| Structural highlights
Disease
[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
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Publication Abstract from PubMed
Phenylalanine hydroxylase catalyzes the stereospecific hydroxylation of L-phenylalanine, the committed step in the degradation of this amino acid. We have solved the crystal structure of the ternary complex (hPheOH-Fe(II).BH(4).THA) of the catalytically active Fe(II) form of a truncated form (DeltaN1-102/DeltaC428-452) of human phenylalanine hydroxylase (hPheOH), using the catalytically active reduced cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) and 3-(2-thienyl)-L-alanine (THA) as a substrate analogue. The analogue is bound in the second coordination sphere of the catalytic iron atom with the thiophene ring stacking against the imidazole group of His285 (average interplanar distance 3.8A) and with a network of hydrogen bonds and hydrophobic contacts. Binding of the analogue to the binary complex hPheOH-Fe(II).BH(4) triggers structural changes throughout the entire molecule, which adopts a slightly more compact structure. The largest change occurs in the loop region comprising residues 131-155, where the maximum r.m.s. displacement (9.6A) is at Tyr138. This loop is refolded, bringing the hydroxyl oxygen atom of Tyr138 18.5A closer to the iron atom and into the active site. The iron geometry is highly distorted square pyramidal, and Glu330 adopts a conformation different from that observed in the hPheOH-Fe(II).BH(4) structure, with bidentate iron coordination. BH(4) binds in the second coordination sphere of the catalytic iron atom, and is displaced 2.6A in the direction of Glu286 and the iron atom, relative to the hPheOH-Fe(II).BH(4) structure, thus changing its hydrogen bonding network. The active-site structure of the ternary complex gives new insight into the substrate specificity of the enzyme, notably the low affinity for L-tyrosine. Furthermore, the structure has implications both for the catalytic mechanism and the molecular basis for the activation of the full-length tetrameric enzyme by its substrate. The large conformational change, moving Tyr138 from a surface position into the active site, may reflect a possible functional role for this residue.
Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis and substrate activation.,Andersen OA, Flatmark T, Hough E J Mol Biol. 2002 Jul 26;320(5):1095-108. PMID:12126628[47]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ 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:http://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:http://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
- ↑ Guldberg P, Mallmann R, Henriksen KF, Guttler F. Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations. Hum Mutat. 1996;8(3):276-9. PMID:8889590 doi:<276::AID-HUMU14>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)8:3<276::AID-HUMU14>3.0.CO;2-#
- ↑ 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
- ↑ Byck S, Tyfield L, Carter K, Scriver CR. Prediction of multiple hypermutable codons in the human PAH gene: codon 280 contains recurrent mutations in Quebec and other populations. Hum Mutat. 1997;9(4):316-21. PMID:9101291 doi:<316::AID-HUMU3>3.0.CO;2-3 10.1002/(SICI)1098-1004(1997)9:4<316::AID-HUMU3>3.0.CO;2-3
- ↑ Bosco P, Cali F, Meli C, Mollica F, Zammarchi E, Cerone R, Vanni C, Palillo L, Greco D, Romano V. Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia. Hum Mutat. 1998;11(3):240-3. PMID:9521426 doi:<240::AID-HUMU9>3.0.CO;2-L 10.1002/(SICI)1098-1004(1998)11:3<240::AID-HUMU9>3.0.CO;2-L
- ↑ De Lucca M, Perez B, Desviat LR, Ugarte M. Molecular basis of phenylketonuria in Venezuela: presence of two novel null mutations. Hum Mutat. 1998;11(5):354-9. PMID:9600453 doi:<354::AID-HUMU2>3.0.CO;2-W 10.1002/(SICI)1098-1004(1998)11:5<354::AID-HUMU2>3.0.CO;2-W
- ↑ 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
- ↑ Popescu T, Blazkova M, Kozak L, Jebeleanu G, Popescu A. Mutation spectrum and phenylalanine hydroxylase RFLP/VNTR background in 44 Romanian phenylketonuric alleles. Hum Mutat. 1998;12(5):314-9. PMID:9792407 doi:<314::AID-HUMU4>3.0.CO;2-D 10.1002/(SICI)1098-1004(1998)12:5<314::AID-HUMU4>3.0.CO;2-D
- ↑ Waters PJ, Parniak MA, Hewson AS, Scriver CR. Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene (PAH). Hum Mutat. 1998;12(5):344-54. PMID:9792411 doi:<344::AID-HUMU8>3.0.CO;2-D 10.1002/(SICI)1098-1004(1998)12:5<344::AID-HUMU8>3.0.CO;2-D
- ↑ 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
- ↑ Hennermann JB, Vetter B, Wolf C, Windt E, Buhrdel P, Seidel J, Monch E, Kulozik AE. Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations. Hum Mutat. 2000;15(3):254-60. PMID:10679941 doi:<254::AID-HUMU6>3.0.CO;2-W 10.1002/(SICI)1098-1004(200003)15:3<254::AID-HUMU6>3.0.CO;2-W
- ↑ 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
- ↑ Acosta A, Silva W Jr, Carvalho T, Gomes M, Zago M. Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria. Hum Mutat. 2001 Feb;17(2):122-30. PMID:11180595 doi:<122::AID-HUMU4>3.0.CO;2-C 10.1002/1098-1004(200102)17:2<122::AID-HUMU4>3.0.CO;2-C
- ↑ 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
- ↑ Bosco P, Cali F, Meli C, Mollica F, Zammarchi E, Cerone R, Vanni C, Palillo L, Greco D, Romano V. Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia. Hum Mutat. 1998;11(3):240-3. PMID:9521426 doi:<240::AID-HUMU9>3.0.CO;2-L 10.1002/(SICI)1098-1004(1998)11:3<240::AID-HUMU9>3.0.CO;2-L
- ↑ 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:http://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
- ↑ Andersen OA, Flatmark T, Hough E. Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis and substrate activation. J Mol Biol. 2002 Jul 26;320(5):1095-108. PMID:12126628
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