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'''Unreleased structure'''


The entry 6hyc is ON HOLD until Paper Publication
==The structure of full-length human phenylalanine hydroxylase in complex with the cofactor and negative regulator tetrahydrobiopterin==
<StructureSection load='6hyc' size='340' side='right'caption='[[6hyc]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hyc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HYC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HYC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phenylalanine_4-monooxygenase Phenylalanine 4-monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.16.1 1.14.16.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hyc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hyc OCA], [http://pdbe.org/6hyc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hyc RCSB], [http://www.ebi.ac.uk/pdbsum/6hyc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hyc ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/PH4H_HUMAN PH4H_HUMAN]] Defects in PAH are the cause of phenylketonuria (PKU) [MIM:[http://omim.org/entry/261600 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.<ref>PMID:8594560</ref> <ref>PMID:2840952</ref> <ref>PMID:2564729</ref> <ref>PMID:2615649</ref> <ref>PMID:1975559</ref> <ref>PMID:1671810</ref> <ref>PMID:2014802</ref> <ref>PMID:1672294</ref> <ref>PMID:1672290</ref> <ref>PMID:1679030</ref> <ref>PMID:1709636</ref> <ref>PMID:1355066</ref> <ref>PMID:1363837</ref> <ref>PMID:1363838</ref> <ref>PMID:8406445</ref> <ref>PMID:8068076</ref> <ref>PMID:7833954</ref> <ref>PMID:8889583</ref> <ref>PMID:8889590</ref> <ref>PMID:9048935</ref> <ref>PMID:9101291</ref> <ref>PMID:9521426</ref> <ref>PMID:9600453</ref> <ref>PMID:10200057</ref> <ref>PMID:9452061</ref> <ref>PMID:9452062</ref> <ref>PMID:9792407</ref> <ref>PMID:9792411</ref> <ref>PMID:9950317</ref> <ref>PMID:10679941</ref> <ref>PMID:11326337</ref> <ref>PMID:11180595</ref> <ref>PMID:11385716</ref> <ref>PMID:11461196</ref> <ref>PMID:12501224</ref> <ref>PMID:18538294</ref> <ref>PMID:22526846</ref> <ref>PMID:22513348</ref>  Defects in PAH are the cause of non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:[http://omim.org/entry/261600 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:[http://omim.org/entry/261600 261600]]. HPA is the mildest form of phenylalanine hydroxylase deficiency.<ref>PMID:9521426</ref> <ref>PMID:11385716</ref> <ref>PMID:12501224</ref> <ref>PMID:1358789</ref> <ref>PMID:8098245</ref> <ref>PMID:8088845</ref> <ref>PMID:9852673</ref> <ref>PMID:11935335</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH4 in the precatalytic state. Crystal structures, solved at 3.18-A resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH4 BH4 forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic Fe(II) Upon BH4 binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH4 Importantly, BH4 binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH4 reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH4 subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH4 from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.


Authors: Alcorlo Pages, M., Flydal, I.M.
Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin.,Flydal MI, Alcorlo-Pages M, Johannessen FG, Martinez-Caballero S, Skjaerven L, Fernandez-Leiro R, Martinez A, Hermoso JA Proc Natl Acad Sci U S A. 2019 May 22. pii: 1902639116. doi:, 10.1073/pnas.1902639116. PMID:31118288<ref>PMID:31118288</ref>


Description: The structure of full-length human phenylalanine hydroxylase in complex with the cofactor and negative regulator tetrahydrobiopterin
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Alcorlo Pages, M]]
<div class="pdbe-citations 6hyc" style="background-color:#fffaf0;"></div>
[[Category: Flydal, I.M]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Phenylalanine 4-monooxygenase]]
[[Category: Flydal, I M]]
[[Category: Pages, M Alcorlo]]
[[Category: Allostery]]
[[Category: Oxidoreductase]]
[[Category: Phenylalanine hydroxylase]]
[[Category: Phenylketonuria]]
[[Category: Tetrahydrobiopterin]]

Revision as of 01:46, 6 June 2019

The structure of full-length human phenylalanine hydroxylase in complex with the cofactor and negative regulator tetrahydrobiopterinThe structure of full-length human phenylalanine hydroxylase in complex with the cofactor and negative regulator tetrahydrobiopterin

Structural highlights

6hyc is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:Phenylalanine 4-monooxygenase, with EC number 1.14.16.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH4 in the precatalytic state. Crystal structures, solved at 3.18-A resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH4 BH4 forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic Fe(II) Upon BH4 binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH4 Importantly, BH4 binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH4 reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH4 subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH4 from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.

Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin.,Flydal MI, Alcorlo-Pages M, Johannessen FG, Martinez-Caballero S, Skjaerven L, Fernandez-Leiro R, Martinez A, Hermoso JA Proc Natl Acad Sci U S A. 2019 May 22. pii: 1902639116. doi:, 10.1073/pnas.1902639116. PMID:31118288[47]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ 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-#
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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
  23. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ 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
  27. ↑ 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
  28. ↑ 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
  29. ↑ 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
  30. ↑ 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
  31. ↑ 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
  32. ↑ 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
  33. ↑ 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
  34. ↑ 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
  35. ↑ 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
  36. ↑ 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
  37. ↑ 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
  38. ↑ 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
  39. ↑ 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
  40. ↑ 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
  41. ↑ 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
  42. ↑ Economou-Petersen E, Henriksen KF, Guldberg P, Guttler F. Molecular basis for nonphenylketonuria hyperphenylalaninemia. Genomics. 1992 Sep;14(1):1-5. PMID:1358789
  43. ↑ 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
  44. ↑ 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
  45. ↑ 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
  46. ↑ 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
  47. ↑ Flydal MI, Alcorlo-Pages M, Johannessen FG, Martinez-Caballero S, Skjaerven L, Fernandez-Leiro R, Martinez A, Hermoso JA. Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin. Proc Natl Acad Sci U S A. 2019 May 22. pii: 1902639116. doi:, 10.1073/pnas.1902639116. PMID:31118288 doi:http://dx.doi.org/10.1073/pnas.1902639116

6hyc, resolution 3.18Å

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