Summary
Thiol groups are important components of proteins and their oxidation can lead to a substantial loss of protein function. Patients with two apparently unrelated inborn errors of metabolism, tyrosinaemia type 1 and glutathione synthetase deficiency, have been reported to show reduced cell glutathione concentrations. We have found that not only glutathione but also protein thiol concentrations are reduced in the liver in tyrosinaemia type 1 patients. We also report a case of glutathione synthetase deficiency with a substantial deficiency of liver 4-fumarylacetoacetate hydrolase and provide evidence that glutathione, or some small-molecular-weight thiol, is essential for maintaining stability of this enzymein vitro. Our results suggest that the availability of thiol groups may modify the phenotype of tyrosinaemia type 1 and that liver 4-fumarylacetoacetate hydrolase deficiency may be a secondary complicating factor in some forms of glutathione synthetase deficiency.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Berger R, van Faassan H, Smith GPA (1983) Biochemical studies on the enzymatic deficiencies in hereditary tyrosinaemia.Clin Chim Acta 134: 129–141.
Berger R, van Faassan H, Taanman JW, DeVries H, Agsteribbe E (1987) Type 1 tyrosinaemia: lack of immunologically detectable fumarylacetoacetase enzyme protein in tissues and cells.Pediatr Res 22: 394–398.
Beutler E, Gelbert T, Pegelow C (1986) Erythrocyte glutathione synthetase deficiency leads not only to glutathione but also to glutathione-S-transferase deficiency.J Clin Invest 77: 38–41.
Divry P, Rouland-Parrott F, Dorehe C et al (1991) 5-Oxoprolinuria (glutathione synthetase deficiency): a case with neonatal presentation and rapid fetal outcome.J Inher Metab Dis 14: 341–344.
Edwards SW, Knox WE (1955a) Enzymes involved in conversion of tyrosine to acetoacetate.Methods Enzymol 2: 287–300.
Edwards SW, Knox WE (1955b) Homogentisate metabolism: the isomerization of maleyl acetoacetate by an enzyme which requires glutathione.J Biol Chem 220: 79–91.
Fellman JH, Fujita TS, Roth ES (1972) Assay, properties and tissue distribution ofp-hydroxy-phenylpyruvate hydroxylase.Biochim Biophys Acta 284: 90–100.
Klebig ML, Russell LB, Rinchik EM (1992) Murine fumarylacetoacetate hydrolase gene is disrupted by a lethal albino deletion that defines the hepatocyte-specific developmental regulation (hs dr-1).Proc Natl Acad Sci USA 89: 1363–1367.
Kvittingen EA (1986) Hereditary tyrosinaemia type 1 — an overview.Scand J Clin Lab Invest 46 (supplement 184): 27–34.
Kvittingen EA (1991) Tyrosinaemia type 1 — an update.J Inher Metab Dis 14: 554–562.
Kvittingen EA, Jellum E, Stokke O (1981) Assay of fumarylacetoacetate fumaryl hydrolase in human liver — deficient activity in a case of hereditary tyrosinaemia.Clin Chim Acta 115: 311–319.
Kvittingen EA, Borresen AL, Stokke O, Van der Hagen CB, Lie SO (1985) Deficiency of fumarylacetoacetase without hereditary tyrosinaemia.Clin Genet 27: 550–554.
Labelle Y, Phaneuf D, Tanguay RM (1991) Cloning and expression analysis of a cDNA encoding fumarylacetoacetate hydrolase: post-transitional modulation in rat liver and kidney.Gene 104: 197–202.
Lehninger AL (1975)Biochemistry. New York: Worth Publshers, 428, 429, 663–668.
Lindblad B, Lindstedt S, Steen G (1977) On the enzymatic defects in hereditary tyrosinaemia.Proc Natl Acad Sci USA 84, 4641–4645.
Nagainis MP, Pu W, Cheng B, Taylor KE, Schmidt DE Jr (1981) Effects of pH and sulphydryl specific reagents on 4-fumarylacetoacetate fumaryl hydrolase.Biochim Biophys Acta 657: 203–211.
Russo A, Bump EA (1988) Detection and quantitation of biological sulphydryls.Methods Biochem Anal 33: 165–241.
Seltzer S (1973) Purification and properties of maleylacetonecis - trans isomerase fromVibrio 01.J Biol Chem 248: 215–222.
Sies H (1993) Strategies of antioxidant defence.Eur J Biochem 215: 213–219.
Smith PK, Krohn RI, Herman GT (1985) Measurement of protein using bicinchoninic acid.Anal Biochem 150: 76–85.
Stoner E, Starkman H, Wellner D et al (1984) Biochemical studies of a patient with hereditary hepatorenal tyrosinaemia: evidence of glutathione deficiency.Pediatr Res 18: 1332–1336.
Tanguay RM, Valet JP, Lescault JL et al (1990) Different molecular basis for fumarylacetoacetate hydrolase deficency in the two clinical forms of hereditary tyrosinaemia (type 1).Am J Hum Genet 47: 308–316.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lloyd, A.J., Gray, R.G.F. & Green, A. Tyrosinaemia type 1 and glutathione synthetase deficiency: two disorders with reduced hepatic thiol group concentrations and a liver 4-fumarylacetoacetate hydrolase deficiency. J Inherit Metab Dis 18, 48–55 (1995). https://doi.org/10.1007/BF00711372
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00711372