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Gene Review

Pah  -  phenylalanine hydroxylase

Mus musculus

Synonyms: AW106920, PAH, Phe-4-monooxygenase, Phenylalanine-4-hydroxylase
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Disease relevance of Pah

  • A recombinant adeno-associated virus (rAAV) vector containing the murine Pah-cDNA was generated, pseudotyped with capsids from AAV serotype 8, and delivered into the liver of PKU mice via single intraportal or tail vein injections [1].
  • Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) which leads to high blood phenylalanine (Phe) levels and consequent damage of the developing brain with severe mental retardation if left untreated in early infancy [1].
  • In treated mice, PAH enzyme activity in whole liver extracts reversed to normal and neither hepatic toxicity nor immunogenicity was observed [1].
  • We have demonstrated the cognitive outcome of biochemical and phenotypic reversal by the adeno-associated virus vector-mediated gene delivery of a human PAH transgene [2].
  • Using this phage integration system, we delivered mouse phenylalanine hydroxylase cDNA to the livers of PKU mice by hydrodynamic injection of plasmid DNA and showed that the severity of the hyperphenylalaninemic phenotype in the treated mice decreased significantly [3].

High impact information on Pah


Chemical compound and disease context of Pah


Biological context of Pah


Anatomical context of Pah


Associations of Pah with chemical compounds

  • In contrast, a lentiviral vector expressing the murine Pah-cDNA, delivered via intraportal vein injection into PKU mice, did not result in therapeutic levels of blood Phe [1].
  • The Pah enzyme activities of the various models correlate inversely with the corresponding phenylalanine levels in plasma and brain and the delay in plasma clearance response following a phenylalanine challenge [12].
  • These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH [15].
  • Our findings thus contribute to the understanding of the regulation of PAH by its cofactor BH4 on an additional level and provide a molecular explanation for cofactor-responsive PKU [8].
  • The loading regimen was also used to gauge the response of mutant hyperphenylalaninemic mice to exposure to chemical compounds required for normal phenylalanine catabolism (i.e. pteridine cofactors of the phenylalanine hydroxylase reaction) [17].

Regulatory relationships of Pah


Other interactions of Pah


Analytical, diagnostic and therapeutic context of Pah

  • The efficacy of bone-marrow-directed gene therapy as a metabolic sink in the treatment of phenylketonuria may be limited, although further experiments with greater marrow PAH expression levels will be necessary to definitively prove this conclusion [16].
  • Phenylalanine clearance may have been limited by the natural perfusion rate of the marrow compartment, by insufficient PAH expression in marrow, or by other cellular factors affecting phenylalanine metabolism in intact marrow cells [16].
  • Western blotting demonstrated that the lower monooxygenase activities resulted from a reduced absolute amount of tyrosine hydroxylase and phenylalanine hydroxylase protein [21].
  • In the present study, we developed a breath test for mice using [1-13C]phenylalanine in order to examine the BH4 responsiveness of normal PAH in vivo [23].
  • The persistent immunosuppression induced by the PAH carcinogen DMBA, including CTL and NK cell tumoricidal functions, may represent an important epigenetic mechanism contributing to tumor outgrowth or metastasis by this class of agents [24].


  1. Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. Ding, Z., Georgiev, P., Thöny, B. Gene Ther. (2006) [Pubmed]
  2. Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy. Oh, H.J., Lee, H., Park, J.W., Rhee, H., Koo, S.K., Kang, S., Jo, I., Jung, S.C. Mol. Genet. Metab. (2005) [Pubmed]
  3. Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA. Chen, L., Woo, S.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Identification of hepatic nuclear factor 1 binding sites in the 5' flanking region of the human phenylalanine hydroxylase gene: implication of a dual function of phenylalanine hydroxylase stimulator in the phenylalanine hydroxylation system. Lei, X.D., Kaufman, S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  5. Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes. Cristiano, R.J., Smith, L.C., Woo, S.L. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Pahhph-5: a mouse mutant deficient in phenylalanine hydroxylase. McDonald, J.D., Bode, V.C., Dove, W.F., Shedlovsky, A. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  7. Mouse models of human phenylketonuria. Shedlovsky, A., McDonald, J.D., Symula, D., Dove, W.F. Genetics (1993) [Pubmed]
  8. Tetrahydrobiopterin protects phenylalanine hydroxylase activity in vivo: implications for tetrahydrobiopterin-responsive hyperphenylalaninemia. Thöny, B., Ding, Z., Martínez, A. FEBS Lett. (2004) [Pubmed]
  9. RNA from rat hepatoma cells can activate phenylalanine hydroxylase gene of mouse erythroleukemia cells. Gopalakrishnan, T.V., Littlefield, J.W. Somatic Cell Genet. (1983) [Pubmed]
  10. BWTG3 hepatoma cells can acquire phenylalanine hydroxylase, cystathionine synthase and CPS-I without genetic manipulation, but activation of the silent OTC gene requires cell fusion with hepatocytes. Farmer, A.A., Goss, S.J. J. Cell. Sci. (1991) [Pubmed]
  11. P-chlorophenylalanine does not inhibit production of recombinant human phenylalanine hydroxylase in NIH3T3 cells or E. coli. Ledley, F.D., Woo, S.L. Biochem. Biophys. Res. Commun. (1987) [Pubmed]
  12. A heteroallelic mutant mouse model: A new orthologue for human hyperphenylalaninemia. Sarkissian, C.N., Boulais, D.M., McDonald, J.D., Scriver, C.R. Mol. Genet. Metab. (2000) [Pubmed]
  13. Manipulation of the phenylalanine metabolism in human keratinocytes by retroviral mediated gene transfer. Christensen, R., Kolvraa, S., Jensen, T.G. Cells Tissues Organs (Print) (2005) [Pubmed]
  14. The activity of the highly inducible mouse phenylalanine hydroxylase gene promoter is dependent upon a tissue-specific, hormone-inducible enhancer. Faust, D.M., Catherin, A.M., Barbaux, S., Belkadi, L., Imaizumi-Scherrer, T., Weiss, M.C. Mol. Cell. Biol. (1996) [Pubmed]
  15. Metabolic engineering as therapy for inborn errors of metabolism--development of mice with phenylalanine hydroxylase expression in muscle. Harding, C.O., Wild, K., Chang, D., Messing, A., Wolff, J.A. Gene Ther. (1998) [Pubmed]
  16. Expression of phenylalanine hydroxylase (PAH) in erythrogenic bone marrow does not correct hyperphenylalaninemia in Pah(enu2) mice. Harding, C.O., Neff, M., Jones, K., Wild, K., Wolff, J.A. The journal of gene medicine. (2003) [Pubmed]
  17. Hyperphenylalaninemia in the hph-1 mouse mutant. McDonald, J.D., Bode, V.C. Pediatr. Res. (1988) [Pubmed]
  18. Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria. Hamman, K., Clark, H., Montini, E., Al-Dhalimy, M., Grompe, M., Finegold, M., Harding, C.O. Mol. Ther. (2005) [Pubmed]
  19. Further studies on tryptophan hydroxylase from neoplastic murine mast cells. Hosoda, S. Biochim. Biophys. Acta (1975) [Pubmed]
  20. Characterization of transgenic mice with the expression of phenylalanine hydroxylase and GTP cyclohydrolase I in the skin. Christensen, R., Alhonen, L., Wahlfors, J., Jakobsen, M., Jensen, T.G. Exp. Dermatol. (2005) [Pubmed]
  21. Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse. Hyland, K., Gunasekera, R.S., Engle, T., Arnold, L.A. J. Neurochem. (1996) [Pubmed]
  22. Isolation and structural characterization of the murine tryptophan hydroxylase gene. Stoll, J., Goldman, D. J. Neurosci. Res. (1991) [Pubmed]
  23. Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Kure, S., Sato, K., Fujii, K., Aoki, Y., Suzuki, Y., Kato, S., Matsubara, Y. Mol. Genet. Metab. (2004) [Pubmed]
  24. Persistent suppression of humoral and cell-mediated immunity in mice following exposure to the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene. Ward, E.C., Murray, M.J., Lauer, L.D., House, R.V., Dean, J.H. Int. J. Immunopharmacol. (1986) [Pubmed]
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