Fumarylacetoacetate hydrolase

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FAH
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FAH, Fumarylacetoacetase
External IDs MGI: 95482 HomoloGene: 110 GeneCards: 2184
RNA expression pattern
PBB GE FAH 202862 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000137

NM_010176

RefSeq (protein)

NP_000128.1

NP_034306.2

Location (UCSC) Chr 15: 80.15 – 80.19 Mb Chr 7: 84.59 – 84.61 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Fumarylacetoacetase is an enzyme that in humans is encoded by the FAH gene located on chromosome 15. The FAH gene is thought to be involved in the catabolism of the amino acid phenylalanine in human.[1][2][3]

Structure[edit]

The FAH gene is located on the chromosome 15q25.1 region and contains 14 exons. It encodes a protein that is 46kDa in size. Multiple isoforms of the protein have been discovered that arose from alternative splicing. The gene is mainly expressed in the liver and the kidney.

Function[edit]

The fumarylacetoacetate hydrolase enzyme catalyzes the hydrolysis of 4-fumarylacetoacetate into fumarate and acetoacetate. This gene encodes the last enzyme in the subpathway that synthesizes acetoacetate and fumarate from L-phenylalanine, which is part of a subpathway involved in phenylalanine degradation, part of the overall biochemical process of amino acid degradation. Other proteins that are involved in the phenylalanine degradation subpathway include phenylalanine-4-hydroxylase (PAH), tyrosine aminotransferase (TAT), 4-hydroxyphenylpyruvate dioxygenase (HPD), homogentisate 1,2-dioxygenase (HGD), maleylacetoacetate isomerase (GSTZ1), fumarylacetoacetase (FAH)

The protein has a number of conserved co-factor binding sites and probably requires Mg2+ and Ca2+ to function.

Clinical Significance[edit]

Mutations in the FAH gene cause type I tyrosinemia,[4][5] an inborn error of metabolism that is characterized by increased tyrosine levels in the blood and urine of patients.[6]

Patients usually develop features including hepatic necrosis and renal tubular injury due to toxic accumulation of tyrosine and phenylalanine and may be treated by tyrosine and phenylalanine dietary restriction and liver transplantation. The disease is also known to cause hypertrophic cardiomyopathy in affected children.[7]

References[edit]

  1. ^ Phaneuf D, Labelle Y, Bérubé D, Arden K, Cavenee W, Gagné R, Tanguay RM (Apr 1991). "Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15". Am J Hum Genet 48 (3): 525–35. PMC 1682993. PMID 1998338. 
  2. ^ Agsteribbe E, van Faassen H, Hartog MV, Reversma T, Taanman JW, Pannekoek H, Evers RF, Welling GM, Berger R (Jun 1990). "Nucleotide sequence of cDNA encoding human fumarylacetoacetase". Nucleic Acids Res 18 (7): 1887. doi:10.1093/nar/18.7.1887. PMC 330610. PMID 2336361. 
  3. ^ "Entrez Gene: FAH fumarylacetoacetate hydrolase (fumarylacetoacetase)". 
  4. ^ Phaneuf D, Lambert M, Laframboise R, Mitchell G, Lettre F, Tanguay RM (1992). "Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient". J. Clin. Invest. 90 (4): 1185–92. doi:10.1172/JCI115979. PMC 443158. PMID 1401056. 
  5. ^ Labelle Y, Phaneuf D, Leclerc B, Tanguay RM (1993). "Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity". Hum. Mol. Genet. 2 (7): 941–6. doi:10.1093/hmg/2.7.941. PMID 8364576. 
  6. ^ http://www.omim.org/entry/276700
  7. ^ Mohamed S, Kambal MA, Al Jurayyan NA, Al-Nemri A, Babiker A, Hasanato R, Al-Jarallah AS (2013). "Tyrosinemia type 1: a rare and forgotten cause of reversible hypertrophic cardiomyopathy in infancy". BMC Res Notes 6: 362. doi:10.1186/1756-0500-6-362. PMC 3846631. PMID 24016420. 

Further reading[edit]

External links[edit]