Skip to main content
SpringerLink
Log in

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

  • Original Investigations
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

PEE:

Phosphate eliminating enzyme

DHBS:

Dihydrobiopterin synthetase

HPLC:

High pressure liquid chromatography

BH4 :

tetrahydrobiopterin

References

  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 128:446–452

    Google Scholar 

  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 93:251–262

    Google Scholar 

  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)

  4. Dhondt JL, Leroux B, Farriaux JP, Largilliere C, Leeming RJ (1983) Dihydrobiopterin biosynthesis deficiency. Eur J Pediatr 141:92–95

    Google Scholar 

  5. Duch DS, Lee CL, Edelstein MP, Nichol CA (1983) Biosynthesis of tetrahydrobiopterin in the presence of dihydrofolate reductase inhibitors. Mol Pharmacol 24:103–108

    Google Scholar 

  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 251:6505–6512

    Google Scholar 

  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 3:69–88

    Google Scholar 

  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 142:126–129

    Google Scholar 

  9. Heintel D, Ghisla S, Curtius H-Ch, Niederwieser A, Levine A (1984) Biosynthesis of tetrahydrobiopterin: possible involvement of tetrahydropterin intermediates. Neurochem Int 6:141–155

    Google Scholar 

  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 127:213–219

    Google Scholar 

  11. Hreidarsson S, Valle D, Kapatos N, Kaufman S (1982) Peripheral defect in biopterin synthesis: A new mutant? Pediatr Res 16: 192A

    Google Scholar 

  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 263–270

    Google Scholar 

  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 117–124

    Google Scholar 

  14. Matalon R (1984) Current status of biopterin screening. J Pediatr 104:579–580

    Google Scholar 

  15. Milstien S, Kaufman S (1983) Tetrahydro-sepiapterin is an intermediate in tetrahydrobiopterin biosynthesis. Biochem Biophys Res Commun 115:883–893

    Google Scholar 

  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:131–133

    Google Scholar 

  17. Niederwieser A, Matasović A, Curtius H-Ch, Endres W, Schaub J (1980) 3′-Hydroxysepiapterin in patients with dihydrobiopterin deficiency. FEBS Lett 118:299–302

    Google Scholar 

  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 293–306

    Google Scholar 

  19. Niederwieser A, Staudenmann W, Wetzel E (1984) HPLC with column switching for the analysis of biogenic amine metabolites and pterins. J Chromatogr 290:237–246

    Google Scholar 

  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]:109–120

    Google Scholar 

  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 55:637–639

    Google Scholar 

  22. Rey F, Saudubray JM, Leeming RJ, Niederwieser A, Curtius HC, Rey J (1983) Les déficits partiels en tetrahydrobiopterine. Arch Fr Pediatr 40:237–241

    Google Scholar 

  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 53:674–676

    Google Scholar 

  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 123–131

    Google Scholar 

  25. Sueoka T, Katoh S (1982) Purification and characterization of sepiapterin reductase from rat erythrocytes. Biochim Biophys Acta 717:265–277

    Google Scholar 

  26. Tanaka K, Akino M, Hagi Y, Doi M, Shiota T (1981) The enzymatic synthesis of sepiapterin by chicken kidney preparations. J Biol chem 256:2963–2972

    Google Scholar 

  27. Yim JJ, Brown GM (1976) Characteristics of guanosine triphosphate cyclohydrolase I purifed from E. coli. J Biol Chem 251:5087–5094

    Google Scholar 

  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 1:74–81

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Zurich, CH-8032, Zurich, Switzerland

    A. Niederwieser, W. Leimbacher & H. Ch. Curtius

  2. Department of Pediatrics, University of Torino, Italy

    A. Ponzone

  3. Hopital des Enfants-Malades, University of Paris, France

    F. Rey

  4. Department of Pediatrics, University of Ulm, Federal Republic of Germany

    D. Leupold

Authors
  1. A. Niederwieser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Leimbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Ch. Curtius
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Ponzone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Leupold
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niederwieser, A., Leimbacher, W., Curtius, H.C. et al. Atypical phenylketonuria with “dihydrobiopterin synthetase” deficiency: Absence of phosphate-eliminating enzyme activity demonstrated in liver. Eur J Pediatr 144, 13–16 (1985). https://doi.org/10.1007/BF00491917

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00491917

Key words

Search

Navigation