Fumarylacetoacetate hydrolase

FAH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1HYO, 1QCN, 1QCO, 1QQJ, 2HZY
Identifiers
Aliases	FAH, Fumarylacetoacetase, fumarylacetoacetate hydrolase
External IDs	OMIM: 613871; MGI: 95482; HomoloGene: 110; GeneCards: FAH; OMA:FAH - orthologs
Gene location (Human) Chr. Chromosome 15 (human) Band 15q25.1 Start 80,152,490 bp End 80,186,946 bp
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7 D3|7 48.36 cM Start 84,234,367 bp End 84,255,930 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver right adrenal gland right adrenal cortex left adrenal cortex adipose tissue abdominal fat C1 segment subcutaneous adipose tissue stromal cell of endometrium human kidney Top expressed in left lobe of liver right kidney human kidney lactiferous gland gallbladder proximal tubule brown adipose tissue white adipose tissue corneal stroma subcutaneous adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function fumarylacetoacetase activity protein binding catalytic activity hydrolase activity metal ion binding Cellular component cytosol extracellular exosome Biological process aromatic amino acid family metabolic process metabolism L-phenylalanine catabolic process arginine catabolic process tyrosine catabolic process homogentisate catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2184 14085 Ensembl ENSG00000103876 ENSMUSG00000030630 UniProt P16930 P35505 RefSeq (mRNA) NM_000137 NM_001374377 NM_001374380 NM_010176 RefSeq (protein) NP_000128 NP_001361306 NP_001361309 NP_034306 Location (UCSC) Chr 15: 80.15 – 80.19 Mb Chr 7: 84.23 – 84.26 Mb PubMed search
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.

Structure

The FAH gene is located on the chromosome 15q25.1 region and contains 14 exons. It encodes a protein that is 46kDa in height. 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

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

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

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.

Further reading

• St-Louis M, Tanguay RM (1997). "Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview". Hum. Mutat. 9 (4): 291–9. doi:10.1002/(SICI)1098-1004(1997)9:4<291::AID-HUMU1>3.0.CO;2-9. PMID 9101289.
• 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.
• Tanguay RM, Valet JP, Lescault A, Duband JL, Laberge C, Lettre F, Plante M (1990). "Different molecular basis for fumarylacetoacetate hydrolase deficiency in the two clinical forms of hereditary tyrosinemia (type I)". Am. J. Hum. Genet. 47 (2): 308–16. PMC 1683717. PMID 2378356.
• Laberge C, Grenier A, Valet JP, Morissette J (1990). "Fumarylacetoacetase measurement as a mass-screening procedure for hereditary tyrosinemia type I". Am. J. Hum. Genet. 47 (2): 325–8. PMC 1683713. PMID 2378358.
• Kvittingen EA, Halvorsen S, Jellum E (1983). "Deficient fumarylacetoacetate fumarylhydrolase activity in lymphocytes and fibroblasts from patients with hereditary tyrosinemia". Pediatr. Res. 17 (7): 541–4. doi:10.1203/00006450-198307000-00005. PMID 6622096.
• Kvittingen EA, Jellum E, Stokke O (1982). "Assay of fumarylacetoacetate fumarylhydrolase in human liver-deficient activity in a case of hereditary tyrosinemia". Clin. Chim. Acta. 115 (3): 311–9. doi:10.1016/0009-8981(81)90244-8. PMID 7296877.
• Hahn SH, Krasnewich D, Brantly M, Kvittingen EA, Gahl WA (1995). "Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1". Hum. Mutat. 6 (1): 66–73. doi:10.1002/humu.1380060113. PMID 7550234.
• St-Louis M, Poudrier J, Phaneuf D, Leclerc B, Laframboise R, Tanguay RM (1995). "Two novel mutations involved in hereditary tyrosinemia type I". Hum. Mol. Genet. 4 (2): 319–20. doi:10.1093/hmg/4.2.319. PMID 7757089.
• Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T (1995). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
• Rootwelt H, Berger R, Gray G, Kelly DA, Coşkun T, Kvittingen EA (1994). "Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1". Am. J. Hum. Genet. 55 (4): 653–8. PMC 1918286. PMID 7942842.
• Rootwelt H, Brodtkorb E, Kvittingen EA (1994). "Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I". Am. J. Hum. Genet. 55 (6): 1122–7. PMC 1918441. PMID 7977370.
• Rootwelt H, Chou J, Gahl WA, Berger R, Coşkun T, Brodtkorb E, Kvittingen EA (1994). "Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase". Hum. Genet. 93 (6): 615–9. doi:10.1007/BF00201558. PMID 8005583.
• Grompe M, St-Louis M, Demers SI, al-Dhalimy M, Leclerc B, Tanguay RM (1994). "A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I". N. Engl. J. Med. 331 (6): 353–7. doi:10.1056/NEJM199408113310603. PMID 8028615.
• St-Louis M, Leclerc B, Laine J, Salo MK, Holmberg C, Tanguay RM (1994). "Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I". Hum. Mol. Genet. 3 (1): 69–72. doi:10.1093/hmg/3.1.69. PMID 8162054.
• Grompe M, al-Dhalimy M (1993). "Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I". Hum. Mutat. 2 (2): 85–93. doi:10.1002/humu.1380020205. PMID 8318997.
• 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.
• Labelle Y, Puymirat J, Tanguay RM (1993). "Localization of cells in the rat brain expressing fumarylacetoacetate hydrolase, the deficient enzyme in hereditary tyrosinemia type 1". Biochim. Biophys. Acta. 1180 (3): 250–6. doi:10.1016/0925-4439(93)90046-4. PMID 8422430.
• Ploos van Amstel JK, Bergman AJ, van Beurden EA, Roijers JF, Peelen T, van den Berg IE, Poll-The BT, Kvittingen EA, Berger R (1996). "Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship". Hum. Genet. 97 (1): 51–9. doi:10.1007/bf00218833. PMID 8557261.

External links

• GeneReviews/NIH/NCBI/UW entry on Tyrosinemia Type 1, FAH Deficiency, Hepatorenal Tyrosinemia, Hereditary Tyrosinemia Type I, Fumarylacetoacetase Deficiency, Fumarylacetoacetate Hydrolase Deficiency
• fumarylacetoacetase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)