Biochemical Observations on So-called Hereditary Tyrosinemia

Abstract

ExtractDecreased activities of methionine-activating enzyme (ATP: L-methionine-S-adenosyl-transferase, EG. 2.5.1.6) (23 and 18 versus normal 86 nmoles product produced/mg soluble protein/h) and cystathionine synthetase [30] (28 and 6 versus normal of 98 nmoles product produced/mg soluble protein/h) in the presence of normal activity of cystathionase [30] (104 and 108 versus normal of 125 nmoles product produced/mg soluble protein/h) were demonstrated in the liver of two patients with so-called hereditary tyrosinemia. This decreased activity also was associated with documented deficiency of jb-hydroxyphenylpyruvic acid oxidase, tyrosine transaminase, and phenylalanine hydroxylase with values of 3 and 1.2 versus normal of 60, 2.6 and 0.8 versus normal of 20, and 3.5 versus normal of 13.7 (imoles/g wet weight of liver/h, respectively (table II). In one patient, the biopsy was performed after the concentration of tyrosine in the plasma had been made normal (less than 1.0 mg/ 100 ml) for 3 months by dietary restriction (fig. 2). This patient has subsequently maintained normal concentrations of amino acids in the plasma on an ad libitum diet for 18 months. These findings give evidence that the abnormalities on the pathway of metabolism of methionine are independent of the abnormality in the metabolism of tyrosine and that the latter may be self-limiting in some cases (table I). SpeculationThese studies suggest that the hypertyrosinemia and the hypermethioninemia seen in so-called hereditary tyrosinemia are each nonspecific manifestations of a phenotype as yet unidentified. Whether or not methionine accumulates in the plasma in the presence of these defects in the transsulfuration pathway is probably a function of an enlarged free amino acid pool in the liver when protein synthesis in that organ is reduced.

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

“…Since AFP production correlates with the degree of methionine metabolism block in these patients, these authors have suggested that the normal ontogenic repression of AFP might depend on a methionine-related metabolic event, for example, the activation of a differentiation control mechanism working through a transmethylase pathway. This suggestion is based in part upon an observation by Gaull et al (1970) that levels of methionine adenosyltransferase (MAT) are greatly decreased in hypermethionemic HT children. More recently Liau et al (1979) reported that livers of children who died of HT showed abnormal MAT isozyme patterns.…”

Development of Mammalian Sulfur Metabolism: Absence of Cystathionase in Human Fetal Tissues

“…Valid comparison with mature human brain is not possible, of course, because biopsy controls cannot be obtained. However, in Table II there are given the activities of these enzymes as well as the concentrations of cystathionine in selected areas of the brain, obtained at autopsy, from a 6-month-old infant with so-called "hereditary tyrosinemia" [7]. It should also be noted that values for the "control" brain may represent a minimum estimate of the activities of methionine-activating enzyme and cystathionine synthase, since it was shown that these activities are considerably reduced in crude extracts of liver from patients with so-called "hereditary tyrosinemia."…”

Enzyme Defect in a Case of Tyrosinemia Type I, Acute Form

“…6, 0.8) Gaul1 et al (8) found decreased activities of methionine ad- enosyltransferase and cystathionine P-synthase, as well as p- Vmax' Range (0.9,1.9) ... (12.0-16.3) (1.7, 1.9) HPPA oxidase, in the liver of tyrosinemia type I and concluded that these enzyme deficiencies were probably secondary mani-* Abbreviations: see "Abbreviations. "…”

“…The excessive excretion of phenolic acids has led some investigators (12,21) to suggest that the enzyme, p-HPPA oxidase, is involved in the pathogenesis of this disorder. In fact, several authors (15,23) confirmed that the p-HPPA oxidase activity was markedly reduced in the liver of patients; this was once considered to be a primary defect, but still is controversial (2,8).…”