On the enzymic defects in hereditary tyrosinemia.
Open accessAbstract
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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In humans, deficiency of FAA hydrolase causes hereditary tyrosinemia type I (HT1).
“In humans, deficiency of FAA hydrolase causes hereditary tyrosinemia type I (HT1), a severe, autosomal recessive inborn error of metabolism (Lindblad et al. 1977; Tanguay et al. 1984).”
From Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice (1993) · cites this paper as Lindblad et al. 1977
The Abstract (page not specified in our copy) says the patients’ metabolites indicate a block at the fumarylacetoacetase step. It suggests that decreased activity of this enzyme may be the primary defect in hereditary tyrosinemia, but does not establish the causal claim as a certainty or identify the condition as type I. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSuccinylacetone is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase.
“Succinylacetone (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase.”
From Hereditary Tyrosinemia and the Heme Biosynthetic Pathway: Profound Inhibition of δ-Aminolevulinic Acid Dehydratase Activity by Succinylacetone (1983) · cites this paper as [7]
The Abstract (p. 4641) reports succinylacetone in urine from patients with hereditary tyrosinemia and identifies a possible block at the fumarylacetoacetase step. It says the metabolites “presumably” originate from upstream compounds and suggests that decreased enzyme activity “may be” the primary defect; it does not establish the inherited deficiency as the cause asserted in the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLow ALA dehydratase activity in hereditary tyrosinemia is thought to result from enzyme inhibition by accumulation of succinylacetone in plasma resulting from deficiency of 4-fumarylacetoacetate hydrolase.
“Low ALA dehydratase activity is thought to result from enzyme inhibition by accumulation of succinylacetone (4,6-dioxoheptanoic acid) in plasma resulting from the deficiency of 4-fumarylacetoacetate hydrolase [EC 3.7.1.2] in this disease (7).”
From Hereditary Tyrosinemia and the Heme Biosynthetic Pathway: Profound Inhibition of δ-Aminolevulinic Acid Dehydratase Activity by Succinylacetone (1983) · cites this paper as [7]
The passage labeled Abstract reports very low porphobilinogen synthase (ALA dehydratase) activity in hereditary tyrosinemia, identifies succinylacetone as an inhibitor in patients’ urine, and suggests a block at the fumarylacetoacetase step. It does not establish the claim’s specific location of succinylacetone accumulation in plasma. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe primary enzymatic defect in hereditary tyrosinemia is a decreased activity of fumarylacetoacetate hydrolase.
“Lindblad et al. (7) first reported that the high urinary excretion of ALA in patients with hereditary tyrosinemia is due to inhibition of ALA dehydratase by succinylacetone and their studies indicated that the primary enzymatic defect in hereditary tyrosinemia might be a decreased activity of fumarylacetoacetate hydrolase, an enzyme deficiency that was later demn r s e tients (26).”
From Hereditary Tyrosinemia and the Heme Biosynthetic Pathway: Profound Inhibition of δ-Aminolevulinic Acid Dehydratase Activity by Succinylacetone (1983) · cites this paper as Lindblad et al. (7)
The Abstract proposes that decreased fumarylacetoacetase activity may be the primary defect in hereditary tyrosinemia. That supports the hedged wording of the citing sentence, but not the unqualified claim that it is the primary defect. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn Tyr 1, deficiency of the enzyme fumarylacetoacetase causes accumulation of tyrosine and toxic metabolites.
“In Tyr 1, the deficiency of the enzyme fumarylacetoacetase causes an accumulation of tyrosine and toxic metabolites (Figure 1) [1].”
From Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice (2014) · cites this paper as [1]
The Abstract reports accumulation of succinylacetone and succinylacetoacetate and says this indicates a block at the fumarylacetoacetase step of tyrosine degradation. It only suggests that decreased fumarylacetoacetase activity may be the primary defect and that accumulated metabolites may cause damage; it does not state that tyrosine itself accumulates as a result of the deficiency. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Patients with hereditary tyrosinemia have low ALA dehydratase activity in erythrocytes and liver.
“Patients with this disease excrete excessive amounts of urinary δ-aminolevulinic acid (ALA)¹ (25) and have low ALA dehydratase [EC 4.2.1.24] activity in erythrocytes (6, 7) and in liver (7).”
From Hereditary Tyrosinemia and the Heme Biosynthetic Pathway: Profound Inhibition of δ-Aminolevulinic Acid Dehydratase Activity by Succinylacetone (1983) · cites this paper as [7]
Lindblad et al. first reported that the high urinary excretion of ALA in patients with hereditary tyrosinemia is due to inhibition of ALA dehydratase by succinylacetone.
“Lindblad et al. (7) first reported that the high urinary excretion of ALA in patients with hereditary tyrosinemia is due to inhibition of ALA dehydratase by succinylacetone and their studies indicated that the primary enzymatic defect in hereditary tyrosinemia might be a decreased activity of fumarylacetoacetate hydrolase, an enzyme deficiency that was later demn r s e tients (26).”
From Hereditary Tyrosinemia and the Heme Biosynthetic Pathway: Profound Inhibition of δ-Aminolevulinic Acid Dehydratase Activity by Succinylacetone (1983) · cites this paper as Lindblad et al. (7)
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Cites
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Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.-N., Finegold, M., & Grompe, M. (1996) · Nature Genetics · doi:10.1038/ng0396-266 · Cited by 549 · see citing works
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“It has been speculated, but not proven, that MAA and FAA are primarily responsible for much of the local tissue damage leading to necrosis of hepatocytes and other cells (Lindblad et al. 1977; Goldsmith and Laberge 1989).”
BackgroundTyrosinaemia type I and NTBC (2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione)
Holme, E., & Lindstedt, S. (1998) · Journal of Inherited Metabolic Disease · doi:10.1023/a:1005410820201 · Cited by 264 · see citing works
Self-citationChinsky, J. M., Singh, R., Ficicioglu, C., van Karnebeek, C. D. M., Grompe, M., Mitchell, G., Waisbren, S. E., Gucsavas-Calikoglu, M., Wasserstein, M. P., Coakley, K., et al. (2017) · Genetics in Medicine · doi:10.1038/gim.2017.101 · Cited by 247 · see citing works
The pathophysiology and treatment of hereditary tyrosinemia type 1
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Inhibition of delta-aminolevulinic acid dehydrase by 4,6-dioxoheptanoic acid.
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Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1
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Cardiomyopathy in tyrosinaemia type I is common but usually benign
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Newborn screening for Tyr-I: Two years' experience of the New York State program
Morrissey, M. A., Sunny, S., Fahim, A., Lubowski, C., & Caggana, M. (2011) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2011.02.017 · Cited by 22 · see citing works
- Authors
- Lindblad, B., Lindstedt, S., & Steen, G.
- Affiliations
- University of Gothenburg (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1977-10
- Volume
- 74
- Issue
- 10
- Pages
- 4641-4645
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC432003
- OpenAlex
- W2086932144
- Cited by
- 447
- References
- 2
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 11 · 2021: 8 · 2020: 12 · 2019: 11 · 2018: 10 · 2017: 16 · 2016: 16 · 2015: 16 · 2014: 9 · 2013: 7 · 2012: 9
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- hereditary tyrosinemia, delta-aminolevulinic acid dehydratase, succinylacetone, enzyme inhibition, tyrosine degradation, erythrocyte enzyme activity, liver injury, kidney injury
- MeSH terms
- Amino Acid Metabolism, Inborn Errors, Porphobilinogen Synthase, Carboxylic Acids, Erythrocytes, Humans, Ketones, Liver, Tyrosine, 4-Hydroxyphenylpyruvate Dioxygenase
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