| 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
The crystal structures of the catalytic domain (DeltaN1-102/DeltaC428-452) of human phenylalanine hydroxylase (hPheOH) in its catalytically competent Fe(II) form and binary complex with the reduced pterin cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) have been determined to 1.7 and 1.5 A, respectively. When compared with the structures reported for various catalytically inactive Fe(III) forms, several important differences have been observed, notably at the active site. Thus, the non-liganded hPheOH-Fe(II) structure revealed well defined electron density for only one of the three water molecules reported to be coordinated to the iron in the high-spin Fe(III) form, as well as poor electron density for parts of the coordinating side-chain of Glu330. The reduced cofactor (BH4), which adopts the expected half-semi chair conformation, is bound in the second coordination sphere of the catalytic iron with a C4a-iron distance of 5.9 A. BH4 binds at the same site as L-erythro-7,8-dihydrobiopterin (BH2) in the binary hPheOH-Fe(III)-BH2 complex forming an aromatic pi-stacking interaction with Phe254 and a network of hydrogen bonds. However, compared to that structure the pterin ring is displaced about 0.5 A and rotated about 10 degrees, and the torsion angle between the hydroxyl groups of the cofactor in the dihydroxypropyl side-chain has changed by approximately 120 degrees enabling O2' to make a strong hydrogen bond (2.4 A) with the side-chain oxygen of Ser251. Carbon atoms in the dihydroxypropyl side-chain make several hydrophobic contacts with the protein. The iron is six-coordinated in the binary complex, but the overall coordination geometry is slightly different from that of the Fe(III) form. Most important was the finding that the binding of BH4 causes the Glu330 ligand to change its coordination to the iron when comparing with non-liganded hPheOH-Fe(III) and the binary hPheOH-Fe(III)-BH2 complex.
High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin.,Andersen OA, Flatmark T, Hough E J Mol Biol. 2001 Nov 23;314(2):279-91. PMID:11718561[47]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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
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- ↑ 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
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- ↑ 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
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- ↑ 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. High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. J Mol Biol. 2001 Nov 23;314(2):279-91. PMID:11718561 doi:10.1006/jmbi.2001.5061
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