On the enzymic defects in hereditary tyrosinemia.

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.In the inborn error of metabolism called hereditary tyrosinemia, the main clinical findings are liver failure, which develops into liver cirrhosis in early childhood, and multiple renal tubular defects with hypophosphatemic rickets (1, 2). The derangement in tyrosine metabolism (i.e., hypertyrosinemia and high urinary excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and to a lesser extent 4-hydroxyphenylacetate) is due to a low activity of the enzyme 4-hydroxyphenylpyruvate dioxygenase [4-hydroxyphenylpyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating), EC 1.13.11.27] (3), which catalyzes the formation of homogentisate (III) (Fig. 1) from 4-hydroxyphenylpyruvate (II).The increased excretion of these phenolic metabolites of tyrosine does not explain the liver and kidney damage in hereditary tyrosinemia because a similar large excretion has been found also in patients without liver and kidney disease-e.g., in a 5-year-old boy with multiple congenital anomalies and with negligible activity of soluble tyrosine aminotransferase (4) and in at least three other patients who were mentally retarded (2,5,6). A large excretion of the same metabolites has also been found in hereditary fructose intolerance (7).In 1967 we reported on a patient who had symptoms similar to those characteristic of acute intermittent porphyria (8). An increased excretion of 5-aminolevulinate has since then been observed in all patients studied by us, even in those without these symptoms (3, 9), but so far it has not been possible to find a biochemical link between the altered tyrosine metabolism and the increased excretion of a porphyrin precursor. In this report we present evidence for an enzyme defect in tyrosine catabolism in hereditary tyrosinemia that explains the increased excretion of 5-aminolevulinate. We also present a hypothesis

The Effects of Levulinic Acid and 4,6-Dioxoheptanoic Acid on the Metabolism of Etiolated and Greening Barley Leaves

“…In a preliminary study, Duggan et al (5) afflicted with hereditary tyrosinemia (16). This compound has been reported to be an effective inhibitor of ALA dehydratase in animal systems (6,16). Here, we report the inhibition of barley ALA dehydratase by DA, in vivo and in vitro.…”

“…LA is also reported to inhibit respiration in Scenedesmus (21), to stimulate paramylum breakdown in Euglena (23), and to retard cell division in Skeletonema (22). In a preliminary study, Duggan et al (5) afflicted with hereditary tyrosinemia (16). This compound has been reported to be an effective inhibitor of ALA dehydratase in animal systems (6,16).…”

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

“…Both delayed development of the tyrosine catabolic pathway in the neonatal period and secondary inactivation of the pathway seem to contribute to survival of hepatocytes in HT1 patients. Indeed, HPD activities are reduced in the livers of HT1 patients (33), and this reduction is proposed to be part of the altered gene expression (34). If this inactivation is inadequate, acute death of hepatocytes is inevitable after the full expression of HPD, the result being the acute form of HT1.…”

Inhibitors of Nonhousekeeping Functions of the Apicoplast Defy Delayed Death in Plasmodium falciparum

“…More importantly, the apicoplast is predicted to provide the microenvironment required for fatty acid synthesis, non-mevalonate isopentenyl diphosphate synthesis, and some of the reactions of the heme biosynthesis pathway, and given the cyanobacterial heritage of the apicoplast, many of the nucleusencoded and apicoplast-targeted enzymes involved in these pathways are fundamentally different from those in their mammalian host counterparts, thereby making them potent drug targets (9,28,29). Inhibitors of these apicoplast resident metabolic pathways-triclosan (7), cerulenin (32), aryloxyphenoxypropionate herbicides (20), NAS-91 (25), succinyl acetone (15), and fosmidomycin (14)-have been demonstrated to kill Plasmodium (8,14,25,28,29,32,33).…”