| FAH | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | FAH , Fumarylacetoacetase, fumarylacetoacetate hydrolase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613871; MGI: 95482; HomoloGene: 110; GeneCards: FAH; OMA:FAH - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Fumarylacetoacetase is an enzyme that in humans is encoded by the FAH gene located on chromosome 15. The enzyme is involved in the catabolism of the amino acid tyrosine in humans. [5] [6] [7]
Fumarylacetoacetate hydrolase (FAH) is a protein homodimer which cleaves fumarylacetoacetate at its carbon-carbon bond during a hydrolysis reaction. [8] As a critical enzyme in phenylalanine and tyrosine metabolism, 4-Fumarylacetoacetate hydrolase catalyzes the final step in the catabolism of 4-fumarylacetoacetate and water into acetoacetate, fumarate, and H+ respectively. [9] These hydrolytic reactions are essential during aromatic amino acid human metabolism. Furthermore, FAH does not share known protein sequence homologs with other nucleotides or amino acids. [8]
The active site of FAH contains Ca2+ which acts to bind the substrate and a Glu-His-Water catalytic triad functions where the imidaxole ring of His133 activates a nucleophilic water molecule to attack the carbon-carbon bond of fumarylactoacetate thus forming fumarate and acetoacetate. [11] Similar to Phenylalanine-associated pathways, the reaction molecular basis is critical in mammalian metabolism, as evidenced by the observed liver enzyme activity in FAH deficiency during hereditary tyrosinemia type 1. [12] [13] In humans, this enzyme is mainly expressed in the liver. FAH is among the amino acid hydroxylases. [10] Tyrosine aminotransferase (TAT), 4-hydroxyphenylpyruvate dioxygenase (HPD), homogentisate 1,2-dioxygenase (HGD), phenylalanine-4-hydroxylase (PAH), maleylacetoacetate isomerase (GSTZ1), and other amino acid catabolic hydroxylases are coupled in the biological process of hydroxylases as well. [7] [14] The FAH subpathway constitutes a part of the main amino-acid L-phenylalanine degradation. [10] For ingested phenylalanine, turnover for FAH protein synthesis is directly linked to treatment based methodology.
The activity of human liver fumarylacetoacetate fumarylhydrolase has been determined with fumarylacetoacetate as the substrate. [15] As an inborn error of metabolism, Tyrosinemia type I stems from a deficiency in the enzymatic catabolic pathway of fumarylacetoacetate hydrolase (FAH). Currently, the mutations reported include silent mutations, amino acid replacements within single base substitutions, nonsense codons, and splicing defects. [15] [16] [17] Mutations spread across the FAH gene observes clusters of amino acid residues such as alanine and aspartic acid residues. [15] Hereditary tyrosinemia type 1 is a metabolic disorder with an autosomal recessive mode of inheritance. The disease is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in the degradation pathway of tyrosine. Hereditary tyrosinemia type 1 manifests in either an acute or a chronic form. [18] [14] However, symptoms may appear in heterozygote mutations in the FAH gene as documented in case of a 12‐year‐old American boy with chronic tyrosinemia type 1. [19] Specifically, maternal alleles for codon 234 exhibit this mutation which changes a tryptophan to a glycine. This possibly suggests HT1 missense mutations also inhibiting enzymatic activity. [18] This is also attributed to observed clustering between amino acid residue active sites 230 and 250 among hundreds of other mutations in the FAH gene. [17] Currently, FAH gene correlation with HT1 does not associate clinical phenotype with genotype. [18] [15] [16]
Possible disease symptom is the development of Hereditary tyrosinemia type 1 (HT1). [15] Caused by the lack of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway, HT 1 is inherited as a rare autosomal recessive disease with a prevalence in Europe of 1 : 50000. [15] [18] However, in isolated parts of Quebec's provinces, the frequency can be as high as 1 : 2000 with a carrier rate of 1:20 possibly due to a single founder mutation. [5] [17] FAH deficiency leads to an accumulation of alkylafing metabolites that cause damage to the liver. The disorder presents as an acute, chronic or intermediate mild phenotype. The acute form manifests itself within the first half year and is characterized by liver failure, renal damage, and possibly death in the first year of life. [20] The chronic form has an age of onset of more than one year after birth; [21] rickets and progressive liver disease often lead to the development of hepatocellular carcinoma. [18] Other symptoms can include renal tubular injury, hepatic necrosis, episodic weakness, seizures. Renal Fanconi syndrome and Porphyric crises are also cited in addition to liver and renal damage. [18]
Currently, there is no cure for tyrosinemia type 1. Diagnosed individuals need special dietary restriction all throughout life for the amino acids, phenylalanine and tyrosine. [22] [23] Affected individuals may also be treated with a FDA-approved medication called nitisinone. Recommended treatment should begin as early as possible when the condition is diagnosed. Bacterial inhibition assay, such as the Guthrie Test, can screen newborns [21] for FAH deficiency in addition to increased phenylalanine levels. [23] [24] Other diagnostic methods include measurements with tandem mass spectrometry fragmentation. Some individuals require a liver transplant if liver disease progresses into advanced development before dietary treatment begins.
A complete FAH genotype has been previously established. [10] All possible bands show two deleterious mutations. The effect of these mutations for the majority of the abnormalities on the FAH mRNA have been analysed. The identification of the gene defects on both alleles enables an initial genotype-phenotype analysis for chronic, subacute and acute HT 1 patients. The FAH gene is located on the chromosome 15q25.1 region and contains 14 exons. It encodes a protein that is 46kDa in height. [8] Multiple isoforms of the protein have been discovered that arose from alternative splicing. The gene is mainly expressed in the liver and the kidney.
Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.
Tyrosinemia or tyrosinaemia is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms of untreated tyrosinemia include liver and kidney disturbances. Without treatment, tyrosinemia leads to liver failure. Today, tyrosinemia is increasingly detected on newborn screening tests before any symptoms appear. With early and lifelong management involving a low-protein diet, special protein formula, and sometimes medication, people with tyrosinemia develop normally, are healthy, and live normal lives.
A synonymous substitution is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair codon; since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing polypeptide chain when the gene is translated. Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations; however, it is not always the case that the mutation is silent.
β-Glucuronidases are members of the glycosidase family of enzymes that catalyze breakdown of complex carbohydrates. Human β-glucuronidase is a type of glucuronidase that catalyzes hydrolysis of β-D-glucuronic acid residues from the non-reducing end of mucopolysaccharides such as heparan sulfate. Human β-glucuronidase is located in the lysosome. In the gut, brush border β-glucuronidase converts conjugated bilirubin to the unconjugated form for reabsorption. β-Glucuronidase is also present in breast milk, which contributes to neonatal jaundice. The protein is encoded by the GUSB gene in humans and by the uidA gene in bacteria.
Boron, Walter F.; Boulpaep, Emile L., eds. (2017). Medical Physiology (3rd ed.). Philadelphia, PA: Elsevier. ISBN 978-1-4557-4377-3.
Adenine phosphoribosyltransferase (APRTase) is an enzyme encoded by the APRT gene, found in humans on chromosome 16. It is part of the Type I PRTase family and is involved in the nucleotide salvage pathway, which provides an alternative to nucleotide biosynthesis de novo in humans and most other animals. In parasitic protozoa such as giardia, APRTase provides the sole mechanism by which AMP can be produced. APRTase deficiency contributes to the formation of kidney stones (urolithiasis) and to potential kidney failure.
4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase, is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxyphenylpyruvate into homogentisate. HPPD also catalyzes the conversion of phenylpyruvate to 2-hydroxyphenylacetate and the conversion of α-ketoisocaproate to β-hydroxy β-methylbutyrate. HPPD is an enzyme that is found in nearly all aerobic forms of life.
Hawkinsinuria is an autosomal dominant metabolic disorder affecting the metabolism of tyrosine.
Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1).
Tyrosine aminotransferase is an enzyme present in the liver and catalyzes the conversion of tyrosine to 4-hydroxyphenylpyruvate.
NADH-cytochrome b5 reductase 3 is an enzyme that in humans is encoded by the CYB5R3 gene.
In enzymology, maleylacetoacetate isomerase is an enzyme that catalyzes the chemical reaction
Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.
In enzymology, an aminoacylase (EC 3.5.1.14) is an enzyme that catalyzes the chemical reaction
Pterin-4-alpha-carbinolamine dehydratase is an enzyme that in humans is encoded by the PCBD1 gene.
Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene. The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex, which is involved in the regulation of cytochrome c oxidase assembly. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).
Pyruvate kinase PKLR is an enzyme that in humans is encoded by the PKLR gene.
Phenylalanyl-tRNA synthetase, mitochondrial (FARS2) is an enzyme that in humans is encoded by the FARS2 gene. This protein encoded by FARS2 localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 14, also known as Alpers encephalopathy, as well as spastic paraplegia 77 and infantile-onset epilepsy and cytochrome c oxidase deficiency.
Glycogen phosphorylase, liver form (PYGL), also known as human liver glycogen phosphorylase (HLGP), is an enzyme that in humans is encoded by the PYGL gene on chromosome 14. This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 14. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Feb 2011].
Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe. If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.
