4pah is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[PH4H_HUMAN] Defects in PAH are the cause of phenylketonuria (PKU) [MIM:261600]. PKU is an autosomal recessive inborn error of phenylalanine metabolism, due to severe phenylalanine hydroxylase deficiency. It is characterized by blood concentrations of phenylalanine persistently above 1200 mumol (normal concentration 100 mumol) which usually causes mental retardation (unless low phenylalanine diet is introduced early in life). They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant 'mousy' odor.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] Defects in PAH are the cause of non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:261600]. Non-PKU HPA is a mild form of phenylalanine hydroxylase deficiency characterized by phenylalanine levels persistently below 600 mumol, which allows normal intellectual and behavioral development without treatment. Non-PKU HPA is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe one. Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:261600]. HPA is the mildest form of phenylalanine hydroxylase deficiency.[39][40][41][42][43][44][45][46]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by catechol derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known catechol inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with catechol hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes.
Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution.,Erlandsen H, Flatmark T, Stevens RC, Hough E Biochemistry. 1998 Nov 10;37(45):15638-46. PMID:9843368[47]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Hoang L, Byck S, Prevost L, Scriver CR. PAH Mutation Analysis Consortium Database: a database for disease-producing and other allelic variation at the human PAH locus. Nucleic Acids Res. 1996 Jan 1;24(1):127-31. PMID:8594560
↑Lichter-Konecki U, Konecki DS, DiLella AG, Brayton K, Marvit J, Hahn TM, Trefz FK, Woo SL. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene. Biochemistry. 1988 Apr 19;27(8):2881-5. PMID:2840952
↑Lyonnet S, Caillaud C, Rey F, Berthelon M, Frezal J, Rey J, Munnich A. Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency. Am J Hum Genet. 1989 Apr;44(4):511-7. PMID:2564729
↑Hofman KJ, Antonarakis SE, Missiou-Tsangaraki S, Boehm CD, Valle D. Phenylketonuria in the Greek population. Haplotype analysis of the phenylalanine hydroxylase gene and identification of a PKU mutation. Mol Biol Med. 1989 Jun;6(3):245-50. PMID:2615649
↑Svensson E, Andersson B, Hagenfeldt L. Two mutations within the coding sequence of the phenylalanine hydroxylase gene. Hum Genet. 1990 Aug;85(3):300-4. PMID:1975559
↑Dianzani I, Forrest SM, Camaschella C, Saglio G, Ponzone A, Cotton RG. Screening for mutations in the phenylalanine hydroxylase gene from Italian patients with phenylketonuria by using the chemical cleavage method: a new splice mutation. Am J Hum Genet. 1991 Mar;48(3):631-5. PMID:1671810
↑Hofman KJ, Steel G, Kazazian HH, Valle D. Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine hydroxylase gene. Am J Hum Genet. 1991 Apr;48(4):791-8. PMID:2014802
↑Okano Y, Wang T, Eisensmith RC, Longhi R, Riva E, Giovannini M, Cerone R, Romano C, Woo SL. Phenylketonuria missense mutations in the Mediterranean. Genomics. 1991 Jan;9(1):96-103. PMID:1672294
↑Dworniczak B, Grudda K, Stumper J, Bartholome K, Aulehla-Scholz C, Horst J. Phenylalanine hydroxylase gene: novel missense mutation in exon 7 causing severe phenylketonuria. Genomics. 1991 Jan;9(1):193-9. PMID:1672290
↑Konecki DS, Schlotter M, Trefz FK, Lichter-Konecki U. The identification of two mis-sense mutations at the PAH gene locus in a Turkish patient with phenylketonuria. Hum Genet. 1991 Aug;87(4):389-93. PMID:1679030
↑Caillaud C, Lyonnet S, Rey F, Melle D, Frebourg T, Berthelon M, Vilarinho L, Vaz Osorio R, Rey J, Munnich A. A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria. J Biol Chem. 1991 May 25;266(15):9351-4. PMID:1709636
↑Lin CH, Hsiao KJ, Tsai TF, Chao HK, Su TS. Identification of a missense phenylketonuria mutation at codon 408 in Chinese. Hum Genet. 1992 Aug;89(6):593-6. PMID:1355066
↑Jaruzelska J, Melle D, Matuszak R, Borski K, Munnich A. A new 15 bp deletion in exon 11 of the phenylalanine hydroxylase gene in phenylketonuria. Hum Mol Genet. 1992 Dec;1(9):763-4. PMID:1363837
↑Desviat LR, Perez B, Ugarte M. A new PKU mutation associated with haplotype 12. Hum Mol Genet. 1992 Dec;1(9):765-6. PMID:1363838
↑Guldberg P, Henriksen KF, Guttler F. Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis. Genomics. 1993 Jul;17(1):141-6. PMID:8406445 doi:https://dx.doi.org/10.1006/geno.1993.1295
↑Goebel-Schreiner B, Schreiner R. Identification of a new missense mutation in Japanese phenylketonuric patients. J Inherit Metab Dis. 1993;16(6):950-6. PMID:8068076
↑Benit P, Rey F, Melle D, Munnich A, Rey J. Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria. Hum Mutat. 1994;4(3):229-31. PMID:7833954 doi:https://dx.doi.org/10.1002/humu.1380040311
↑Knappskog PM, Eiken HG, Martinez A, Bruland O, Apold J, Flatmark T. PKU mutation (D143G) associated with an apparent high residual enzyme activity: expression of a kinetic variant form of phenylalanine hydroxylase in three different systems. Hum Mutat. 1996;8(3):236-46. PMID:8889583 doi:<236::AID-HUMU7>3.0.CO;2-7 10.1002/(SICI)1098-1004(1996)8:3<236::AID-HUMU7>3.0.CO;2-7
↑Argiolas A, Bosco P, Cali F, Ceratto N, Anello G, Riva E, Biasucci G, Carducci C, Romano V. Two novel PAH gene mutations detected in Italian phenylketonuric patients. Hum Genet. 1997 Feb;99(2):275-8. PMID:9048935
↑Mallolas J, Campistol J, Lambruschini N, Vilaseca MA, Cambra FJ, Estivill X, Mila M. Two novel mutations in exon 11 of the PAH gene (V1163del TG and P362T) associated with classic phenylketonuira and mild phenylketonuria. Mutations in brief no. 143. Online. Hum Mutat. 1998;11(6):482. PMID:10200057 doi:<482::AID-HUMU14>3.0.CO;2-H 10.1002/(SICI)1098-1004(1998)11:6<482::AID-HUMU14>3.0.CO;2-H
↑Park YS, Seoung CS, Lee SW, Oh KH, Lee DH, Yim J. Identification of three novel mutations in Korean phenylketonuria patients: R53H, N207D, and Y325X. Hum Mutat. 1998;Suppl 1:S121-2. PMID:9452061
↑Michiels L, Francois B, Raus J, Vandevyver C. Identification of seven new mutations in the phenylalanine hydroxylase gene, associated with hyperphenylalaninemia in the Belgian population. Hum Mutat. 1998;Suppl 1:S123-4. PMID:9452062
↑Corsello G, Bosco P, Cali F, Greco D, Cammarata M, Ciaccio M, Piccione M, Romano V. Maternal phenylketonuria in two Sicilian families identified by maternal blood phenylalanine level screening and identification of a new phenylalanine hydroxylase gene mutation (P407L) Eur J Pediatr. 1999 Jan;158(1):83-4. PMID:9950317
↑Gjetting T, Petersen M, Guldberg P, Guttler F. Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Am J Hum Genet. 2001 Jun;68(6):1353-60. Epub 2001 Apr 20. PMID:11326337 doi:S0002-9297(07)61046-5
↑Yang Y, Drummond-Borg M, Garcia-Heras J. Molecular analysis of phenylketonuria (PKU) in newborns from Texas. Hum Mutat. 2001 Jun;17(6):523. PMID:11385716 doi:10.1002/humu.1141
↑Gjetting T, Romstad A, Haavik J, Knappskog PM, Acosta AX, Silva WA Jr, Zago MA, Guldberg P, Guttler F. A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics. Mol Genet Metab. 2001 Jul;73(3):280-4. PMID:11461196 doi:10.1006/mgme.2001.3180
↑Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002 Dec 26;347(26):2122-32. PMID:12501224 doi:10.1056/NEJMoa021654
↑Gersting SW, Kemter KF, Staudigl M, Messing DD, Danecka MK, Lagler FB, Sommerhoff CP, Roscher AA, Muntau AC. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am J Hum Genet. 2008 Jul;83(1):5-17. doi: 10.1016/j.ajhg.2008.05.013. Epub 2008, Jun 5. PMID:18538294 doi:10.1016/j.ajhg.2008.05.013
↑Sterl E, Paul K, Paschke E, Zschocke J, Brunner-Krainz M, Windisch E, Konstantopoulou V, Moslinger D, Karall D, Scholl-Burgi S, Sperl W, Lagler F, Plecko B. Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients. J Inherit Metab Dis. 2013 Jan;36(1):7-13. doi: 10.1007/s10545-012-9485-y. Epub, 2012 Apr 25. PMID:22526846 doi:10.1007/s10545-012-9485-y
↑Groselj U, Tansek MZ, Kovac J, Hovnik T, Podkrajsek KT, Battelino T. Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene. Mol Genet Metab. 2012 Jun;106(2):142-8. doi: 10.1016/j.ymgme.2012.03.015. Epub, 2012 Apr 1. PMID:22513348 doi:10.1016/j.ymgme.2012.03.015
↑Yang Y, Drummond-Borg M, Garcia-Heras J. Molecular analysis of phenylketonuria (PKU) in newborns from Texas. Hum Mutat. 2001 Jun;17(6):523. PMID:11385716 doi:10.1002/humu.1141
↑Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002 Dec 26;347(26):2122-32. PMID:12501224 doi:10.1056/NEJMoa021654
↑Economou-Petersen E, Henriksen KF, Guldberg P, Guttler F. Molecular basis for nonphenylketonuria hyperphenylalaninemia. Genomics. 1992 Sep;14(1):1-5. PMID:1358789
↑Abadie V, Jaruzelska J, Lyonnet S, Millasseau P, Berthelon M, Rey F, Munnich A, Rey J. Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria. Hum Mol Genet. 1993 Jan;2(1):31-4. PMID:8098245
↑Guldberg P, Henriksen KF, Thony B, Blau N, Guttler F. Molecular heterogeneity of nonphenylketonuria hyperphenylalaninemia in 25 Danish patients. Genomics. 1994 May 15;21(2):453-5. PMID:8088845 doi:https://dx.doi.org/10.1006/geno.1994.1296
↑Kibayashi M, Nagao M, Chiba S. Mutation analysis of the phenylalanine hydroxylase gene and its clinical implications in two Japanese patients with non-phenylketonuria hyperphenylalaninemia. J Hum Genet. 1998;43(4):231-6. PMID:9852673 doi:10.1007/s100380050079
↑Chen KJ, Chao HK, Hsiao KJ, Su TS. Identification and characterization of a novel liver-specific enhancer of the human phenylalanine hydroxylase gene. Hum Genet. 2002 Mar;110(3):235-43. Epub 2002 Feb 5. PMID:11935335 doi:10.1007/s00439-002-0677-7
↑Erlandsen H, Flatmark T, Stevens RC, Hough E. Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution. Biochemistry. 1998 Nov 10;37(45):15638-46. PMID:9843368 doi:10.1021/bi9815290
