Abstract
Succinylacetone which has been isolated from urine from patients with hereditary tyrosinemia inhibits porphobilinogen synthase (EC 4.2.1.24) both in liver and erythrocytes. It accumulates together with succinylacetoacetate secondary to a low activity of fumarylacetoacetase (EC 3.7.1.2) in liver (0.09-2.3 U/g protein, n=9, ref. values 5-17 U/g protein, n=5). We suggest that this is the primary enzyme defect and that the severe liver and kidney damage arise secondary to accumulation of maleylacetoacetate and/or fumarylacetoacetase. This is supported by the following facts (1) maleylacetoacetate and fumarylacetoacetate react with SH-groups and are therefore potentially toxic metabolites, (2) injection of glutathione decreases S-succinylacetoacetate and S-succinylacetone probably by reacting with maleylacetoacetate and fumarylacetoacetate, (3) injection of homogentisate increases the tubular proteinuria, (4) among nine patients those with a more benign form of the disease had the lowest activity of 4-hydroxyphenylpyruvate dioxygenase in liver, i.e. accumulate less of maleylacetoacetate and fumarylacetoacetate, (5) 4-hydroxyphenulpyruvate dioxygenase (EC 1.13.11.27) is present only in the tissues seriously damaged in hereditary tyrosinemia. Oral treatment with SH-reagents like penicillamine and N-acetylcysteine has been evaluated in clinical trials in combination with dietary restriction of phenylalanine and tyrosine intake.
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Fällström, SP., Lindblad, B., Lindstedt, S. et al. Hereditary tyrosinemia - fumarylacetoacetase deficiency. Pediatr Res 13, 78 (1979). https://doi.org/10.1203/00006450-197901000-00056
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DOI: https://doi.org/10.1203/00006450-197901000-00056
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