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Fungal metabolic model for human type I hereditary tyrosinaemia.

Abstract
Type I hereditary tyrosinaemia (HT1) is a severe human inborn disease resulting from loss of fumaryl-acetoacetate hydrolase (Fah). Homozygous disruption of the gene encoding Fah in mice causes neonatal lethality, seriously limiting use of this animal as a model. We report here that fahA, the gene encoding Fah in the fungus Aspergillus nidulans, encodes a polypeptide showing 47.1% identity to its human homologue, fahA disruption results in secretion of succinylacetone (a diagnostic compound for human type I tyrosinaemia) and phenylalanine toxicity. We have isolated spontaneous suppressor mutations preventing this toxicity, presumably representing loss-of-function mutations in genes acting upstream of fahA in the phenylalanine catabolic pathway. Analysis of a class of these mutations demonstrates that loss of homogentisate dioxygenase (leading to alkaptonuria in humans) prevents the effects of a Fah deficiency. Our results strongly suggest human homogentisate dioxygenase as a target for HT1 therapy and illustrate the usefulness of this fungus as an alternative to animal models for certain aspects of human metabolic diseases.
AuthorsJ M Fernández-Cañón, M A Peñalva
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 92 Issue 20 Pg. 9132-6 (Sep 26 1995) ISSN: 0027-8424 [Print] United States
PMID7568087 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Heptanoates
  • Tyrosine
  • Phenylalanine
  • succinylacetone
  • Oxygenases
  • Dioxygenases
  • Homogentisate 1,2-Dioxygenase
  • Hydrolases
  • fumarylacetoacetase
Topics
  • Amino Acid Metabolism, Inborn Errors (genetics)
  • Amino Acid Sequence
  • Aspergillus nidulans (genetics, metabolism)
  • Chromatography, High Pressure Liquid
  • Dioxygenases
  • Enzyme Inhibitors (analysis)
  • Gas Chromatography-Mass Spectrometry
  • Genes, Fungal
  • Heptanoates (analysis, metabolism)
  • Homogentisate 1,2-Dioxygenase
  • Humans
  • Hydrolases (biosynthesis, genetics)
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Open Reading Frames
  • Oxygenases (analysis, genetics, metabolism)
  • Phenylalanine (metabolism)
  • Restriction Mapping
  • Sequence Homology, Amino Acid
  • Tyrosine (metabolism)

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