic Lesion Mimics Macrophage Nervous Mechanism of Pain Generation on Proteome and Metabolome Levels Benjamin Neuditschko 1,2,† , Marlene Leibetseder 1,† , Julia Brunmair 1 , Gerhard Hagn 1 , Lukas Skos 1, Marlene C. Gerner 3 , Samuel M. Meier-Menches 1,2,4 , Iveta Yotova 5 and Christopher Gerner 1,4,* 1 Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria; [email protected] (B.N.); [email protected] (M.L.); [email protected] (J.B.); [email protected] (G.H.); [email protected] (L.S.); [email protected] (S.M.M.-M.) 2 Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, 1090 Vienna, Austria 3 Division of Biomedical Science, University of Applied Sciences, FH Campus Wien, Favoritenstraße 226, 1100 Vienna, Austria; [email protected] 4 Joint Metabolome Facility, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria 5 Department of Obstetrics and Gynaecology, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; [email protected] Citation: Neuditschko, B.; * Correspondence: [email protected] Leibetseder, M.; Brunmair, J.; Hagn, † Authors contributed equally. G.; Skos, L.; Gerner, M.C.; Meier-Menches, S.M.; Yotova, I.; Abstract: Endometriosis is a benign disease affecting one in ten women of reproductive age world- Gerner, C. Epithelial Cell Line wide. Although the pain level is not correlated to the extent of the disease, it is still one of the Derived from Endometriotic Lesion cardinal symptoms strongly affecting the patients’ quality of life.
    [Show full text]
  • Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment
    Published online: 2018-10-29 2 Review Article Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment Heiko Brennenstuhl1 Sabine Jung-Klawitter1 Birgit Assmann1 Thomas Opladen1 1 Division of Neuropediatrics and Metabolic Medicine, Department of Address for correspondence Prof. Dr. Thomas Opladen, MD, Division General Pediatrics, University Children’s Hospital Heidelberg, of Neuropediatrics and Metabolic Medicine, Department of General Heidelberg, Germany Pediatrics, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany (e-mail: [email protected]). Neuropediatrics 2019;50:2–14. Abstract Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Keywords Classical signs are hypotonia, movement disorders, autonomous dysregulations, and ► inherited monoamine impaired development. Diagnosis depends on quantitative detection of neurotrans- neurotransmitter mitters in cerebrospinal
    [Show full text]
  • Two Filipino Patients with 6-Pyruvoyltetrahydropterin Synthase Deficiency
    CASE REPORT Two Filipino Patients with 6-Pyruvoyltetrahydropterin Synthase Deficiency John Karl L. de Dios1,2, Mary Anne D. Chiong,1,2 1Department of Pediatrics, College of Medicine and Philippine General Hospital, University of the Philippines Manila; 2Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila ABSTRACT enzymes: guanosine triphosphate cyclohydrolase Hyperphenylalaninemia can result from defects in either the (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), phenylalanine hydroxylase (PAH) enzyme or in the synthesis or dihydropteridine reductase (DHPR) and pterin-4a- recycling of the active pterin, tetrahydrobiopterin (BH4), which is an carbinolamine dehydratase (PCD). The first two enzymes are obligate co-factor for the PAH enzyme, as well as tyrosine hydroxylase and tryptophan hydroxylase. One of the most common causes of BH4 involved in the biosynthesis of tetrahydrobiopterin, the last 3 deficiency is a defect in the synthesis of 6-pyruvoyltetrahydropterin two in its regeneration. A third enzyme in the biosynthesis synthase (PTPS) enzyme. Patients present with progressive neurological of BH4 is sepiapterin reductase, but its deficiency is not disease such as mental retardation, convulsions and disturbance of associated with hyperphenylalaninemia 1 (Figure 1). tone and posture despite strict adherence to diet and good metabolic Clinical manifestations for a severe PAH defect or BH4 control. The authors report the first two cases of PTPS deficiency in the synthesis/recycling defect can be similar, with patients Philippines. Both are females with initial phenylalanine levels of more presenting with progressive neurological impairment than 1300 umol/L who continued to develop neurologic deterioration during infancy. Since management of these patients will despite good metabolic control and strict adherence to diet.
    [Show full text]
  • Building Microbial Factories for The
    Contents lists available at ScienceDirect Metabolic Engineering journal homepage: www.elsevier.com/locate/meteng Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products ∗ Mingfeng Caoa,b,1, Meirong Gaoa,b,1, Miguel Suásteguia,b, Yanzhen Meie, Zengyi Shaoa,b,c,d, a Department of Chemical and Biological Engineering, Iowa State University, USA b NSF Engineering Research Center for Biorenewable Chemicals (CBiRC), Iowa State University, USA c Interdepartmental Microbiology Program, Iowa State University, USA d The Ames Laboratory, USA e School of Life Sciences, No.1 Wenyuan Road, Nanjing Normal University, Qixia District, Nanjing, 210023, China ARTICLE INFO ABSTRACT Keywords: The aromatic amino acid biosynthesis pathway, together with its downstream branches, represents one of the Aromatic amino acid biosynthesis most commercially valuable biosynthetic pathways, producing a diverse range of complex molecules with many Shikimate pathway useful bioactive properties. Aromatic compounds are crucial components for major commercial segments, from De novo biosynthesis polymers to foods, nutraceuticals, and pharmaceuticals, and the demand for such products has been projected to Microbial production continue to increase at national and global levels. Compared to direct plant extraction and chemical synthesis, Flavonoids microbial production holds promise not only for much shorter cultivation periods and robustly higher yields, but Stilbenoids Benzylisoquinoline alkaloids also for enabling further derivatization to improve compound efficacy by tailoring new enzymatic steps. This review summarizes the biosynthetic pathways for a large repertoire of commercially valuable products that are derived from the aromatic amino acid biosynthesis pathway, and it highlights both generic strategies and spe- cific solutions to overcome certain unique problems to enhance the productivities of microbial hosts.
    [Show full text]
  • Tetrahydrobiopterin Deficiency
    Blau et al.: Tetrahydrobiopterin deficiency Pteridines Vol. 4, 1993. pp. 1-10 Review Tetrahydrobiopterin Deficiency: From Phenotype to Genotype* Nenad Blau i! §, Beat Thonyi!, Claus W. Heizmann i!, and Jean-Louis Dhondt t :I Division of Clinical Chemistry. University Children's Hospital. Steinwiesstr. 75. CH-8032 ZUlich. Switzerland tCentre Hospitalier Sanit-Philbert Faculte Libre de Medecine. Lomme Cedex, France (Received January 10. 1993) Summary As a result of the selective screening worldwide during the last 18 years, approximately 250 patients with tetrahydrobiopterin deficiency were discovered. Most patients suffer from 6-pyruvoyl tetrahydropterin synthase deficiency (58%), followed by dihydropteridine reductase deficiency (35%), GTP cyclohydrolase I deficiency (3%), and "primapterinuria" (4%). The patients can be treated with neurotransmitter precursors, as well as with tetrahydrobiopterin. However, data on long term treatment are still scarce and it is therefore of great value to investigate all newborns with even mild hyperphenylalaninemia. Cloning of the enzymes involved in the biosynthesis and regeneration of tetrahydrobiopterin makes them to be easily accessible for biochemical and biological studies. So far, all proteins expressed heterologous are active in E. coli. Cloning of the wild type gene and mutant analysis of patients allow the rapid identification of the defective gene on the molecular level. Key words: Tetrahydrobiopterin, Deficiency, Hyperphenylalaninemia, Gene cloning, DNA. In troducti on Early detection of tetrahydrobiopterin (BH4) defi­ nine to tyrosine: tyrosine-3-hydroxylase and trypto­ ciency became essential soon after it was recognized phan-5-hydroxylase are the rate-limiting enzymes in that a number of patients with hyperphenylalanin­ the biosynthesis of catecholamines and serotonin, emia (HPA) show progressive neurological illness de­ respectively (4).
    [Show full text]
  • Neurological Aspects of Biopterin Metabolism
    Arch Dis Child: first published as 10.1136/adc.61.2.130 on 1 February 1986. Downloaded from Archives of Disease in Childhood, 1986, 61, 130-137 Neurological aspects of biopterin metabolism I SMITH, R J LEEMING, N P C CAVANAGH, AND K HYLAND Hospital for Sick Children and Institute of Child Health, London, and The General Hospital, Birmingham SUMMARY Plasma total biopterin concentration was measured by bioassay in 59 infants with hyperphenylalaninaemia and in 50 children with developmental regression and or movement disorder with normal plasma phenylalanine concentrations. In infants with raised phenylalanine concentrations plasma biopterin concentrations were significantly raised in proportion to the phenylalanine values. Five patients had plasma biopterin concentrations at the extremes of the range, and of these two had defective biopterin metabolism. One with low plasma biopterin concentration apparently had a partial defect of biopterin synthesis but died before investigations were complete. One with high plasma biopterin concentration, even when phenylalanine concentrations had fallen to the normal range, had dihydropteridine reductase deficiency. In this patient concentrations of homovanillic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid (CSF) were severely reduced. In children without hyperphenylalaninaemia plasma biopterin concentrations were normal. Twenty two patients were subjected to lumbar puncture, of whom six with developmental regression without movement disorder had normal CSF biopterin concentrations, and 11 withcopyright. movement disorder other than torsion dystonia had significantly lower CSF biopterin concentrations. Five patients with torsion dystonia had normal biopterin concentrations. Tetrahydrobiopterin is the essential cofactor for three hydroxylation reactions, the conversion of GTP http://adc.bmj.com/ phenylalanine to tyrosine, tyrosine to L-dopa, and tryptophan to 5-hydroxytryptophan.' These last two B, BH2 j reactions are the rate limiting steps of catecholamine Ne 2P3 --- NeH2 and serotonin synthesis.
    [Show full text]
  • Oral Berberine Improves Brain Dopa/Dopamine Levels to Ameliorate Parkinson’S Disease by Regulating Gut Microbiota
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE OPEN Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota Yan Wang1, Qian Tong2, Shu-Rong Ma1, Zhen-Xiong Zhao1, Li-Bin Pan1, Lin Cong1, Pei Han1, Ran Peng1, Hang Yu1, Yuan Lin1, Tian-Le Gao1, Jia-Wen Shou1, Xiao-Yang Li1, Xian-Feng Zhang2, Zheng-Wei Zhang1, Jie Fu1, Bao-Ying Wen1, Jin-Bo Yu1, Xuetao Cao3 and Jian-Dong Jiang 1 The phenylalanine–tyrosine–dopa–dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa (L-dopa) with tetrahydrobiopterin (BH4) as a coenzyme. Here, we show that oral berberine (BBR) might supply H• through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH4 from dihydrobiopterin; the increased BH4 enhances TH activity, which accelerates the production of L-dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The L-dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut–brain dialog activated by BBR’s effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson’s disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)- derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus, and BBR strengthened the imaging intensity of brain dopamine.
    [Show full text]
  • Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future
    cells Review Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future Sabine Jung-Klawitter * and Oya Kuseyri Hübschmann Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-(0)6221-5639586 Received: 30 June 2019; Accepted: 4 August 2019; Published: 9 August 2019 Abstract: Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases. Keywords: inborn errors of metabolism; catecholamines; pterins; HPLC; fluorescence detection; electrochemical detection; MS/MS 1.
    [Show full text]
  • Early Diagnosis of 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency
    Shintaku: Early diagnosis of 6-pyruvoyl-tetrahydropterin synthase deficiency Pteridines Vol. 5, 1994, pp. 18-27 Early Diagnosis of 6-Pyruvoyl-tetrahydropterin Synthase Deficiency Haruo Shintaku Department of Pediatrics, Osaka City University Medical School, Osaka 545, Japan (Received December 10, 1993) Summary 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, which used to be called dihydrobiopterin synthase deficiency, is the most common kind of tetrahydrobiopterin deficiency. Early treatment by administration of tetrahydrobiopterin and neurotransmitter precursors helps to prevent neurological injury, so prompt diag­ nosis of neonates with hyperphenylalaninemia discovered by screening for phenylketonuria is necessary. Three patients with PTPS deficiency were diagnosed by pteridine analysis. All patients had low biopterin and high neopterin levels in the urine, resulting in a neopterin to biopterin ratio (NIB) much higher than that of age-matched controls. The mean NIB in the parents of these patients was twice that of healthy unrelated adults. PTPS activity was measured in one of these patients with PTPS deficiency and in his family members; the patient was homozygous and his parents were heterozygous for PTPS deficiency. This result meant that NIB could be used as an index of PTPS activity. In healthy subjects studied cross­ sectionally, urinary levels of pteridine decreased in groups of increasing age, and the same change was found in subjects with hyperphenylalaninemia studied cross-sectionally. Thus, pteridine values of patients
    [Show full text]
  • Tetrahydropiopterin Deficiencies: Diagnosis, Treatment and Follow-Up
    TETRAHYDROPIOPTERIN DEFICIENCIES: DIAGNOSIS, TREATMENT AND FOLLOW-UP Alberto Burlina Division of Metabolic Disorders Department of Pediatrics - University Hospital Padova, Italy PHENYLALANINE HYDROXYLATING SYSTEM • Phenylalanine hydroxylase deficiency Phenylketonuria Phenylketonuria responsiveness to tetrahydrobiopterin • Tetrahydrobiopterin deficiencies GTP-CH PTPS SR DHPR PAH PCD DE NOVO BIOSYNTHETIC PATHWAY FROM GTP GFRP + BH4 RECYCLING PATHWAY SYNTHESIS OF TETRAHYDROBIOPTERIN (salvage pathway) TETRAHYDROBIOPTERIN COFACTOR DEFICIENCIES WITHOUT HYPERPHENYLALANINEMIA Segawa disease Sepiapterin reductase deficiency (SR) WITH HYPERPHENYLALANINEMIA GTP cyclohydrolase I deficiency (GTPCH) 6-Pyruvoyltetrahydropterin synthase deficiency (PTPS) Dihydropteridine reductase deficiency (DHPR) Pterin-4-α-carbinolamine dehydratase (PCD) DIFFERENTIAL DIAGNOSIS OF BH4 DEFECTS + + + +/- TETRAHYDROBIOPTERIN METABOLISM PATHWAY GTP GTP-Cyclohydrolase NH2TP Neopterin PTPS 6PTP SR BH4 Tyr Trp DHPR PAH TH TPH L-Dopa 5-HTP qBH2 COMT / MAO AADC MAO HVA Dopamine Serotonin 5HIAA DH SNA HIOMT MHPG Norepinephrine N-acetylserotonin Melatonin LOGISTICS OF CSF INVESTIGATIONS • Sample preparation • Freeze CSF immediately at – – preservatives 70º C – snap freezing • Contamination with blood disturb results (centrifuge – volume immediately before freezing) • Sample storage & transport • Chose the right technique (s) • Certain amount of CSF is (very low levels of metabolites necessary (3-4 ml), collect in at in CSF) least 5 fractions 0,5 – 1 ml • Establish own control
    [Show full text]
  • Consensus Guideline for the Diagnosis and Treatment of Tetrahydrobiopterin
    Opladen et al. Orphanet Journal of Rare Diseases (2020) 15:126 https://doi.org/10.1186/s13023-020-01379-8 REVIEW Open Access Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies Thomas Opladen1*†, Eduardo López-Laso2†, Elisenda Cortès-Saladelafont3,4†, Toni S. Pearson5, H. Serap Sivri6, Yilmaz Yildiz6, Birgit Assmann1, Manju A. Kurian7,8, Vincenzo Leuzzi9, Simon Heales10, Simon Pope10, Francesco Porta11, Angeles García-Cazorla3, Tomáš Honzík12, Roser Pons13, Luc Regal14, Helly Goez15, Rafael Artuch16, Georg F. Hoffmann1, Gabriella Horvath17, Beat Thöny18, Sabine Scholl-Bürgi19, Alberto Burlina20, Marcel M. Verbeek21, Mario Mastrangelo9, Jennifer Friedman22, Tessa Wassenberg14, Kathrin Jeltsch1†, Jan Kulhánek12*†, Oya Kuseyri Hübschmann1† and on behalf of the International Working Group on Neurotransmitter related Disorders (iNTD) Abstract Background: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world
    [Show full text]