Phenylalanine Hydroxylase Function
Published by Anonymous on 2007/9/29 (3543 reads)
1: Hum Mutat. 1998;11(1):4-17.
In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function.
Waters PJ, Parniak MA, Nowacki P, Scriver CR.
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Mutations in the human phenylalanine hydroxylase gene (PAH) altering the expressed cDNA nucleotide sequence (GenBank U49897) can impair activity of the corresponding enzyme product (hepatic phenylalanine hydroxylase, PAH) and cause hyperphenylalaninemia (HPA), a metabolic phenotype for which the major disease form is phenylketonuria (PKU; OMIM 261600). In vitro expression analysis of inherited human mutations in eukaryotic, prokaryotic, and cell-free systems is informative about the mechanisms of mutation effects on enzymatic activity and their predicted effect on the metabolic phenotype. Corresponding analysis of site-directed mutations in rat Pah cDNA has assigned critical functional roles to individual amino acid residues within the best understood species of phenylalanine hydroxylase. Data on in vitro expression of 35 inherited human mutations and 22 created rat mutations are reviewed here. The core data are accessible at the PAH Mutation Analysis Consortium Web site (http://www.mcgill.ca/pahdb).
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9450897 [PubMed - indexed for MEDLINE]
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2: Acta Paediatr Suppl. 1994 Dec;407:86-8.
Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.
Lou HC.
John F Kennedy Institute, Glostrup, Denmark.
Phenylalanine and tyrosine constitute the two initial steps in the biosynthesis of dopamine, which, in its turn, is the metabolic precursor of noradrenaline and adrenaline. The extracellular phenylalanine concentration influences brain function in phenylalanine deficiency (PHD) by decreased dopamine synthesis. It has been shown to induce EEG slowing, and prolonged the performance time on neuropsychological tests. The tyrosine concentration in the CNS is reduced in PHD, possibly implying insufficient substrate (= tyrosine) for catecholamine synthesis due to competition inhibition, for instance across the blood brain barrier. In experimental studies it has been shown that the synthesis and release of dopamine can be influenced by an increase in the availability of tyrosine. In PHD an extra dietary intake of three doses of tyrosine (160 mg/kg/24h) induced a shortening of reaction time and decreased variability, and in a double-blind crossover study a similar dose has been reported to induce an improvement on psychological tests. In a study with lower doses of tyrosine (110 mg/kg/24 h) no effect was found on reaction time tests. These findings need to be substantiated, and more detailed information should be obtained.
Publication Types:
Review
PMID: 7766968 [PubMed - indexed for MEDLINE]
In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function.
Waters PJ, Parniak MA, Nowacki P, Scriver CR.
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Mutations in the human phenylalanine hydroxylase gene (PAH) altering the expressed cDNA nucleotide sequence (GenBank U49897) can impair activity of the corresponding enzyme product (hepatic phenylalanine hydroxylase, PAH) and cause hyperphenylalaninemia (HPA), a metabolic phenotype for which the major disease form is phenylketonuria (PKU; OMIM 261600). In vitro expression analysis of inherited human mutations in eukaryotic, prokaryotic, and cell-free systems is informative about the mechanisms of mutation effects on enzymatic activity and their predicted effect on the metabolic phenotype. Corresponding analysis of site-directed mutations in rat Pah cDNA has assigned critical functional roles to individual amino acid residues within the best understood species of phenylalanine hydroxylase. Data on in vitro expression of 35 inherited human mutations and 22 created rat mutations are reviewed here. The core data are accessible at the PAH Mutation Analysis Consortium Web site (http://www.mcgill.ca/pahdb).
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9450897 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Acta Paediatr Suppl. 1994 Dec;407:86-8.
Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.
Lou HC.
John F Kennedy Institute, Glostrup, Denmark.
Phenylalanine and tyrosine constitute the two initial steps in the biosynthesis of dopamine, which, in its turn, is the metabolic precursor of noradrenaline and adrenaline. The extracellular phenylalanine concentration influences brain function in phenylalanine deficiency (PHD) by decreased dopamine synthesis. It has been shown to induce EEG slowing, and prolonged the performance time on neuropsychological tests. The tyrosine concentration in the CNS is reduced in PHD, possibly implying insufficient substrate (= tyrosine) for catecholamine synthesis due to competition inhibition, for instance across the blood brain barrier. In experimental studies it has been shown that the synthesis and release of dopamine can be influenced by an increase in the availability of tyrosine. In PHD an extra dietary intake of three doses of tyrosine (160 mg/kg/24h) induced a shortening of reaction time and decreased variability, and in a double-blind crossover study a similar dose has been reported to induce an improvement on psychological tests. In a study with lower doses of tyrosine (110 mg/kg/24 h) no effect was found on reaction time tests. These findings need to be substantiated, and more detailed information should be obtained.
Publication Types:
Review
PMID: 7766968 [PubMed - indexed for MEDLINE]
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Phenylalanine Hydroxylase Structure
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