Fungal metabolic model for human type I hereditary tyrosinaemia.

Fernández-Cañón, José M.; Peñalva, Miguel A.

doi:10.1073/pnas.92.20.9132

Cited by 54 publications

(70 citation statements)

References 19 publications

(27 reference statements)

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“…These findings are particularly important as they demonstrate the functional identity of the predicted homologs and order the genes in the degradation pathway at a genetic level. These results are also consistent with findings from fungal and mouse models where mutations in upstream genes are able to rescue the lethality associated with FAH mutations (14,44,49,50).…”

Section: Conservation Of the Tyrosine Degradation Pathway In Worms-supporting

confidence: 81%

“…The K10C2.4 Phenotype Is Dependent upon Tyrosine and the Tyrosine Degradation Pathway-Mice and fungi with mutations in downstream enzymes in the tyrosine degradation pathway have been shown to be sensitive to levels of dietary tyrosine (44,48). To test whether the observed phenotype is due to altered tyrosine metabolism, we examined the effects of supplemental tyrosine.…”

Section: K10c24 Encodes a Homolog Of Fumarylacetoacetatementioning

confidence: 99%

“…1) (41). We focused our analysis on the gene K10C2.4, which is predicted to encode the C. elegans homolog of FAH given the severe effects of mutations affecting this enzyme in people, rodents, and fungi (8,(42)(43)(44). Alignment of K10C2.4 with FAH genes from other species with ClustalW revealed 34.7% identity between K10C2.4 and the other genes (supplemental Fig.…”

Section: K10c24 Encodes a Homolog Of Fumarylacetoacetatementioning

confidence: 99%

“…4). Both mice and fungi with FAH mutations are rescued by mutations in the 4-hydroxyphenylpyruvate dioxygenase and homogentisate dioxygenase genes (14,44,49,50). We find that the phenotype is critically dependent on an intact tyrosine degradation pathway, because combining K10C2.4 RNAi with RNAi directed against F42D1.2, T21C12.2, or W06D4.1 is able to completely rescue treated worms from the effects of K10C2.4 RNAi (Fig.…”

Section: K10c24 Encodes a Homolog Of Fumarylacetoacetatementioning

confidence: 99%

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The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family

Fisher

Page

Lithgow

et al. 2008

Journal of Biological Chemistry

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In eukaryotes and many bacteria, tyrosine is degraded to produce energy via a five-step tyrosine degradation pathway. Mutations affecting the tyrosine degradation pathway are also of medical importance as mutations affecting enzymes in the pathway are responsible for type I, type II, and type III tyrosinemia. The most severe of these is type I tyrosinemia, which is caused by mutations affecting the last enzyme in the pathway, fumarylacetoacetate hydrolase (FAH). So far, tyrosine degradation in the nematode Caenorhabditis elegans has not been studied; however, genes predicted to encode enzymes in this pathway have been identified in several microarray, proteomic, and RNA interference (RNAi) screens as perhaps being involved in aging and the control of protein folding. We sought to identify and characterize the genes in the worm tyrosine degradation pathway as an initial step in understanding these findings. Here we describe the characterization of the K10C2.4, which encodes a homolog of FAH. RNAi directed against K10C2.4 produces a lethal phenotype consisting of death in young adulthood, extensive damage to the intestine, impaired fertility, and activation of oxidative stress and endoplasmic stress response pathways. This phenotype is due to alterations in tyrosine metabolism as increases in dietary tyrosine enhance it, and inhibition of upstream enzymes in tyrosine degradation with RNAi or genetic mutations reduces the phenotype. We also use our model to identify genes that suppress the damage produced by K10C2.4 RNAi in a pilot genetic screen. Our results establish worms as a model for the study of type I tyrosinemia.

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Section: Conservation Of the Tyrosine Degradation Pathway In Worms-supporting

confidence: 81%

Section: K10c24 Encodes a Homolog Of Fumarylacetoacetatementioning

confidence: 99%

Section: K10c24 Encodes a Homolog Of Fumarylacetoacetatementioning

confidence: 99%

Section: K10c24 Encodes a Homolog Of Fumarylacetoacetatementioning

confidence: 99%

See 2 more Smart Citations

The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family

Fisher

Page

Lithgow

et al. 2008

Journal of Biological Chemistry

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“…Tyrosine and phenylalanine are metabolized through a pathway involving p-hydroxyphenylpyruvate dioxygenase (HPD4 gene) (Fig. 5A) (41)(42)(43). Inhibitors of this pathway are known, and a block in this pathway leads to the generation of toxic intermediates (44).…”

Section: Resultsmentioning

confidence: 99%

Gene discovery and gene function assignment in filamentous fungi

Hamer

Adachi²,

Montenegro-Chamorro³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

101

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Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposonarrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens.A powerful asset for functional genomic analysis is the ability to create large annotated single gene mutant collections. For model research organisms such as baker's yeast, Drosophila, Caenorhabditis, Arabidopsis, and mice, whole genome knockout collections (1), transposon lines (2), or insertional mutant collections (3, 4) are well developed. However, in addition to these model organisms there is a vast array of economically important organisms where genome sequences and functional genomic technologies are lacking. For example, filamentous fungi are causal agents of severe human (5, 6) and crop (7, 8) diseases, and many others are being exploited in the fermentation and food industries (9). Few of these fungal genomes have been analyzed, and large-scale approaches to functional analysis are needed.The model fungus, Saccharomyces cerevisiae, has Ϸ6000 genes in 12 Mb of DNA sequence (10). Targeted integration (TI) for creating gene-specific mutations is very efficient and requires only 50-bp fragments of target gene homology on either side of a selectable marker (11,12). In contrast, many filamentous fungi have genome sizes in the range of 30-40 Mb and are estimated to contain at least 10,000 genes (13). Genome studies using expressed sequence tag analysis suggest that more than half of these genes lack homologues in S. cerevisiae (14). TI occurs at very low frequencies (1-20%) for many filamentous fungi, and larger fragments of target gene homology must be used to obtain targeted insertion events (15).To initiate genome-wide mutagenesis studies in filamentous fungi we developed an approach we call transposon-arrayed gene knockouts (TAGKO) (Fig. 1). In vitro transposition (IVT) (16-19) into cosmid libraries is used to create gene sequencing templates. Subsequent sequencing and analysis from these templates creates an annotated collection of insertional gene disruption vectors. We demonstrate that IVT can...

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Fungal metabolic model for human type I hereditary tyrosinaemia.

Cited by 54 publications

References 19 publications

The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family

The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family

Gene discovery and gene function assignment in filamentous fungi

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