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. 1977 Oct;74(10):4641–4645. doi: 10.1073/pnas.74.10.4641

On the enzymic defects in hereditary tyrosinemia.

B Lindblad, S Lindstedt, G Steen
PMCID: PMC432003  PMID: 270706

Abstract

The activity of the enzyme porphobilinogen synthase (EC 4.2.1.24) in erythrocytes from patients with hereditary tyrosinemia was less than 5% of that in a control group and the activity in liver tissue was less than 1% of the reported normal activity. Urine from patients with hereditary tyrosinemia contained an inhibitor that was isolated and identified as succinylacetone (4,6-dioxoheptanoic acid) by gas/liquid chromatography-mass spectrometry. Fresh urine samples contained succinylacetoacetate (3,5-dioxooctanedioic acid) as well as succinylacetone. The inhibition of porphobilinogen synthase explains the high excretion of 5-aminolevulinate observed in hereditary tyrosinemia. Succinylacetone and succinylacetoacetate presumably originate from maleylacetoacetate or fumarylacetoacetate, or both, and their accumulation indicates a block at the fumarylacetoacetase (EC 3.7.1.2) step in the degradation of tyrosine. We suggest that the severe liver and kidney damage in hereditary tyrosinemia may be due to the accumulation of these tyrosine metabolites and that the primary enzyme defect in hereditary tyrosinemia may be decreased activity of fumarylacetoacetase.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Björkman L., McLean C., Steen G. Organic acids in urine from human newborns. Clin Chem. 1976 Jan;22(1):49–52. [PubMed] [Google Scholar]
  2. Bodegård G., Gentz J., Lindblad B., Lindstedt S., Zetterström R. Hereditary tyrosinemia. 3. On the differential diagnosis and the lack of effect of early dietary treatment. Acta Paediatr Scand. 1969 Jan;58(1):37–48. doi: 10.1111/j.1651-2227.1969.tb04327.x. [DOI] [PubMed] [Google Scholar]
  3. Collier H. B. A study of the determination of 5-aminolevulinate hydro-lyase (delta-aminolevulinate dehydratase) activity in hemolysates of human erythrocytes. Clin Biochem. 1971 Dec;4(4):222–232. doi: 10.1016/s0009-9120(71)91692-4. [DOI] [PubMed] [Google Scholar]
  4. EDWARDS S. W., KNOX W. E. Homogentisate metabolism: the isomerization of maleylacetoacetate by an enzyme which requires glutathione. J Biol Chem. 1956 May;220(1):79–91. [PubMed] [Google Scholar]
  5. Fellman J. H., Fujita T. S., Roth E. S. Assay, properties and tissue distribution of p-hydroxyphenylpyruvate hydroxylase. Biochim Biophys Acta. 1972 Sep 19;284(1):90–100. doi: 10.1016/0005-2744(72)90048-4. [DOI] [PubMed] [Google Scholar]
  6. GENTZ J., JAGENBURG R., ZETTERSTROEM R. TYROSINEMIA. J Pediatr. 1965 Apr;66:670–696. doi: 10.1016/s0022-3476(65)80002-6. [DOI] [PubMed] [Google Scholar]
  7. GIBSON K. D., NEUBERGER A., SCOTT J. J. The purification and properties of delta-aminolaevulic acid dehydrase. Biochem J. 1955 Dec;61(4):618–629. doi: 10.1042/bj0610618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gentz J., Heinrich J., Lindblad B., Lindstedt S., Zetterström R. Enzymatic studies in a case of hereditary tyrosinemia with hepatoma. Acta Paediatr Scand. 1969 Jul;58(4):393–396. doi: 10.1111/j.1651-2227.1969.tb04736.x. [DOI] [PubMed] [Google Scholar]
  9. Gentz J., Johansson S., Lindblad B., Lindstedt S., Zetterström R. Exertion of delta-aminolevulinic acid in hereditary tyrosinemia. Clin Chim Acta. 1969 Feb;23(2):257–263. doi: 10.1016/0009-8981(69)90040-0. [DOI] [PubMed] [Google Scholar]
  10. Gentz J., Lindblad B., Lindstedt S., Levy L., Shasteen W., Zetterstrom R. Dietary treatment in tyrosinemia (tyrosinosis). With a note on the possible recognition of the carrier state. Am J Dis Child. 1967 Jan;113(1):31–37. doi: 10.1001/archpedi.1967.02090160081006. [DOI] [PubMed] [Google Scholar]
  11. Gentz J., Lindblad B. p-hydroxyphenylpyruvate hydroxylase activity in fine-needle aspiration liver biopsies in hereditary tyrosinemia. Scand J Clin Lab Invest. 1972 Feb;29(1):115–126. doi: 10.3109/00365517209081063. [DOI] [PubMed] [Google Scholar]
  12. Gillette J. R. Commentary. A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity. Biochem Pharmacol. 1974 Oct 15;23(20):2785–2794. doi: 10.1016/0006-2952(74)90052-5. [DOI] [PubMed] [Google Scholar]
  13. Holston J. L., Jr, Levy H. L., Tomlin G. A., Atkins R. J., Patton T. H., Hosty T. S. Tyrosinosis: a patient without liver or renal disease. Pediatrics. 1971 Sep;48(3):393–400. [PubMed] [Google Scholar]
  14. JARRETT A., RIMINGTON C., WILLOUGHBY D. A. Delta-Aminolaevulic acid and porphyria. Lancet. 1956 Jan 21;270(6908):125–127. doi: 10.1016/s0140-6736(56)91091-1. [DOI] [PubMed] [Google Scholar]
  15. Jollow D. J., Mitchell J. R., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther. 1973 Oct;187(1):195–202. [PubMed] [Google Scholar]
  16. KNOX W. E., EDWARDS S. W. The properties of maleylacetoacetate, the initial product of homogentisate oxidation in liver. J Biol Chem. 1955 Oct;216(2):489–498. [PubMed] [Google Scholar]
  17. Kang E. S., Gerald P. S. Hereditary tyrosinemia and abnormal pyrrole metabolism. J Pediatr. 1970 Sep;77(3):397–406. doi: 10.1016/s0022-3476(70)80006-3. [DOI] [PubMed] [Google Scholar]
  18. Kramer S., Becker D., Viljoen D. Significance of the porphyrin precursors delta-aminolaevulinic acid (ALA) and porphobilinogen (PBG) in the acute attack of porphyria. S Afr Med J. 1973 Sep 29;47(38):1735–1738. [PubMed] [Google Scholar]
  19. LACK L. Enzymic cis-trans isomerization of maleylpyruvic acid. J Biol Chem. 1961 Nov;236:2835–2840. [PubMed] [Google Scholar]
  20. Lindblad B., Lindstedt G., Lindstedt S., Rundgren M. Purification and some properties of human 4-hydroxyphenylpyruvate dioxygenase (I). J Biol Chem. 1977 Jul 25;252(14):5073–5084. [PubMed] [Google Scholar]
  21. Lindblad B., Lindstedt S., Olander B., Omfeldt M. Purification of p-hydroxyphenylpyruvate hydroxylase from human liver. Acta Chem Scand. 1970;25(1):329–330. doi: 10.3891/acta.chem.scand.25-0329. [DOI] [PubMed] [Google Scholar]
  22. Lindblad B. Radiochemical assays for p-hydroxyphenylpyruvate hydroxylase activity in human liver. Clin Chim Acta. 1971 Aug;34(1):113–121. doi: 10.1016/0009-8981(71)90074-x. [DOI] [PubMed] [Google Scholar]
  23. Lindemann R., Gjessing L. R., Merton B., Löken A. C., Halvorsen S. Amino acid metabolism in hereditary fructosemia. Acta Paediatr Scand. 1970 Mar;59(2):141–147. doi: 10.1111/j.1651-2227.1970.tb08979.x. [DOI] [PubMed] [Google Scholar]
  24. Mitchell J. R., Jollow D. J., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973 Oct;187(1):185–194. [PubMed] [Google Scholar]
  25. Mitchell J. R., Jollow D. J., Potter W. Z., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther. 1973 Oct;187(1):211–217. [PubMed] [Google Scholar]
  26. Morgan E. J., Friedmann E. Interaction of maleic acid with thiol compounds. Biochem J. 1938 Apr;32(4):733–742. doi: 10.1042/bj0320733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Perlroth M. G., Tschudy D. P., Marver H. S., Berard C. W., Zeigel R. F., Rechcigl M., Collins A. Acute intermittent porphyria. New morphologic and biochemical findings. Am J Med. 1966 Jul;41(1):149–162. doi: 10.1016/0002-9343(66)90012-x. [DOI] [PubMed] [Google Scholar]
  28. Potter W. Z., Davis D. C., Mitchell J. R., Jollow D. J., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther. 1973 Oct;187(1):203–210. [PubMed] [Google Scholar]
  29. TSCHUDY D. P., COLLINS A. Effect of 3-amino-1, 2, 4-triazole on delta-amino-levulinic acid dehydrase activity. Science. 1957 Jul 26;126(3265):168–168. doi: 10.1126/science.126.3265.168. [DOI] [PubMed] [Google Scholar]
  30. Wadman S. K., van Sprang F. J., Maas J. W., Ketting D. An exceptional case of tyrosinosis. J Ment Defic Res. 1968 Dec;12(4):269–281. doi: 10.1111/j.1365-2788.1968.tb00267.x. [DOI] [PubMed] [Google Scholar]
  31. Weinberg A. G., Mize C. E., Worthen H. G. The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediatr. 1976 Mar;88(3):434–438. doi: 10.1016/s0022-3476(76)80259-4. [DOI] [PubMed] [Google Scholar]

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