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.
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Authors | J M Fernández-Cañón, M A Peñalva |
Journal | Proceedings 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 |
PMID | 7568087
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Heptanoates
- Tyrosine
- Phenylalanine
- succinylacetone
- Oxygenases
- Dioxygenases
- Homogentisate 1,2-Dioxygenase
- Hydrolases
- fumarylacetoacetase
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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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