title: 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.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Fernández-Cañón
authors.forename: M A
authors.initials: MA
authors.lastname: Peñalva
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D000595:Amino Acid Sequence; D001233:Aspergillus nidulans / Q000235:genetics* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D049308:Dioxygenases; D004791:Enzyme Inhibitors / Q000032:analysis; D008401:Gas Chromatography-Mass Spectrometry; D005800:Genes, Fungal; D006537:Heptanoates / Q000032:analysis / Q000378:metabolism; D050560:Homogentisate 1,2-Dioxygenase; D006801:Humans; D006867:Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010105:Oxygenases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D006537:Heptanoates; D014443:Tyrosine; D010649:Phenylalanine; C020804:succinylacetone; D010105:Oxygenases; D049308:Dioxygenases; D050560:Homogentisate 1,2-Dioxygenase; D006867:Hydrolases; C020156:fumarylacetoacetase