ArticleThe Journal of biological chemistry2019
Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 18 citations in OpenAlex.
- A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer.Science advances · 2026Article
- A Diagnostic Dilemma: Hypophosphatemic Rickets Unmasking Tyrosinemia Type 1: A Case Report.Clinical case reports · 2026Article
- Aminolevulinate inhibition of human coproporphyrinogen oxidase clarifies coproporphyrin III accumulation in porphyrias.Bioscience reports · 2026Article
- Inherited metabolic disorders: presentation, clinical types, laboratory diagnosis and genetic markers.Orphanet journal of rare diseases · 2025Review
- Iron-binding biomolecules in the soluble hepatic fraction of the northern pike (Esox lucius): two-dimensional chromatographic separation with mass spectrometry detection.Analytical and bioanalytical chemistry · 2024Article
- Clinical Spectrum of Hereditary Tyrosinemia Type 1 in a Cohort of Pakistani Children.Clinical medicine insights. Pediatrics · 2024Article
- Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin.Life (Basel, Switzerland) · 2023Article
- Review
- mRNA-based therapy proves superior to the standard of care for treating hereditary tyrosinemia 1 in a mouse model.Molecular therapy. Methods & clinical development · 2022Article
- Cosolute modulation of protein oligomerization reactions in the homeostatic timescale.Biophysical journal · 2021Article
- Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I.International journal of molecular sciences · 2021Article
- E3 Ubiquitin Ligase APC/CInternational journal of molecular sciences · 2020Article
- Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein.Journal of personalized medicine · 2020Article
- Chemopreventive Effect of Dietary Anthocyanins against Gastrointestinal Cancers: A Review of Recent Advances and Perspectives.International journal of molecular sciences · 2020Review
- Protein Degradation and the Pathologic Basis of Phenylketonuria and Hereditary Tyrosinemia.International journal of molecular sciences · 2020Review
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Authors and funding
7 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
More than 100 mutations in the gene encoding fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1), a metabolic disorder characterized by elevated blood levels of tyrosine. Some of these mutations are known to decrease FAH catalytic activity, but the mechanisms of FAH mutation-induced pathogenicity remain poorly understood. Here, using diffusion ordered NMR spectroscopy, cryo-EM, and CD analyses, along with site-directed mutagenesis, enzymatic assays, and molecular dynamics simulations, we investigated the putative role of thermodynamic and kinetic stability in WT FAH and a representative set of 19 missense mutations identified in individuals with HT1. We found that at physiological temperatures and concentrations, WT FAH is in equilibrium between a catalytically active dimer and a monomeric species, with the latter being inactive and prone to oligomerization and aggregation. We also found that the majority of the deleterious mutations reduce the kinetic stability of the enzyme and always accelerate the FAH aggregation pathway. Depending mainly on the position of the amino acid in the structure, pathogenic mutations either reduced the dimer population or decreased the energy barrier that separates the monomer from the aggregate. The mechanistic insights reported here pave the way for the development of pharmacological chaperones that target FAH to tackle the severe disease HT1.
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