European Journal of Pediatrics

, Volume 144, Issue 1, pp 13–16 | Cite as

Atypical phenylketonuria with “dihydrobiopterin synthetase” deficiency: Absence of phosphate-eliminating enzyme activity demonstrated in liver

  • A. Niederwieser
  • W. Leimbacher
  • H. Ch. Curtius
  • A. Ponzone
  • F. Rey
  • D. Leupold
Original Investigations

Abstract

An assay for the phosphate-eliminating enzyme (PEE) activity in liver was developed which required only 5–10 mg tissue. PEE catalyses the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin (BH4). In the presence of substrate, magnesium, NADPH, and a sepiapterin reductase fraction from human liver, PEE catalysed the formation of BH4 which was measured by HPLC and electrochemical detection. In adult human liver, a PEE activity of 1.02±0.134 μU/mg protein (mean ±1 SD; n=5) was observed. In liver needle biopsy material from five patients with defective biopterin biosynthesis, no PEE activity was found (less than 2% and 6% of the control values, respectively). The presence of an endogenous inhibitor was excluded. In a patient who died without definite diagnosis and in a patient with β-thalassaemia liver PEE activity was increased. Sepiapterin reductase activity was present in all cases. Results indicate that in “dihydrobiopterin synthetase” deficiency, the most frequent of the rare BH4-deficient variants of hyperphenylalaninaemia, the molecular defect consists in a defect of PEE.

Key words

Phenylketonuria Biopterin Dihydrobiopterin Inborn errors of metabolism 

Abbreviations

PEE

Phosphate eliminating enzyme

DHBS

Dihydrobiopterin synthetase

HPLC

High pressure liquid chromatography

BH4

tetrahydrobiopterin

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References

  1. 1.
    Blau N, Niederwieser A (1983) Guanosine triphosphate cyclohydrolase I assay in human and rat liver using high-performance liquid chromatography of neopterin phosphates and guanine nucleotides. Anal Biochem 128:446–452Google Scholar
  2. 2.
    Curtius H-Ch, Niederwieser A, Viscontini M, Otten A, Schaub J, Scheibenreiter S, Schmidt H (1979) Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin, and sepiapterin. Clin Chim Acta 93:251–262Google Scholar
  3. 3.
    Curtius H-Ch, Heintel D, Ghisla S, Kuster Th, Leimbacher W, Niederwieser A (1985) Biosynthesis of tetrahydrobiopterin in man. J Inherited Metab Dis (in press)Google Scholar
  4. 4.
    Dhondt JL, Leroux B, Farriaux JP, Largilliere C, Leeming RJ (1983) Dihydrobiopterin biosynthesis deficiency. Eur J Pediatr 141:92–95Google Scholar
  5. 5.
    Duch DS, Lee CL, Edelstein MP, Nichol CA (1983) Biosynthesis of tetrahydrobiopterin in the presence of dihydrofolate reductase inhibitors. Mol Pharmacol 24:103–108Google Scholar
  6. 6.
    Eto I, Fukushima K, Shiota T (1976) Enzymatic synthesis of biopterin from d-erythro dihydroneopterin triphosphate by extracts of kidneys from Syrian golden hamsters. J Biol Chem 251:6505–6512Google Scholar
  7. 7.
    Gàl EM, Nelson JM, Sherman AD (1978) Biopterin III. Purification and characterization of enzymes involved in the cerebral synthesis of 7,8-dihydrobiopterin. Neurochem Res 3:69–88Google Scholar
  8. 8.
    Güttler F, Lou H, Lykkelund C, Niederwieser A (1984) Combined tetrahydrobiopterin—phenylalanine loading test in the detection of patially defective biopterin synthesis. Eur J Pediatr 142:126–129Google Scholar
  9. 9.
    Heintel D, Ghisla S, Curtius H-Ch, Niederwieser A, Levine A (1984) Biosynthesis of tetrahydrobiopterin: possible involvement of tetrahydropterin intermediates. Neurochem Int 6:141–155Google Scholar
  10. 10.
    Heintel D, Leimbacher W, Redweik U, Zagalak B, Curtius H-Ch (1985) Purification and properties of the phosphate eliminating enzyme involved in the biosynthesis of BH4 in man. Biochem Biophys Res Commun 127:213–219Google Scholar
  11. 11.
    Hreidarsson S, Valle D, Kapatos N, Kaufman S (1982) Peripheral defect in biopterin synthesis: A new mutant? Pediatr Res 16: 192AGoogle Scholar
  12. 12.
    Kapatos G, Katoh S, Kaufman S (1981) Sepiapterin (6-lactyl-7,8-dihydropterin) is an intermediate in biopterin biosynthesis in a cell-free preparation from rat striatum. In: Usdin E, Weiner N, Youdim MB (eds) Function and regulation of monoamine enzymes: basic and clinical aspects. MacMillan, London, pp 263–270Google Scholar
  13. 13.
    Kaufman S (1979) Biopterin and metabolic disease. In: Kisliuk RL, Brown GM (eds) Chemistry and biology of pteridines. Elsevier-North Holland, New York, pp 117–124Google Scholar
  14. 14.
    Matalon R (1984) Current status of biopterin screening. J Pediatr 104:579–580Google Scholar
  15. 15.
    Milstien S, Kaufman S (1983) Tetrahydro-sepiapterin is an intermediate in tetrahydrobiopterin biosynthesis. Biochem Biophys Res Commun 115:883–893Google Scholar
  16. 16.
    Niederwieser A, Curtius HC, Bettoni O, Bieri J, Schircks B, Viscontini M, Schaub J (1979) Atypical phenylketonuria caused by 7,8-dihydrobiopterin synthetase deficiency. Lancet I:131–133Google Scholar
  17. 17.
    Niederwieser A, Matasović A, Curtius H-Ch, Endres W, Schaub J (1980) 3′-Hydroxysepiapterin in patients with dihydrobiopterin deficiency. FEBS Lett 118:299–302Google Scholar
  18. 18.
    Niederwieser A, Matasović A, Staudenmann W, Wang M, Curtius H-Ch (1982) Screening for tetrahydrobiopterin deficiency. In: Wachter H, Curtius H-Ch, Pfleiderer W (eds) Biochemical and clinical aspects of pteridines, vol 1. de Gruyter, Berlin, pp 293–306Google Scholar
  19. 19.
    Niederwieser A, Staudenmann W, Wetzel E (1984) HPLC with column switching for the analysis of biogenic amine metabolites and pterins. J Chromatogr 290:237–246Google Scholar
  20. 20.
    Rey F, Harpey JP, Leeming RJ, Blair JA, Aicardi J, Rey J (1977) Les hyperphenylalaninémies avec activité normale de la phénylalanine hydroxylase. Arch Fr Pediatr 34 [Suppl 1]:109–120Google Scholar
  21. 21.
    Rey F, Leeming RJ, Blair JA, Rey J (1980) Biopterin defect in a normal appearing child affected by a transient phenylketonuria. Arch Dis Child 55:637–639Google Scholar
  22. 22.
    Rey F, Saudubray JM, Leeming RJ, Niederwieser A, Curtius HC, Rey J (1983) Les déficits partiels en tetrahydrobiopterine. Arch Fr Pediatr 40:237–241Google Scholar
  23. 23.
    Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, Schircks B, Bieri J (1978) Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child 53:674–676Google Scholar
  24. 24.
    Smith GK, Nichol CA (1983) Studies on the biosynthesis of tetrahydrobiopterin in bovine adrenal medulla preparations. In: Curtius HC, Pfleiderer W, Wachter H (eds) Biochemical and clinical aspects of pteridines, vol 2. W de Gruyter, Berlin, pp 123–131Google Scholar
  25. 25.
    Sueoka T, Katoh S (1982) Purification and characterization of sepiapterin reductase from rat erythrocytes. Biochim Biophys Acta 717:265–277Google Scholar
  26. 26.
    Tanaka K, Akino M, Hagi Y, Doi M, Shiota T (1981) The enzymatic synthesis of sepiapterin by chicken kidney preparations. J Biol chem 256:2963–2972Google Scholar
  27. 27.
    Yim JJ, Brown GM (1976) Characteristics of guanosine triphosphate cyclohydrolase I purifed from E. coli. J Biol Chem 251:5087–5094Google Scholar
  28. 28.
    Yoshioka S, Masada M, Yoshida T, Mizokami T, Akino M, Matsuo N (1984) Atypical phenylketonuria due to biopterin deficiency: Diagnosis by assay of an enzyme involved in the synthesis of sepiapterin from dihydroneopterin triphosphate. Zoolog Sci 1:74–81Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • A. Niederwieser
    • 1
  • W. Leimbacher
    • 1
  • H. Ch. Curtius
    • 1
  • A. Ponzone
    • 2
  • F. Rey
    • 3
  • D. Leupold
    • 4
  1. 1.Department of PediatricsUniversity of ZurichZurichSwitzerland
  2. 2.Department of PediatricsUniversity of TorinoItaly
  3. 3.Hopital des Enfants-MaladesUniversity of ParisFrance
  4. 4.Department of PediatricsUniversity of UlmFederal Republic of Germany

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