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Gene Review

PAH  -  phenylalanine hydroxylase

Homo sapiens

Synonyms: PH, PKU, PKU1, Phe-4-monooxygenase, Phenylalanine-4-hydroxylase
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Disease relevance of PAH


Psychiatry related information on PAH

  • OBJECTIVES: In the search for chromosome 12 genes potentially involved in the pathogenesis of bipolar disorder we will screen Phenylalanine hydroxylase and human LIM-homeobox LHX5 genes for sequence variants, both of which have been suggested as candidate genes [6].
  • Phenylketonuria (PKU) is a classic 'monogenic' autosomal recessive disease in which mutation at the human PAH locus was deemed sufficient to explain the impaired function of the enzyme phenylalanine hydroxylase (enzymic phenotype), the attendant hyperphenylalaninemia (metabolic phenotype) and the resultant mental retardation (cognitive phenotype) [7].
  • The sources of the PAH burden in the lake are apportioned, and the implications of these results are discussed including likely response times to changes in loadings [8].
  • PAH exposure of road builders was actually not higher than that of policemen; the slight difference resulted from diverging life-styles [9].
  • Risk evaluation for human health was carried out using PCB and PAH concentrations measured in seven fish species from Lake Iseo (Italy) and comparing the experimental data with legal levels and the two new approaches proposed by the US FDA and the US EPA to protect local populations with different food habits [10].

High impact information on PAH


Chemical compound and disease context of PAH


Biological context of PAH

  • During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases [19].
  • The mode of coordination of Glu330 to the iron moiety seems to determine the amino acid substrate specificity in PAH and in the homologous enzyme tyrosine hydroxylase [20].
  • Using a common polymorphism within the gene, we found that this gene did not cause the discordant results and thus, did not modify the PAH phenotype [21].
  • The possibility that a modifying gene was linked to the PAH gene on chromosome 12 was investigated using markers closely linked to the gene; however, no evidence for a modifying gene close to the PAH gene was found [21].
  • Genetic evaluation of the family members of subjects with the PAH K274E mutation showed that all individuals with the K274E mutation also exhibited the PAH L321L polymorphism in the catalytic domain of the PAH enzyme [22].

Anatomical context of PAH


Associations of PAH with chemical compounds

  • The conformation and distances to the catalytic iron of both L-Phe and the cofactor analogue L-erythro-7,8-dihydrobiopterin (BH2) simultaneously bound to recombinant human PAH have been estimated by (1)H NMR [20].
  • Tyrosine-, tryptophan- and phenylalanine hydroxylase (TH, TPH and PAH, respectively) were transiently activated at low urea concentrations and rapidly inactivated in >3 M urea [28].
  • A mutation in the functionally critical tetrahydrobiopterin cofactor binding domain of the PAH gene had been identified in African-American patients with the diagnosis of schizophrenia, and biochemical analyses suggested that this mutation has physiological consequences related to amine neurotransmitter function [22].
  • Despite favorable energy scores, tyrosine in a position trans to PAH residue His290 or TH residue His336 interferes with the access of the essential cofactor dioxygen to the catalytic center, thereby blocking the enzymatic reaction [29].
  • Nevertheless, significant problems such as the substrate specificity of PAH and the different susceptibility of TH to feedback inhibition by l-3,4-dihydroxyphenylalanine (l-DOPA) compared with dopamine (DA) remain unresolved [29].

Regulatory relationships of PAH

  • Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1 [30].
  • These results are also consistent with the hypothesis that BP (PAH) induce G:C to T:A transversion mutations in the hotspot codons of the p53 tumor suppressor gene and are thus involved in malignant transformation of the lung tissue of smokers [31].
  • Mutagenicity of C24H14 PAH in human cells expressing CYP1A1 [32].
  • The AhR is a ligand-activated transcription factor that mediates immunosuppression by environmental PAH [33].

Other interactions of PAH


Analytical, diagnostic and therapeutic context of PAH

  • A clone encoding PAH was used for in vitro transcription/translation, followed by immunoprecipitation with sera from 94 APS I patients and 70 healthy controls [35].
  • Western-blot analysis of liver extracts showed that PH8 reacted with phenylalanine hydroxylase from a wide range of vertebrate species [36].
  • These results support the use of the human PAH probe in prenatal diagnosis and detection of carriers, to provide new opportunities for the biochemical characterization of normal and mutant enzymes, and in the investigation of alternative genetic therapies for PKU [37].
  • Sequence analysis of DNA from a single individual, homozygous for the new MspI associated haplotype, shows homozygosity for a C----T transition at nucleotide 896 in exon 7 of the PAH cDNA, resulting in the conversion of leucine 255 to serine (L255S) [38].
  • On this basis, single-site mutagenesis of key residues in these regions of the human PAH tetramer was performed in the present study, and their functional impact was measured by steady-state kinetics and the global conformational transition as assessed by surface plasmon resonance and intrinsic tryptophan fluorescence spectroscopy [39].


  1. Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes. Mallolas, J., Vilaseca, M.A., Pavia, C., Lambruschini, N., Cambra, F.J., Campistol, J., Gómez, D., Carrió, A., Estivill, X., Milà, M. J. Mol. Med. (2001) [Pubmed]
  2. Benzo[a]pyrene-induced DNA damage and p53 modulation in human hepatoma HepG2 cells for the identification of potential biomarkers for PAH monitoring and risk assessment. Park, S.Y., Lee, S.M., Ye, S.K., Yoon, S.H., Chung, M.H., Choi, J. Toxicol. Lett. (2006) [Pubmed]
  3. Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Gjetting, T., Petersen, M., Guldberg, P., Güttler, F. Am. J. Hum. Genet. (2001) [Pubmed]
  4. Sex differences in risk of lung cancer: Expression of genes in the PAH bioactivation pathway in relation to smoking and bulky DNA adducts. Mollerup, S., Berge, G., Baera, R., Skaug, V., Hewer, A., Phillips, D.H., Stangeland, L., Haugen, A. Int. J. Cancer (2006) [Pubmed]
  5. Racial influence on the prevalence of prostate carcinoma in Brazilian volunteers. Paschoalin, E.L., Martins, A.C., Pastorello, M., Sândis, K.A., Maciel, L.M., Silva, W.A., Zago, M.A., Bessa, J. International braz j urol : official journal of the Brazilian Society of Urology. (2003) [Pubmed]
  6. Mutational analysis of two positional candidate susceptibility genes for bipolar disorder on chromosome 12q23-q24: phenylalanine hydroxylase and human LIM-homeobox LHX5. Green, E.K., Elvidge, G.P., Owen, M.J., Craddock, N. Psychiatr. Genet. (2003) [Pubmed]
  7. Monogenic traits are not simple: lessons from phenylketonuria. Scriver, C.R., Waters, P.J. Trends Genet. (1999) [Pubmed]
  8. Mass balance model of source apportionment, transport and fate of PAHs in Lac Saint Louis, Quebec. Mackay, D., Hickie, B. Chemosphere (2000) [Pubmed]
  9. Polycyclic aromatic hydrocarbon exposure and burden of outdoor workers in Budapest. Szaniszló, J., Ungváry, G. J. Toxicol. Environ. Health Part A (2001) [Pubmed]
  10. Risk for human health of some POPs due to fish from Lake Iseo. Binelli, A., Provini, A. Ecotoxicol. Environ. Saf. (2004) [Pubmed]
  11. Tetrahydropterin-dependent amino acid hydroxylases. Fitzpatrick, P.F. Annu. Rev. Biochem. (1999) [Pubmed]
  12. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Pontoglio, M., Barra, J., Hadchouel, M., Doyen, A., Kress, C., Bach, J.P., Babinet, C., Yaniv, M. Cell (1996) [Pubmed]
  13. Molecular basis of phenotypic heterogeneity in phenylketonuria. Okano, Y., Eisensmith, R.C., Güttler, F., Lichter-Konecki, U., Konecki, D.S., Trefz, F.K., Dasovich, M., Wang, T., Henriksen, K., Lou, H. N. Engl. J. Med. (1991) [Pubmed]
  14. The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations. Konecki, D.S., Lichter-Konecki, U. Hum. Genet. (1991) [Pubmed]
  15. L-phenylalanine binding and domain organization in human phenylalanine hydroxylase: a differential scanning calorimetry study. Thórólfsson, M., Ibarra-Molero, B., Fojan, P., Petersen, S.B., Sanchez-Ruiz, J.M., Martínez, A. Biochemistry (2002) [Pubmed]
  16. Toward PKU enzyme replacement therapy: PEGylation with activity retention for three forms of recombinant phenylalanine hydroxylase. Gámez, A., Wang, L., Straub, M., Patch, M.G., Stevens, R.C. Mol. Ther. (2004) [Pubmed]
  17. Glomerular response mechanisms to glycemic changes in insulin-dependent diabetics. Wiseman, M.J., Mangili, R., Alberetto, M., Keen, H., Viberti, G. Kidney Int. (1987) [Pubmed]
  18. Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells. Aguado, C., Pérez, B., Ugarte, M., Desviat, L.R. FEBS Lett. (2006) [Pubmed]
  19. A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. Martínez, A., Knappskog, P.M., Haavik, J. Current medicinal chemistry. (2001) [Pubmed]
  20. The structural basis of the recognition of phenylalanine and pterin cofactors by phenylalanine hydroxylase: implications for the catalytic mechanism. Teigen, K., Frøystein, N.A., Martínez, A. J. Mol. Biol. (1999) [Pubmed]
  21. Genotype and intellectual phenotype in untreated phenylketonuria patients. Ramus, S.J., Forrest, S.M., Pitt, D.D., Cotton, R.G. Pediatr. Res. (1999) [Pubmed]
  22. Aromatic amino acid hydroxylase genes and schizophrenia. Chao, H.M., Richardson, M.A. Am. J. Med. Genet. (2002) [Pubmed]
  23. Amplification of phenylalanine hydroxylase and cystathionine beta-synthase transcripts in human peripheral lymphocytes by RT-PCR. Devi, K.S., Devi, A.R., Kondaiah, P. Biochem. Mol. Biol. Int. (1998) [Pubmed]
  24. PKU mutation (D143G) associated with an apparent high residual enzyme activity: expression of a kinetic variant form of phenylalanine hydroxylase in three different systems. Knappskog, P.M., Eiken, H.G., Martínez, A., Bruland, O., Apold, J., Flatmark, T. Hum. Mutat. (1996) [Pubmed]
  25. Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene (PAH). Waters, P.J., Parniak, M.A., Hewson, A.S., Scriver, C.R. Hum. Mutat. (1998) [Pubmed]
  26. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Cogan, J.D., Pauciulo, M.W., Batchman, A.P., Prince, M.A., Robbins, I.M., Hedges, L.K., Stanton, K.C., Wheeler, L.A., Phillips, J.A., Loyd, J.E., Nichols, W.C. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  27. Human phenylalanine hydroxylase is activated by H2O2: a novel mechanism for increasing the L-tyrosine supply for melanogenesis in melanocytes. Schallreuter, K.U., Wazir, U., Kothari, S., Gibbons, N.C., Moore, J., Wood, J.M. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  28. Different stabilities and denaturation pathways for structurally related aromatic amino acid hydroxylases. Kleppe, R., Haavik, J. FEBS Lett. (2004) [Pubmed]
  29. Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase. Maass, A., Scholz, J., Moser, A. Eur. J. Biochem. (2003) [Pubmed]
  30. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Yang, X., Long, L., Southwood, M., Rudarakanchana, N., Upton, P.D., Jeffery, T.K., Atkinson, C., Chen, H., Trembath, R.C., Morrell, N.W. Circ. Res. (2005) [Pubmed]
  31. CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation. Alexandrov, K., Cascorbi, I., Rojas, M., Bouvier, G., Kriek, E., Bartsch, H. Carcinogenesis (2002) [Pubmed]
  32. Mutagenicity of C24H14 PAH in human cells expressing CYP1A1. Durant, J.L., Lafleur, A.L., Busby, W.F., Donhoffner, L.L., Penman, B.W., Crespi, C.L. Mutat. Res. (1999) [Pubmed]
  33. CYP1A1 in polycyclic aromatic hydrocarbon-induced B lymphocyte growth suppression. Allan, L.L., Schlezinger, J.J., Shansab, M., Sherr, D.H. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  34. Polymorphism and mapping of the IGF1 gene, and absence of association with stature among African Pygmies. Bowcock, A., Sartorelli, V. Hum. Genet. (1990) [Pubmed]
  35. Pteridin-dependent hydroxylases as autoantigens in autoimmune polyendocrine syndrome type I. Ekwall, O., Hedstrand, H., Haavik, J., Perheentupa, J., Betterle, C., Gustafsson, J., Husebye, E., Rorsman, F., Kämpe, O. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  36. A monoclonal antibody to aromatic amino acid hydroxylases. Identification of the epitope. Cotton, R.G., McAdam, W., Jennings, I., Morgan, F.J. Biochem. J. (1988) [Pubmed]
  37. Gene transfer and expression of human phenylalanine hydroxylase. Ledley, F.D., Grenett, H.E., DiLella, A.G., Kwok, S.C., Woo, S.L. Science (1985) [Pubmed]
  38. Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine hydroxylase gene. Hofman, K.J., Steel, G., Kazazian, H.H., Valle, D. Am. J. Hum. Genet. (1991) [Pubmed]
  39. Probing the role of crystallographically defined/predicted hinge-bending regions in the substrate-induced global conformational transition and catalytic activation of human phenylalanine hydroxylase by single-site mutagenesis. Stokka, A.J., Carvalho, R.N., Barroso, J.F., Flatmark, T. J. Biol. Chem. (2004) [Pubmed]
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