PAH (gene)
From Wikipedia, the free encyclopedia
phenylalanine hydroxylase
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Identifiers | |
Symbol | PAH |
HUGO | 8582 |
Entrez | 5053 |
OMIM | 261600 |
RefSeq | NM_000277 |
UniProt | P00439 |
Other data | |
EC number | 1.14.16.1 |
Locus | Chr. 12 q22-q24.2 |
PAH (phenylalanine hydroxylase) is a human gene that provides instructions for making an enzyme called phenylalanine hydroxylase. Phenylalanine hydroxylase is responsible for the first step in processing the amino acid phenylalanine, which is a building block of proteins. Phenylalanine is obtained through the diet, including some artificial sweeteners. Phenylalanine hydroxylase is responsible for the conversion of phenylalanine to another amino acid, tyrosine. Tyrosine is necessary for the production of certain hormones, chemicals that transmit signals in the brain (neurotransmitters), and a pigment (melanin) that gives hair and skin their color. Phenylalanine hydroxylase must work together with a substance called tetrahydrobiopterin (BH4), to function properly.
The PAH gene is located on the long (q) arm of chromosome 12 between positions 22 and 24.2, from base pair 101,734,570 to base pair 101,813,847.
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[edit] Related conditions
Phenylketonuria (PKU) is caused by mutations in the PAH gene. More than 450 mutations in the PAH gene have been identified in people with phenylketonuria. Although no single mutation accounts for all cases of PKU, some mutations are more common than others. Most of the known mutations cause a switch in a single amino acid in the phenylalanine hydroxylase enzyme. The most common mutation is a replacement of the amino acid arginine by the amino acid tryptophan at position 408 in the enzyme (written as Arg408Trp or R408W).
PAH mutations reduce the activity of phenylalanine hydroxylase, which allows phenylalanine to build up to toxic levels in the bloodstream and other tissues. Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent. As a result, people with untreated classic PKU have very high levels of phenylalanine that cause brain damage. Mutations in the PAH gene that allow some enzyme activity cause mild or moderate forms of PKU.
[edit] See also
[edit] References
- Blau N, Erlandsen H (2004). "The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency". Mol Genet Metab 82 (2): 101-11. PMID 15171997.
- Erlandsen H, Patch MG, Gamez A, Straub M, Stevens RC (2003). "Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria". Pediatrics 112 (6 Pt 2): 1557-65. PMID 14654665.
- Erlandsen H, Stevens RC (1999). "The structural basis of phenylketonuria". Mol Genet Metab 68 (2): 103-25. PMID 10527663.
- Guttler F, Azen C, Guldberg P, Romstad A, Hanley WB, Levy HL, Matalon R, Rouse BM, Trefz F, de la Cruz F, Koch R (2003). "Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome". Pediatrics 112 (6 Pt 2): 1530-3. PMID 14654659.
- Kim W, Erlandsen H, Surendran S, Stevens RC, Gamez A, Michols-Matalon K, Tyring SK, Matalon R (2004). "Trends in enzyme therapy for phenylketonuria". Mol Ther 10 (2): 220-4. PMID 15294168.
- Pey AL, Desviat LR, Gamez A, Ugarte M, Perez B (2003). "Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH". Hum Mutat 21 (4): 370-8. PMID 12655546.
- Steinfeld R, Kohlschutter A, Ullrich K, Lukacs Z (2003). "A hypothesis on the biochemical mechanism of BH(4)-responsiveness in phenylalanine hydroxylase deficiency". Amino Acids 25 (1): 63-8. PMID 12836060.
- Thony B, Auerbach G, Blau N (2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions". Biochem J 347 Pt 1: 1-16. PMID 10727395.
- Thony B, Ding Z, Martinez A (2004). "Tetrahydrobiopterin protects phenylalanine hydroxylase activity in vivo: implications for tetrahydrobiopterin-responsive hyperphenylalaninemia". FEBS Lett 577 (3): 507-11. PMID 15556637.
- Waters PJ (2003). "How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression". Hum Mutat 21 (4): 357-69. PMID 12655545.