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Gene Review

Pah  -  phenylalanine hydroxylase

Rattus norvegicus

Synonyms: PAH, Phe-4-monooxygenase, Phenylalanine-4-hydroxylase
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Disease relevance of Pah


Psychiatry related information on Pah

  • Hyperphenylalaninemia, which can cause neurological disorders and mental retardation, results from a mutation in phenylalanine hydroxylase or an enzyme required for biosynthesis or regeneration of its cofactor, tetrahydrobiopterin [6].

High impact information on Pah

  • Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase, EC [7].
  • To define the molecular basis of PKU, we characterized twelve restriction fragment-length polymorphism (RFLP) haplotypes of the PAH locus in the northern European population and observed that 90% of the PKU alleles in this population are confined to four common RFLP haplotypes [7].
  • We have recently reported a splicing mutation in the PAH gene that is associated with RFLP haplotype 3 which is present at about 40% of mutant alleles [7].
  • This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH [7].
  • Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes [7].

Chemical compound and disease context of Pah


Biological context of Pah


Anatomical context of Pah


Associations of Pah with chemical compounds


Regulatory relationships of Pah


Other interactions of Pah


Analytical, diagnostic and therapeutic context of Pah


  1. Isolation and sequence of a cDNA clone which contains the complete coding region of rat phenylalanine hydroxylase. Structural homology with tyrosine hydroxylase, glucocorticoid regulation, and use of alternate polyadenylation sites. Dahl, H.H., Mercer, J.F. J. Biol. Chem. (1986) [Pubmed]
  2. Sequence comparison of rat liver phenylalanine hydroxylase and its cDNA clones. Robson, K.J., Beattie, W., James, R.J., Cotton, R.C., Morgan, F.J., Woo, S.L. Biochemistry (1984) [Pubmed]
  3. Crystal structure of DCoH, a bifunctional, protein-binding transcriptional coactivator. Endrizzi, J.A., Cronk, J.D., Wang, W., Crabtree, G.R., Alber, T. Science (1995) [Pubmed]
  4. Epigenetic activation of phenylalanine hydroxylase in mouse erythroleukemia cells by the cytoplast of rat hepatoma cells. Gopalakrishnan, T.V., Anderson, W.F. Proc. Natl. Acad. Sci. U.S.A. (1979) [Pubmed]
  5. Cloning and expression of Chromobacterium violaceum phenylalanine hydroxylase in Escherichia coli and comparison of amino acid sequence with mammalian aromatic amino acid hydroxylases. Onishi, A., Liotta, L.J., Benkovic, S.J. J. Biol. Chem. (1991) [Pubmed]
  6. Hyperphenylalaninemia and 7-pterin excretion associated with mutations in 4a-hydroxy-tetrahydrobiopterin dehydratase/DCoH: analysis of enzyme activity in intestinal biopsies. Ayling, J.E., Bailey, S.W., Boerth, S.R., Giugliani, R., Braegger, C.P., Thöny, B., Blau, N. Mol. Genet. Metab. (2000) [Pubmed]
  7. An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. DiLella, A.G., Marvit, J., Brayton, K., Woo, S.L. Nature (1987) [Pubmed]
  8. Mechanism of inactivation of phenylalanine hydroxylase by p-chlorophenylalanine in hepatome cells in culture. Two possible models. Miller, M.R., McClure, D., Shiman, R. J. Biol. Chem. (1976) [Pubmed]
  9. Measurement of phenylalanine hydroxylase turnover in cultured hepatoma cells. Baker, R.E., Shiman, R. J. Biol. Chem. (1979) [Pubmed]
  10. Structural basis of autoregulation of phenylalanine hydroxylase. Kobe, B., Jennings, I.G., House, C.M., Michell, B.J., Goodwill, K.E., Santarsiero, B.D., Stevens, R.C., Cotton, R.G., Kemp, B.E. Nat. Struct. Biol. (1999) [Pubmed]
  11. Amino acid sequence at the phosphorylated site of rat liver phenylalanine hydroxylase and phosphorylation of a corresponding synthetic peptide. Wretborn, M., Humble, E., Ragnarsson, U., Engström, L. Biochem. Biophys. Res. Commun. (1980) [Pubmed]
  12. Polysome immunoprecipitation of phenylalanine hydroxylase mRNA from rat liver and cloning of its cDNA. Robson, K.J., Chandra, T., MacGillivray, R.T., Woo, S.L. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  13. Full-length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases. Grenett, H.E., Ledley, F.D., Reed, L.L., Woo, S.L. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  14. Expression of rat liver phenylalanine hydroxylase in insect cells and site-directed mutagenesis of putative non-heme iron-binding sites. Gibbs, B.S., Wojchowski, D., Benkovic, S.J. J. Biol. Chem. (1993) [Pubmed]
  15. Studies on the phenylalanine hydroxylase system in vivo. An in vivo assay based on the liberation of deuterium or tritium into the body water from ring-labeled L-phenylalanine. Milstien, S., Kaufman, S. J. Biol. Chem. (1975) [Pubmed]
  16. The two molecular weight forms of rat phenylalanine hydroxylase are encoded by different messenger RNAs. Mercer, J.F., Hunt, S.M., Cotton, R.G. J. Biol. Chem. (1983) [Pubmed]
  17. Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity. Harada, T., Kagamiyama, H., Hatakeyama, K. Science (1993) [Pubmed]
  18. Alpha-methylphenylalanine, a new inducer of chronic hyperphenylalaninemia in sucling rats. Greengard, O., Yoss, M.S., Del Valle, J.A. Science (1976) [Pubmed]
  19. Immunocytochemical identification of phenylalanine hydroxylase and albumin in cultured hepatoma cells and isolated rat hepatocytes. Baker, R.E., Jefferson, L.S., Shiman, R. J. Cell Biol. (1981) [Pubmed]
  20. The role of insulin in the modulation of glucagon-dependent control of phenylalanine hydroxylation in isolated liver cells. Fisher, M.J., Dickson, A.J., Pogson, C.I. Biochem. J. (1987) [Pubmed]
  21. A flexible loop in tyrosine hydroxylase controls coupling of amino acid hydroxylation to tetrahydropterin oxidation. Daubner, S.C., McGinnis, J.T., Gardner, M., Kroboth, S.L., Morris, A.R., Fitzpatrick, P.F. J. Mol. Biol. (2006) [Pubmed]
  22. Studies on the interaction of a thiol-dependent hydrogen peroxide scavenging enzyme and phenylalanine hydroxylase. Milstien, S., Dorche, C., Kaufman, S. Arch. Biochem. Biophys. (1990) [Pubmed]
  23. Hepatoma variants (C2) are defective for transcriptional and post-transcriptional actions from both endogenous and viral genomes. Friedman, J.M., Babiss, L.E., Weiss, M., Darnell, J.E. EMBO J. (1987) [Pubmed]
  24. Sequence analysis of the rat phenylalanine hydroxylase gene promoter. Rees, D., Fisher, M.J., McDowall, I.L. DNA Seq. (2001) [Pubmed]
  25. Identity of 4a-carbinolamine dehydratase, a component of the phenylalanine hydroxylation system, and DCoH, a transregulator of homeodomain proteins. Citron, B.A., Davis, M.D., Milstien, S., Gutierrez, J., Mendel, D.B., Crabtree, G.R., Kaufman, S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  26. Proteolytic modification of the amino-terminal and carboxyl-terminal regions of rat hepatic phenylalanine hydroxylase. Iwaki, M., Phillips, R.S., Kaufman, S. J. Biol. Chem. (1986) [Pubmed]
  27. Delineation of the catalytic core of phenylalanine hydroxylase and identification of glutamate 286 as a critical residue for pterin function. Dickson, P.W., Jennings, I.G., Cotton, R.G. J. Biol. Chem. (1994) [Pubmed]
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