ID   PH4H_HUMAN              Reviewed;         452 AA.
AC   P00439; Q16717; Q8TC14;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   10-JUN-2008, entry version 120.
DE   Phenylalanine-4-hydroxylase (EC 1.14.16.1) (PAH) (Phe-4-
DE   monooxygenase).
GN   Name=PAH;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   MEDLINE=85199778; PubMed=2986678; DOI=10.1021/bi00324a002;
RA   Kwok S.C.M., Ledley F.D., Dilella A.G., Robson K.J.H., Woo S.L.C.;
RT   "Nucleotide sequence of a full-length complementary DNA clone and
RT   amino acid sequence of human phenylalanine hydroxylase.";
RL   Biochemistry 24:556-561(1985).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Scriver C.R., Nowacki P.M., Byck S., Prevost L.;
RL   Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Liver;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   PROTEIN SEQUENCE OF 131-144.
RX   MEDLINE=89061656; PubMed=2461704;
RA   Cotton R.G., McAdam W., Jennings I., Morgan F.J.;
RT   "A monoclonal antibody to aromatic amino acid hydroxylases.
RT   Identification of the epitope.";
RL   Biochem. J. 255:193-196(1988).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 117-424.
RX   MEDLINE=98069646; PubMed=9406548; DOI=10.1038/nsb1297-995;
RA   Erlandsen H., Fusetti F., Martinez A., Hough E., Flatmark T.,
RA   Stevens R.C.;
RT   "Crystal structure of the catalytic domain of human phenylalanine
RT   hydroxylase reveals the structural basis for phenylketonuria.";
RL   Nat. Struct. Biol. 4:995-1000(1997).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 117-424.
RX   MEDLINE=99060040; PubMed=9843368; DOI=10.1021/bi9815290;
RA   Erlandsen H., Flatmark T., Stevens R.C., Hough E.;
RT   "Crystallographic analysis of the human phenylalanine hydroxylase
RT   catalytic domain with bound catechol inhibitors at 2.0-A resolution.";
RL   Biochemistry 37:15638-15646(1998).
RN   [7]
RP   X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 117-452.
RX   MEDLINE=98307935; PubMed=9642259; DOI=10.1074/jbc.273.27.16962;
RA   Fusetti F., Erlandsen H., Flatmark T., Stevens R.C.;
RT   "Structure of tetrameric human phenylalanine hydroxylase and its
RT   implications for phenylketonuria.";
RL   J. Biol. Chem. 273:16962-16967(1998).
RN   [8]
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 118-424.
RX   MEDLINE=20160497; PubMed=10694386; DOI=10.1021/bi992531+;
RA   Erlandsen H., Bjorgo E., Flatmark T., Stevens R.C.;
RT   "Crystal structure and site-specific mutagenesis of pterin-bound human
RT   phenylalanine hydroxylase.";
RL   Biochemistry 39:2208-2217(2000).
RN   [9]
RP   X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 103-427.
RX   MEDLINE=21576340; PubMed=11718561; DOI=10.1006/jmbi.2001.5061;
RA   Andersen O.A., Flatmark T., Hough E.;
RT   "High resolution crystal structures of the catalytic domain of human
RT   phenylalanine hydroxylase in its catalytically active Fe(II) form and
RT   binary complex with tetrahydrobiopterin.";
RL   J. Mol. Biol. 314:279-291(2001).
RN   [10]
RP   REVIEW ON PKU VARIANTS.
RX   MEDLINE=91348681; PubMed=1679029;
RA   Konecki D.S., Lichter-Konecki U.;
RT   "The phenylketonuria locus: current knowledge about alleles and
RT   mutations of the phenylalanine hydroxylase gene in various
RT   populations.";
RL   Hum. Genet. 87:377-388(1991).
RN   [11]
RP   REVIEW ON PKU VARIANTS.
RX   MEDLINE=91061429; PubMed=2246858; DOI=10.1007/BF01799577;
RA   Cotton R.G.;
RT   "Heterogeneity of phenylketonuria at the clinical, protein and DNA
RT   levels.";
RL   J. Inherit. Metab. Dis. 13:739-750(1990).
RN   [12]
RP   REVIEW ON PKU VARIANTS.
RX   MEDLINE=93244826; PubMed=1301187;
RA   Eisensmith R.C., Woo S.L.C.;
RT   "Molecular basis of phenylketonuria and related
RT   hyperphenylalaninemias: mutations and polymorphisms in the human
RT   phenylalanine hydroxylase gene.";
RL   Hum. Mutat. 1:13-22(1992).
RN   [13]
RP   DATABASE OF PKU VARIANTS.
RX   MEDLINE=96174613; PubMed=8594560; DOI=10.1093/nar/24.1.127;
RA   Hoang L., Byck S., Prevost L., Scriver C.R.;
RT   "PAH Mutation Analysis Consortium Database: a database for disease-
RT   producing and other allelic variation at the human PAH locus.";
RL   Nucleic Acids Res. 24:127-131(1996).
RN   [14]
RP   VARIANT PKU PRO-311.
RX   MEDLINE=88294030; PubMed=2840952; DOI=10.1021/bi00408a032;
RA   Lichter-Konecki U., Konecki D.S., Dilella A.G., Brayton K., Marvit J.,
RA   Hahn T.M., Trefz F.K., Woo S.L.C.;
RT   "Phenylalanine hydroxylase deficiency caused by a single base
RT   substitution in an exon of the human phenylalanine hydroxylase gene.";
RL   Biochemistry 27:2881-2885(1988).
RN   [15]
RP   VARIANT PKU LYS-280.
RX   MEDLINE=89190664; PubMed=2564729;
RA   Lyonnet S., Caillaud C., Rey F., Berthelon M., Frezal J., Rey J.,
RA   Munnich A.;
RT   "Molecular genetics of phenylketonuria in Mediterranean countries: a
RT   mutation associated with partial phenylalanine hydroxylase
RT   deficiency.";
RL   Am. J. Hum. Genet. 44:511-517(1989).
RN   [16]
RP   VARIANT PKU PRO-311.
RX   MEDLINE=90136055; PubMed=2615649;
RA   Hofman K.J., Antonarakis S.E., Missiou-Tsangaraki S., Boehm C.D.,
RA   Valle D.;
RT   "Phenylketonuria in the Greek population. Haplotype analysis of the
RT   phenylalanine hydroxylase gene and identification of a PKU mutation.";
RL   Mol. Biol. Med. 6:245-250(1989).
RN   [17]
RP   VARIANT PKU LEU-364 DEL.
RX   MEDLINE=90368081; PubMed=1975559; DOI=10.1007/BF00206750;
RA   Svensson E., Andersson B., Hagenfeldt L.;
RT   "Two mutations within the coding sequence of the phenylalanine
RT   hydroxylase gene.";
RL   Hum. Genet. 85:300-304(1990).
RN   [18]
RP   VARIANT PKU GLN-261.
RX   MEDLINE=91150775; PubMed=1671810;
RA   Dianzani I., Forrest S.M., Camaschella C., Saglio G., Ponzone A.,
RA   Cotton R.G.;
RT   "Screening for mutations in the phenylalanine hydroxylase gene from
RT   Italian patients with phenylketonuria by using the chemical cleavage
RT   method: a new splice mutation.";
RL   Am. J. Hum. Genet. 48:631-635(1991).
RN   [19]
RP   VARIANT PKU SER-255.
RX   MEDLINE=91196738; PubMed=2014802;
RA   Hofman K.J., Steel G., Kazazian H.H. Jr., Valle D.;
RT   "Phenylketonuria in U.S. blacks: molecular analysis of the
RT   phenylalanine hydroxylase gene.";
RL   Am. J. Hum. Genet. 48:791-798(1991).
RN   [20]
RP   VARIANTS PKU TRP-252 AND LEU-281.
RX   MEDLINE=91169521; PubMed=1672294; DOI=10.1016/0888-7543(91)90225-4;
RA   Okano Y., Wang T., Eisensmith R.C., Longhi R., Riva E., Giovannini M.,
RA   Cerone R., Romano C., Woo S.L.C.;
RT   "Phenylketonuria missense mutations in the Mediterranean.";
RL   Genomics 9:96-103(1991).
RN   [21]
RP   VARIANT PKU LEU-281.
RX   MEDLINE=91169506; PubMed=1672290; DOI=10.1016/0888-7543(91)90238-A;
RA   Dworniczak B., Grudda K., Stumper J., Bartholome K.,
RA   Aulehla-Scholz C., Horst J.;
RT   "Phenylalanine hydroxylase gene: novel missense mutation in exon 7
RT   causing severe phenylketonuria.";
RL   Genomics 9:193-199(1991).
RN   [22]
RP   VARIANTS PKU SER-48 AND GLY-221.
RX   MEDLINE=91348682; PubMed=1679030;
RA   Konecki D.S., Schlotter M., Trefz F.K., Lichter-Konecki U.;
RT   "The identification of two mis-sense mutations at the PAH gene locus
RT   in a Turkish patient with phenylketonuria.";
RL   Hum. Genet. 87:389-393(1991).
RN   [23]
RP   VARIANT PKU ILE-94 DEL.
RX   MEDLINE=91236693; PubMed=1709636;
RA   Caillaud C., Lyonnet S., Rey F., Melle D., Frebourg T., Berthelon M.,
RA   Vilarinho L., Vaz Osorio R., Rey J., Munnich A.;
RT   "A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene
RT   results in a kinetic variant of phenylketonuria.";
RL   J. Biol. Chem. 266:9351-9354(1991).
RN   [24]
RP   VARIANTS NON-PKU HPA VAL-306 AND ASN-415.
RX   MEDLINE=93052278; PubMed=1358789; DOI=10.1016/S0888-7543(05)80274-5;
RA   Economou-Petersen E., Henriksen K.F., Guldberg P., Guettler F.;
RT   "Molecular basis for nonphenylketonuria hyperphenylalaninemia.";
RL   Genomics 14:1-5(1992).
RN   [25]
RP   VARIANTS PKU GLN-408 AND TRP-408.
RX   MEDLINE=92380641; PubMed=1355066; DOI=10.1007/BF00221944;
RA   Lin C.H., Hsiao K.J., Tsai T.F., Chao H.K., Su T.S.;
RT   "Identification of a missense phenylketonuria mutation at codon 408 in
RT   Chinese.";
RL   Hum. Genet. 89:593-596(1992).
RN   [26]
RP   VARIANT PKU 364-LEU--GLU-368 DEL.
RX   MEDLINE=93258322; PubMed=1363837; DOI=10.1093/hmg/1.9.763;
RA   Jaruzelska J., Melle D., Matuszak R., Borski K., Munnich A.;
RT   "A new 15 bp deletion in exon 11 of the phenylalanine hydroxylase gene
RT   in phenylketonuria.";
RL   Hum. Mol. Genet. 1:763-764(1992).
RN   [27]
RP   VARIANT PKU LEU-244.
RX   MEDLINE=93258323; PubMed=1363838; DOI=10.1093/hmg/1.9.765;
RA   Desviat L.R., Perez B., Ugarte M.;
RT   "A new PKU mutation associated with haplotype 12.";
RL   Hum. Mol. Genet. 1:765-766(1992).
RN   [28]
RP   VARIANTS PKU.
RX   MEDLINE=94010878; PubMed=8406445; DOI=10.1006/geno.1993.1295;
RA   Guldberg P., Henriksen K.F., Guettler F.;
RT   "Molecular analysis of phenylketonuria in Denmark: 99% of the
RT   mutations detected by denaturing gradient gel electrophoresis.";
RL   Genomics 17:141-146(1993).
RN   [29]
RP   VARIANT NON-PKU HPA GLY-390.
RX   MEDLINE=93258345; PubMed=8098245; DOI=10.1093/hmg/2.1.31;
RA   Abadie V., Jaruzelska J., Lyonnet S., Millasseau P., Berthelon M.,
RA   Rey F., Munnich A., Rey J.;
RT   "Illegitimate transcription of the phenylalanine hydroxylase gene in
RT   lymphocytes for identification of mutations in phenylketonuria.";
RL   Hum. Mol. Genet. 2:31-34(1993).
RN   [30]
RP   VARIANT PKU VAL-276.
RX   MEDLINE=94172999; PubMed=8068076; DOI=10.1007/BF00711510;
RA   Goebel-Schreiner B., Schreiner R.;
RT   "Identification of a new missense mutation in Japanese phenylketonuric
RT   patients.";
RL   J. Inherit. Metab. Dis. 16:950-956(1993).
RN   [31]
RP   VARIANTS NON-PKU HPA VAL-47; ARG-87; LEU-176 AND ALA-245.
RX   MEDLINE=94375078; PubMed=8088845; DOI=10.1006/geno.1994.1296;
RA   Guldberg P., Henriksen K.F., Thoeny B., Blau N., Guettler F.;
RT   "Molecular heterogeneity of nonphenylketonuria hyperphenylalaninemia
RT   in 25 Danish patients.";
RL   Genomics 21:453-455(1994).
RN   [32]
RP   VARIANTS PKU THR-164; ALA-171; SER-239; GLN-252 AND LEU-331.
RX   MEDLINE=95135457; PubMed=7833954;
RA   Benit P., Rey F., Melle D., Munnich A., Rey J.;
RT   "Five novel missense mutations of the phenylalanine hydroxylase gene
RT   in phenylketonuria.";
RL   Hum. Mutat. 4:229-231(1994).
RN   [33]
RP   CHARACTERIZATION OF VARIANT PKU GLY-143.
RX   MEDLINE=97044512; PubMed=8889583;
RX   DOI=10.1002/(SICI)1098-1004(1996)8:3<236::AID-HUMU7>3.3.CO;2-J;
RA   Knappskog P.M., Eiken H.G., Martinez A., Bruland O., Apold J.,
RA   Flatmark T.;
RT   "PKU mutation (D143G) associated with an apparent high residual enzyme
RT   activity: expression of a kinetic variant form of phenylalanine
RT   hydroxylase in three different systems.";
RL   Hum. Mutat. 8:236-246(1996).
RN   [34]
RP   VARIANTS PKU LEU-40; SER-46; SER-48; 63-PRO-ASN-64; THR-65; SER-68;
RP   CYS-241; ALA-245; GLN-261; LYS-280; LEU-281; CYS-299; GLY-390;
RP   HIS-394; VAL-403; TRP-408 AND CYS-414.
RX   MEDLINE=97044519; PubMed=8889590;
RX   DOI=10.1002/(SICI)1098-1004(1996)8:3<276::AID-HUMU14>3.3.CO;2-T;
RA   Guldberg P., Mallmann R., Henriksen K.F., Guettler F.;
RT   "Phenylalanine hydroxylase deficiency in a population in Germany:
RT   mutational profile and nine novel mutations.";
RL   Hum. Mutat. 8:276-279(1996).
RN   [35]
RP   VARIANTS PKU CYS-204 AND SER-207.
RX   MEDLINE=97201124; PubMed=9048935; DOI=10.1007/s004390050353;
RA   Argiolas A., Bosco P., Cali F., Ceratto N., Anello G., Riva E.,
RA   Biasucci G., Carducci C., Romano V.;
RT   "Two novel PAH gene mutations detected in Italian phenylketonuric
RT   patients.";
RL   Hum. Genet. 99:275-278(1997).
RN   [36]
RP   VARIANTS PKU.
RX   MEDLINE=97255960; PubMed=9101291;
RX   DOI=10.1002/(SICI)1098-1004(1997)9:4<316::AID-HUMU3>3.3.CO;2-X;
RA   Byck S., Tyfield L., Carter K., Scriver C.R.;
RT   "Prediction of multiple hypermutable codons in the human PAH gene:
RT   codon 280 contains recurrent mutations in Quebec and other
RT   populations.";
RL   Hum. Mutat. 9:316-321(1997).
RN   [37]
RP   CHARACTERIZATION OF VARIANTS.
RX   MEDLINE=98111373; PubMed=9450897;
RX   DOI=10.1002/(SICI)1098-1004(1998)11:1<4::AID-HUMU2>3.3.CO;2-8;
RA   Waters P.J., Parniak M.A., Nowacki P., Scriver C.R.;
RT   "In vitro expression analysis of mutations in phenylalanine
RT   hydroxylase: linking genotype to phenotype and structure to
RT   function.";
RL   Hum. Mutat. 11:4-17(1998).
RN   [38]
RP   VARIANTS PKU AND NON-PKU.
RX   MEDLINE=98180723; PubMed=9521426;
RX   DOI=10.1002/(SICI)1098-1004(1998)11:3<240::AID-HUMU9>3.3.CO;2-C;
RA   Bosco P., Cali F., Meli C., Mollica F., Zammarchi E., Cerone R.,
RA   Vanni C., Palillo L., Greco D., Romano V.;
RT   "Eight new mutations of the phenylalanine hydroxylase gene in Italian
RT   patients with hyperphenylalaninemia.";
RL   Hum. Mutat. 11:240-243(1998).
RN   [39]
RP   VARIANTS PKU GLN-243; LEU-349 AND TRP-408.
RX   MEDLINE=98261080; PubMed=9600453;
RX   DOI=10.1002/(SICI)1098-1004(1998)11:5<354::AID-HUMU2>3.3.CO;2-N;
RA   de Lucca M., Perez B., Desviat L.R., Ugarte M.;
RT   "Molecular basis of phenylketonuria in Venezuela: presence of two
RT   novel null mutations.";
RL   Hum. Mutat. 11:354-359(1998).
RN   [40]
RP   VARIANT PKU THR-362.
RX   PubMed=10200057;
RX   DOI=10.1002/(SICI)1098-1004(1998)11:6<482::AID-HUMU15>3.3.CO;2-5;
RA   Mallolas J., Campistol J., Lambruscini N., Vilaseca M.A., Cambra J.F.,
RA   Estivill X., Milo M.;
RT   "Two novel mutations in exon 11 of the PAH gene (1163/1164 del TG and
RT   P362T) associated with classic phenylketonuria and mild
RT   phenylketonuria.";
RL   Hum. Mutat. 11:482-482(1998).
RN   [41]
RP   VARIANTS PKU HIS-53; ASP-207 AND LEU-388.
RX   MEDLINE=98112440; PubMed=9452061;
RA   Park Y.S., Seoung C.S., Lee S.W., Oh K.H., Lee D.H., Yim J.;
RT   "Identification of three novel mutations in Korean phenylketonuria
RT   patients: R53H, N207D, and Y325X.";
RL   Hum. Mutat. Suppl. 1:S121-S122(1998).
RN   [42]
RP   VARIANTS PKU PHE-39 DEL; THR-65; GLN-158; ILE-167; ALA-190; CYS-241
RP   AND TRP-408.
RX   MEDLINE=98112441; PubMed=9452062;
RA   Michiels L., Francois B., Raus J., Vandevyver C.;
RT   "Identification of seven new mutations in the phenylalanine
RT   hydroxylase gene, associated with hyperphenylalaninemia in the Belgian
RT   population.";
RL   Hum. Mutat. Suppl. 1:S123-S124(1998).
RN   [43]
RP   VARIANTS PKU.
RX   MEDLINE=99006893; PubMed=9792407;
RX   DOI=10.1002/(SICI)1098-1004(1998)12:5<314::AID-HUMU4>3.0.CO;2-D;
RA   Popescu T., Blazkova M., Kozak L., Jebeleanu G., Popescu A.;
RT   "Mutation spectrum and phenylalanine hydroxylase RFLP/VNTR background
RT   in 44 Romanian phenylketonuric alleles.";
RL   Hum. Mutat. 12:314-319(1998).
RN   [44]
RP   CHARACTERIZATION OF VARIANTS PKU ASP-104 AND ASN-157.
RX   MEDLINE=99006897; PubMed=9792411;
RX   DOI=10.1002/(SICI)1098-1004(1998)12:5<344::AID-HUMU8>3.3.CO;2-7;
RA   Waters P.J., Parniak M.A., Hewson A.S., Scriver C.R.;
RT   "Alterations in protein aggregation and degradation due to mild and
RT   severe missense mutations (A104D, R157N) in the human phenylalanine
RT   hydroxylase gene.";
RL   Hum. Mutat. 12:344-354(1998).
RN   [45]
RP   VARIANTS NON-PKU HPA CYS-241; GLN-243 AND PRO-413.
RX   MEDLINE=99069775; PubMed=9852673; DOI=10.1007/s100380050079;
RA   Kibayashi M., Nagao M., Chiba S.;
RT   "Mutation analysis of the phenylalanine hydroxylase gene and its
RT   clinical implications in two Japanese patients with non-
RT   phenylketonuria hyperphenylalaninemia.";
RL   J. Hum. Genet. 43:231-236(1998).
RN   [46]
RP   VARIANTS PKU.
RX   MEDLINE=20145667; PubMed=10679941;
RX   DOI=10.1002/(SICI)1098-1004(200003)15:3<254::AID-HUMU6>3.3.CO;2-N;
RA   Hennermann J.B., Vetter B., Wolf C., Windt E., Buehrdel P., Seidel J.,
RA   Moench E., Kulozik A.E.;
RT   "Phenylketonuria and hyperphenylalaninemia in eastern Germany: a
RT   characteristic molecular profile and 15 novel mutations.";
RL   Hum. Mutat. 15:254-260(2000).
RN   [47]
RP   CHARACTERIZATION OF VARIANTS PKU.
RX   MEDLINE=21313102; PubMed=11326337; DOI=10.1086/320604;
RA   Gjetting T., Petersen M., Guldberg P., Guettler F.;
RT   "Missense mutations in the N-terminal domain of human phenylalanine
RT   hydroxylase interfere with binding of regulatory phenylalanine.";
RL   Am. J. Hum. Genet. 68:1353-1360(2001).
RN   [48]
RP   VARIANTS PKU.
RX   MEDLINE=21113221; PubMed=11180595;
RX   DOI=10.1002/1098-1004(200102)17:2<122::AID-HUMU4>3.0.CO;2-C;
RA   Acosta A.X., Silva W.A. Jr., Carvalho T.M., Gomes M., Zago M.A.;
RT   "Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian
RT   patients with phenylketonuria.";
RL   Hum. Mutat. 17:122-130(2001).
RN   [49]
RP   VARIANTS PKU, AND VARIANTS HPA.
RX   MEDLINE=21278636; PubMed=11385716; DOI=10.1002/humu.1141.abs;
RA   Yang Y., Drummond-Borg M., Garcia-Heras J.;
RT   "Molecular analysis of phenylketonuria (PKU) in newborns from Texas.";
RL   Hum. Mutat. 17:523-523(2001).
RN   [50]
RP   VARIANTS PKU TRP-252 AND THR-318, AND VARIANT GLU-274.
RX   MEDLINE=21354782; PubMed=11461196; DOI=10.1006/mgme.2001.3180;
RA   Gjetting T., Romstad A., Haavik J., Knappskog P.M., Acosta A.X.,
RA   Silva W.A. Jr., Zago M.A., Guldberg P., Guettler F.;
RT   "A phenylalanine hydroxylase amino acid polymorphism with implications
RT   for molecular diagnostics.";
RL   Mol. Genet. Metab. 73:280-284(2001).
CC   -!- CATALYTIC ACTIVITY: L-phenylalanine + tetrahydrobiopterin + O(2) =
CC       L-tyrosine + 4a-hydroxytetrahydrobiopterin.
CC   -!- COFACTOR: Fe(2+) ion.
CC   -!- ENZYME REGULATION: N-terminal region of PAH is thought to contain
CC       allosteric binding sites for phenylalanine and to constitute an
CC       "inhibitory" domain that regulates the activity of a catalytic
CC       domain in the C-terminal portion of the molecule.
CC   -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation;
CC       acetoacetate and fumarate from L-phenylalanine: step 1/6.
CC   -!- SUBUNIT: Homodimer.
CC   -!- POLYMORPHISM: The Glu-274 variant occurs on approximately 4% of
CC       African-American PAH alleles. The enzyme activity of the variant
CC       protein is indistinguishable from that of the wild-type form.
CC   -!- DISEASE: Defects in PAH are the cause of phenylketonuria (PKU)
CC       [MIM:261600]. PKU is an autosomal recessive inborn error of
CC       phenylalanine metabolism, due to severe phenylalanine hydroxylase
CC       deficiency. It is characterized by blood concentrations of
CC       phenylalanine persistently above 1200 mumol (normal concentration
CC       100 mumol) which usually causes mental retardation (unless low
CC       phenylalanine diet is introduced early in life). They tend to have
CC       light pigmentation, rashes similar to eczema, epilepsy, extreme
CC       hyperactivity, psychotic states and an unpleasant 'mousy' odor.
CC   -!- DISEASE: Defects in PAH are the cause of non-phenylketonuria
CC       hyperphenylalaninemia (Non-PKU HPA) [MIM:261600]. Non-PKU HPA is a
CC       mild form of phenylalanine hydroxylase deficiency characterized by
CC       phenylalanine levels persistently below 600 mumol, which allows
CC       normal intellectual and behavioral development without treatment.
CC       Non-PKU HPA is usually caused by the combined effect of a mild
CC       hyperphenylalaninemia mutation and a severe one.
CC   -!- DISEASE: Defects in PAH are the cause of hyperphenylalaninemia
CC       (HPA) [MIM:261600]. HPA is the mildest form of phenylalanine
CC       hydroxylase deficiency.
CC   -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC       hydroxylase family.
CC   -!- SIMILARITY: Contains 1 ACT domain.
CC   -!- WEB RESOURCE: Name=PAHdb; Note=Phenylalanine hydroxylase locus
CC       knowledgebase;
CC       URL="http://www.pahdb.mcgill.ca/";
CC   -!- WEB RESOURCE: Name=GeneReviews;
CC       URL="http://www.genetests.org/query?gene=PAH";
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Phenylalanine hydroxylase
CC       entry;
CC       URL="http://en.wikipedia.org/wiki/Phenylalanine_hydroxylase";
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DR   EMBL; K03020; AAA60082.1; -; mRNA.
DR   EMBL; U49897; AAC51772.1; -; mRNA.
DR   EMBL; S61296; AAD13926.1; -; mRNA.
DR   EMBL; BC026251; AAH26251.1; -; mRNA.
DR   PIR; A00508; WHHUF.
DR   RefSeq; NP_000268.1; -.
DR   UniGene; Hs.643451; -.
DR   PDB; 1DMW; X-ray; 2.00 A; A=118-424.
DR   PDB; 1J8T; X-ray; 1.70 A; A=103-427.
DR   PDB; 1J8U; X-ray; 1.50 A; A=103-427.
DR   PDB; 1KW0; X-ray; 2.50 A; A=103-427.
DR   PDB; 1LRM; X-ray; 2.10 A; A=103-427.
DR   PDB; 1MMK; X-ray; 2.00 A; A=103-427.
DR   PDB; 1MMT; X-ray; 2.00 A; A=103-427.
DR   PDB; 1PAH; X-ray; 2.00 A; A=117-424.
DR   PDB; 1TDW; X-ray; 2.10 A; A=117-424.
DR   PDB; 1TG2; X-ray; 2.20 A; A=117-424.
DR   PDB; 2PAH; X-ray; 3.10 A; A/B=118-452.
DR   PDB; 3PAH; X-ray; 2.00 A; A=117-424.
DR   PDB; 4PAH; X-ray; 2.00 A; A=117-424.
DR   PDB; 5PAH; X-ray; 2.10 A; A=117-424.
DR   PDB; 6PAH; X-ray; 2.15 A; A=117-424.
DR   PDBsum; 1DMW; -.
DR   PDBsum; 1J8T; -.
DR   PDBsum; 1J8U; -.
DR   PDBsum; 1KW0; -.
DR   PDBsum; 1LRM; -.
DR   PDBsum; 1MMK; -.
DR   PDBsum; 1MMT; -.
DR   PDBsum; 1PAH; -.
DR   PDBsum; 1TDW; -.
DR   PDBsum; 1TG2; -.
DR   PDBsum; 2PAH; -.
DR   PDBsum; 3PAH; -.
DR   PDBsum; 4PAH; -.
DR   PDBsum; 5PAH; -.
DR   PDBsum; 6PAH; -.
DR   SMR; P00439; 19-427.
DR   PhosphoSite; P00439; -.
DR   HSC-2DPAGE; P00439; -.
DR   Ensembl; ENSG00000171759; Homo sapiens.
DR   GeneID; 5053; -.
DR   KEGG; hsa:5053; -.
DR   NMPDR; fig|9606.3.peg.8135; -.
DR   H-InvDB; HIX0010929; -.
DR   HGNC; HGNC:8582; PAH.
DR   MIM; 261600; gene+phenotype.
DR   Orphanet; 716; Phenylketonuria.
DR   PharmGKB; PA32911; -.
DR   HOGENOM; P00439; -.
DR   HOVERGEN; P00439; -.
DR   BioCyc; MetaCyc:MON-12066; -.
DR   Reactome; REACT_13; Metabolism of amino acids.
DR   DrugBank; DB00668; Epinephrine.
DR   DrugBank; DB00120; L-Phenylalanine.
DR   DrugBank; DB01235; Levodopa.
DR   DrugBank; DB00368; Norepinephrine.
DR   DrugBank; DB00360; Tetrahydrobiopterin.
DR   LinkHub; P00439; -.
DR   ArrayExpress; P00439; -.
DR   CleanEx; HS_PAH; -.
DR   GermOnline; ENSG00000171759; Homo sapiens.
DR   GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; TAS:ProtInc.
DR   GO; GO:0008652; P:amino acid biosynthetic process; TAS:ProtInc.
DR   InterPro; IPR001273; Aaa_hydroxylase.
DR   InterPro; IPR002912; ACT_bd.
DR   InterPro; IPR005961; Phe-4-hydroxylase_tetra.
DR   Gene3D; G3DSA:1.10.800.10; Aaa_hydroxylase; 1.
DR   PANTHER; PTHR11473; Aaa_hydroxylase; 1.
DR   Pfam; PF01842; ACT; 1.
DR   Pfam; PF00351; Biopterin_H; 1.
DR   PRINTS; PR00372; FYWHYDRXLASE.
DR   ProDom; PD002559; Aaa_hydroxylase; 1.
DR   TIGRFAMs; TIGR01268; Phe4hydrox_tetr; 1.
DR   PROSITE; PS00367; BIOPTERIN_HYDROXYL; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Allosteric enzyme; Direct protein sequencing;
KW   Disease mutation; Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW   Phenylalanine catabolism; Phenylketonuria; Phosphoprotein;
KW   Polymorphism.
FT   CHAIN         1    452       Phenylalanine-4-hydroxylase.
FT                                /FTId=PRO_0000205548.
FT   DOMAIN       35    110       ACT.
FT   METAL       285    285       Iron (By similarity).
FT   METAL       290    290       Iron (By similarity).
FT   METAL       330    330       Iron (By similarity).
FT   MOD_RES      16     16       Phosphoserine; by PKA (By similarity).
FT   VARIANT      16     16       S -> P (in PKU).
FT                                /FTId=VAR_000869.
FT   VARIANT      20     20       Q -> L (in HPA).
FT                                /FTId=VAR_009239.
FT   VARIANT      39     39       F -> L (in PKU; haplotype 1).
FT                                /FTId=VAR_000870.
FT   VARIANT      39     39       Missing (in PKU; haplotypes 9,21).
FT                                /FTId=VAR_000871.
FT   VARIANT      40     40       S -> L (in PKU).
FT                                /FTId=VAR_000872.
FT   VARIANT      41     41       L -> F (in PKU).
FT                                /FTId=VAR_000873.
FT   VARIANT      41     41       L -> P (in PKU; mild).
FT                                /FTId=VAR_009240.
FT   VARIANT      42     42       K -> I (in PKU; haplotype 21).
FT                                /FTId=VAR_000874.
FT   VARIANT      46     46       G -> S (in PKU; haplotype 5;
FT                                significantly reduces phenylalanine
FT                                binding).
FT                                /FTId=VAR_000875.
FT   VARIANT      47     47       A -> V (in non-PKU HPA; haplotype 4;
FT                                significantly reduces phenylalanine
FT                                binding).
FT                                /FTId=VAR_000876.
FT   VARIANT      48     48       L -> S (in PKU; mild; haplotypes 3,4).
FT                                /FTId=VAR_000877.
FT   VARIANT      53     53       R -> H (in PKU).
FT                                /FTId=VAR_000878.
FT   VARIANT      55     55       F -> L (in PKU).
FT                                /FTId=VAR_000879.
FT   VARIANT      56     56       E -> D (in PKU; haplotype 10).
FT                                /FTId=VAR_000880.
FT   VARIANT      63     64       TH -> PN (in PKU; haplotype 1; abolishes
FT                                phenylalanine binding).
FT                                /FTId=VAR_000881.
FT   VARIANT      65     65       I -> N (in PKU).
FT                                /FTId=VAR_000882.
FT   VARIANT      65     65       I -> T (in PKU; haplotypes 1,5,9,21,B;
FT                                abolishes phenylalanine binding).
FT                                /FTId=VAR_000883.
FT   VARIANT      67     67       S -> P (in PKU; haplotype 4).
FT                                /FTId=VAR_000884.
FT   VARIANT      68     68       R -> S (in PKU; haplotype 1;
FT                                significantly reduces phenylalanine
FT                                binding).
FT                                /FTId=VAR_000885.
FT   VARIANT      76     76       E -> A (in PKU).
FT                                /FTId=VAR_000886.
FT   VARIANT      84     84       D -> Y (in PKU; haplotype 4).
FT                                /FTId=VAR_000887.
FT   VARIANT      87     87       S -> R (in non-PKU HPA; haplotype 1).
FT                                /FTId=VAR_000888.
FT   VARIANT      92     92       T -> I (in PKU).
FT                                /FTId=VAR_000889.
FT   VARIANT      94     94       Missing (in PKU; mild; haplotype 2).
FT                                /FTId=VAR_000890.
FT   VARIANT      98     98       L -> S (in non-PKU HPA).
FT                                /FTId=VAR_000891.
FT   VARIANT     104    104       A -> D (in PKU; mild; haplotype 1).
FT                                /FTId=VAR_000892.
FT   VARIANT     110    110       S -> C (in HPA).
FT                                /FTId=VAR_009241.
FT   VARIANT     124    124       T -> I (in PKU; haplotype 28).
FT                                /FTId=VAR_000893.
FT   VARIANT     129    129       D -> Y (in PKU).
FT                                /FTId=VAR_000894.
FT   VARIANT     143    143       D -> G (in PKU; haplotype 11).
FT                                /FTId=VAR_000895.
FT   VARIANT     145    145       D -> V (in PKU).
FT                                /FTId=VAR_011566.
FT   VARIANT     146    146       H -> Y (in PKU).
FT                                /FTId=VAR_000896.
FT   VARIANT     148    148       G -> S (in PKU; haplotypes 1,2,7).
FT                                /FTId=VAR_000897.
FT   VARIANT     151    151       D -> H (in PKU; haplotypes 1,8).
FT                                /FTId=VAR_000898.
FT   VARIANT     154    154       Y -> N (in PKU).
FT                                /FTId=VAR_000899.
FT   VARIANT     155    155       R -> P (in PKU).
FT                                /FTId=VAR_009242.
FT   VARIANT     157    157       R -> N (in PKU; severe; 5% activity;
FT                                requires 2 nucleotide substitutions).
FT                                /FTId=VAR_000900.
FT   VARIANT     158    158       R -> Q (in PKU; haplotypes 1,2,4,7,16,
FT                                28).
FT                                /FTId=VAR_000901.
FT   VARIANT     158    158       R -> W (in PKU).
FT                                /FTId=VAR_000902.
FT   VARIANT     160    160       Q -> P (in PKU).
FT                                /FTId=VAR_000903.
FT   VARIANT     161    161       F -> S (in PKU; haplotype 4).
FT                                /FTId=VAR_000904.
FT   VARIANT     164    164       I -> T (in PKU; haplotype 1).
FT                                /FTId=VAR_000905.
FT   VARIANT     167    167       N -> I (in PKU).
FT                                /FTId=VAR_000906.
FT   VARIANT     167    167       N -> S (in HPA).
FT                                /FTId=VAR_011567.
FT   VARIANT     169    169       R -> H (in PKU).
FT                                /FTId=VAR_011568.
FT   VARIANT     170    170       H -> D (in HPA).
FT                                /FTId=VAR_011569.
FT   VARIANT     170    170       H -> R (in PKU).
FT                                /FTId=VAR_000907.
FT   VARIANT     171    171       G -> A (in PKU; haplotype 1).
FT                                /FTId=VAR_000908.
FT   VARIANT     171    171       G -> R (in PKU).
FT                                /FTId=VAR_000909.
FT   VARIANT     173    173       P -> T (in PKU; haplotype 4).
FT                                /FTId=VAR_000910.
FT   VARIANT     174    174       I -> T (in PKU; haplotype 1).
FT                                /FTId=VAR_000911.
FT   VARIANT     174    174       I -> V (in PKU).
FT                                /FTId=VAR_011570.
FT   VARIANT     175    175       P -> A (in PKU).
FT                                /FTId=VAR_000912.
FT   VARIANT     176    176       R -> L (in non-PKU HPA).
FT                                /FTId=VAR_000913.
FT   VARIANT     176    176       R -> P (in PKU).
FT                                /FTId=VAR_000914.
FT   VARIANT     177    177       V -> L (in PKU; haplotype 6).
FT                                /FTId=VAR_000915.
FT   VARIANT     178    178       E -> G (in non-PKU HPA).
FT                                /FTId=VAR_000916.
FT   VARIANT     183    183       E -> Q (in PKU).
FT                                /FTId=VAR_009243.
FT   VARIANT     190    190       V -> A (in PKU; haplotype 3).
FT                                /FTId=VAR_000917.
FT   VARIANT     194    194       L -> P (in PKU).
FT                                /FTId=VAR_000918.
FT   VARIANT     194    194       Missing (in PKU).
FT                                /FTId=VAR_000919.
FT   VARIANT     197    197       Missing (in PKU).
FT                                /FTId=VAR_000920.
FT   VARIANT     198    198       Missing (in PKU; haplotype 2).
FT                                /FTId=VAR_000921.
FT   VARIANT     201    201       H -> R (in PKU).
FT                                /FTId=VAR_000922.
FT   VARIANT     201    201       H -> Y (in non-PKU HPA; haplotype 1).
FT                                /FTId=VAR_000923.
FT   VARIANT     204    204       Y -> C (in PKU; mild; haplotypes 3,4).
FT                                /FTId=VAR_000924.
FT   VARIANT     205    205       E -> A (in PKU).
FT                                /FTId=VAR_011571.
FT   VARIANT     206    206       Y -> D (in PKU).
FT                                /FTId=VAR_000925.
FT   VARIANT     207    207       N -> D (in PKU).
FT                                /FTId=VAR_000926.
FT   VARIANT     207    207       N -> S (in PKU; severe; haplotype 4).
FT                                /FTId=VAR_000927.
FT   VARIANT     211    211       P -> T (in PKU; haplotype 4).
FT                                /FTId=VAR_000928.
FT   VARIANT     212    212       L -> P (in PKU).
FT                                /FTId=VAR_000929.
FT   VARIANT     213    213       L -> P (in PKU; severe).
FT                                /FTId=VAR_000930.
FT   VARIANT     217    217       C -> G (in PKU).
FT                                /FTId=VAR_000931.
FT   VARIANT     218    218       G -> V (in PKU; haplotypes 1,2).
FT                                /FTId=VAR_000932.
FT   VARIANT     221    221       E -> G (in PKU; haplotype 4).
FT                                /FTId=VAR_000933.
FT   VARIANT     222    222       D -> V (in PKU; haplotypes 3,4).
FT                                /FTId=VAR_000934.
FT   VARIANT     224    224       I -> M (in PKU; haplotype 4).
FT                                /FTId=VAR_000935.
FT   VARIANT     225    225       P -> R (in PKU).
FT                                /FTId=VAR_000936.
FT   VARIANT     225    225       P -> T (in PKU; haplotype 1).
FT                                /FTId=VAR_000937.
FT   VARIANT     230    230       V -> I (in non-PKU HPA; haplotype 4).
FT                                /FTId=VAR_000938.
FT   VARIANT     231    231       S -> F (in PKU).
FT                                /FTId=VAR_009244.
FT   VARIANT     231    231       S -> P (in PKU).
FT                                /FTId=VAR_000939.
FT   VARIANT     233    233       F -> L (in PKU; haplotypes 2,3).
FT                                /FTId=VAR_000940.
FT   VARIANT     238    238       T -> P (in PKU; haplotype 4).
FT                                /FTId=VAR_000941.
FT   VARIANT     239    239       G -> S (in PKU).
FT                                /FTId=VAR_000942.
FT   VARIANT     240    240       F -> S (in PKU).
FT                                /FTId=VAR_011572.
FT   VARIANT     241    241       R -> C (in non-PKU HPA and PKU; haplotype
FT                                34).
FT                                /FTId=VAR_000943.
FT   VARIANT     241    241       R -> H (in PKU; haplotypes 1,5).
FT                                /FTId=VAR_000944.
FT   VARIANT     241    241       R -> L (in PKU).
FT                                /FTId=VAR_000945.
FT   VARIANT     242    242       L -> F (in PKU).
FT                                /FTId=VAR_000946.
FT   VARIANT     243    243       R -> Q (in non-PKU HPA and PKU;
FT                                haplotypes 4,7,9).
FT                                /FTId=VAR_000947.
FT   VARIANT     244    244       P -> L (in PKU; haplotype 12).
FT                                /FTId=VAR_000948.
FT   VARIANT     245    245       V -> A (in non-PKU HPA; haplotypes 3,7).
FT                                /FTId=VAR_000949.
FT   VARIANT     245    245       V -> E (in PKU; haplotype 11).
FT                                /FTId=VAR_000950.
FT   VARIANT     245    245       V -> L (in PKU).
FT                                /FTId=VAR_000951.
FT   VARIANT     246    246       A -> D (in PKU).
FT                                /FTId=VAR_000952.
FT   VARIANT     247    247       G -> V (in PKU; haplotype 4).
FT                                /FTId=VAR_000953.
FT   VARIANT     248    248       L -> P (in PKU).
FT                                /FTId=VAR_000954.
FT   VARIANT     249    249       L -> F (in PKU; haplotype 1).
FT                                /FTId=VAR_000955.
FT   VARIANT     252    252       R -> G (in PKU; haplotype 7).
FT                                /FTId=VAR_000956.
FT   VARIANT     252    252       R -> Q (in PKU; haplotype 1).
FT                                /FTId=VAR_000957.
FT   VARIANT     252    252       R -> W (in PKU; haplotypes 1,6,7,8,42,
FT                                69; complete loss of activity).
FT                                /FTId=VAR_000958.
FT   VARIANT     255    255       L -> S (in PKU; haplotype 36).
FT                                /FTId=VAR_000960.
FT   VARIANT     255    255       L -> V (in PKU; haplotypes 18,21).
FT                                /FTId=VAR_000959.
FT   VARIANT     257    257       G -> C (in PKU).
FT                                /FTId=VAR_000961.
FT   VARIANT     259    259       A -> T (in PKU; haplotype 3).
FT                                /FTId=VAR_000962.
FT   VARIANT     259    259       A -> V (in PKU; haplotypes 7,42).
FT                                /FTId=VAR_000963.
FT   VARIANT     261    261       R -> P (in PKU).
FT                                /FTId=VAR_000964.
FT   VARIANT     261    261       R -> Q (in PKU; mild; haplotypes
FT                                1,2,4,22, 24,28; dbSNP:rs5030849).
FT                                /FTId=VAR_000965.
FT   VARIANT     263    263       F -> L (in PKU).
FT                                /FTId=VAR_000966.
FT   VARIANT     264    264       H -> L (in PKU).
FT                                /FTId=VAR_000967.
FT   VARIANT     265    265       C -> G (in PKU).
FT                                /FTId=VAR_000968.
FT   VARIANT     269    269       I -> L (in non-PKU HPA).
FT                                /FTId=VAR_000969.
FT   VARIANT     270    270       R -> K (in PKU).
FT                                /FTId=VAR_000970.
FT   VARIANT     270    270       R -> S (in PKU; haplotype 1).
FT                                /FTId=VAR_000971.
FT   VARIANT     271    271       H -> Y (in PKU).
FT                                /FTId=VAR_000972.
FT   VARIANT     273    273       S -> F (in PKU; haplotype 7).
FT                                /FTId=VAR_000973.
FT   VARIANT     274    274       K -> E.
FT                                /FTId=VAR_011573.
FT   VARIANT     276    276       M -> I (in PKU).
FT                                /FTId=VAR_000974.
FT   VARIANT     276    276       M -> V (in PKU; haplotype 4).
FT                                /FTId=VAR_000975.
FT   VARIANT     277    277       Y -> C (in PKU).
FT                                /FTId=VAR_000976.
FT   VARIANT     277    277       Y -> D (in PKU; haplotype 2).
FT                                /FTId=VAR_000977.
FT   VARIANT     278    278       T -> A (in PKU).
FT                                /FTId=VAR_000978.
FT   VARIANT     278    278       T -> N (in PKU).
FT                                /FTId=VAR_000979.
FT   VARIANT     280    280       E -> K (in PKU; haplotypes 1,2,4,16,38;
FT                                partial residual activity).
FT                                /FTId=VAR_000980.
FT   VARIANT     281    281       P -> L (in PKU; haplotypes 1,4).
FT                                /FTId=VAR_000981.
FT   VARIANT     282    282       D -> N (in PKU; haplotype 1).
FT                                /FTId=VAR_000982.
FT   VARIANT     283    283       I -> F (in PKU; haplotype 21).
FT                                /FTId=VAR_000983.
FT   VARIANT     283    283       I -> N (in PKU; severe).
FT                                /FTId=VAR_000984.
FT   VARIANT     297    297       R -> C (in PKU; haplotype 4).
FT                                /FTId=VAR_000985.
FT   VARIANT     297    297       R -> H (in PKU).
FT                                /FTId=VAR_000986.
FT   VARIANT     299    299       F -> C (in PKU; haplotype 8).
FT                                /FTId=VAR_000987.
FT   VARIANT     300    300       A -> S (in PKU; haplotype 1).
FT                                /FTId=VAR_000988.
FT   VARIANT     300    300       A -> V (in PKU).
FT                                /FTId=VAR_000989.
FT   VARIANT     303    303       S -> P (in PKU; haplotype 5).
FT                                /FTId=VAR_000990.
FT   VARIANT     304    304       Q -> R (in PKU).
FT                                /FTId=VAR_000991.
FT   VARIANT     306    306       I -> V (in non-PKU HPA; haplotype 4).
FT                                /FTId=VAR_000992.
FT   VARIANT     309    309       A -> D (in PKU; haplotype 7).
FT                                /FTId=VAR_000993.
FT   VARIANT     309    309       A -> V (in PKU).
FT                                /FTId=VAR_000994.
FT   VARIANT     310    310       S -> F (in PKU; haplotype 7).
FT                                /FTId=VAR_000995.
FT   VARIANT     311    311       L -> P (in PKU; haplotypes 1,7,10).
FT                                /FTId=VAR_000996.
FT   VARIANT     314    314       P -> H (in PKU).
FT                                /FTId=VAR_000997.
FT   VARIANT     318    318       I -> T (in PKU; partial loss of
FT                                activity).
FT                                /FTId=VAR_011574.
FT   VARIANT     322    322       A -> G (in PKU; haplotype 12).
FT                                /FTId=VAR_000998.
FT   VARIANT     322    322       A -> T (in PKU; haplotype 1).
FT                                /FTId=VAR_000999.
FT   VARIANT     325    325       Y -> C (in PKU).
FT                                /FTId=VAR_009245.
FT   VARIANT     330    330       E -> D (in PKU).
FT                                /FTId=VAR_009246.
FT   VARIANT     331    331       F -> L (in PKU; haplotype 1).
FT                                /FTId=VAR_001000.
FT   VARIANT     333    333       L -> F (in PKU).
FT                                /FTId=VAR_001001.
FT   VARIANT     334    334       C -> S (in PKU).
FT                                /FTId=VAR_001002.
FT   VARIANT     337    337       G -> V (in PKU).
FT                                /FTId=VAR_001003.
FT   VARIANT     338    338       D -> Y (in PKU; haplotype 4).
FT                                /FTId=VAR_001004.
FT   VARIANT     341    341       K -> R (in PKU).
FT                                /FTId=VAR_001005.
FT   VARIANT     341    341       K -> T (in PKU).
FT                                /FTId=VAR_001006.
FT   VARIANT     342    342       A -> T (in PKU; haplotype 5).
FT                                /FTId=VAR_001007.
FT   VARIANT     343    343       Y -> C (in PKU).
FT                                /FTId=VAR_001008.
FT   VARIANT     344    344       G -> R (in PKU).
FT                                /FTId=VAR_009247.
FT   VARIANT     344    344       G -> V (in PKU).
FT                                /FTId=VAR_009248.
FT   VARIANT     345    345       A -> S (in PKU).
FT                                /FTId=VAR_001009.
FT   VARIANT     345    345       A -> T (in PKU; haplotype 7).
FT                                /FTId=VAR_001010.
FT   VARIANT     347    347       L -> F (in PKU).
FT                                /FTId=VAR_001011.
FT   VARIANT     348    348       L -> V (in PKU; mild haplotype 9).
FT                                /FTId=VAR_001012.
FT   VARIANT     349    349       S -> L (in PKU; severe).
FT                                /FTId=VAR_001013.
FT   VARIANT     349    349       S -> P (in PKU; haplotypes 1,4).
FT                                /FTId=VAR_001014.
FT   VARIANT     350    350       S -> T (in PKU; haplotype 2).
FT                                /FTId=VAR_001015.
FT   VARIANT     357    357       C -> G (in PKU).
FT                                /FTId=VAR_011575.
FT   VARIANT     362    362       P -> T (in PKU).
FT                                /FTId=VAR_001016.
FT   VARIANT     364    368       Missing (in PKU).
FT                                /FTId=VAR_001018.
FT   VARIANT     364    364       Missing (in PKU; haplotype 5).
FT                                /FTId=VAR_001017.
FT   VARIANT     366    366       P -> H (in PKU).
FT                                /FTId=VAR_001019.
FT   VARIANT     372    372       T -> S (in PKU).
FT                                /FTId=VAR_001020.
FT   VARIANT     377    377       Y -> C (in PKU; haplotype 4).
FT                                /FTId=VAR_001021.
FT   VARIANT     380    380       T -> M (in non-PKU HPA; haplotype 4).
FT                                /FTId=VAR_001022.
FT   VARIANT     386    386       Y -> C (in PKU; common mutation).
FT                                /FTId=VAR_001023.
FT   VARIANT     387    387       Y -> H (in PKU; haplotype 1).
FT                                /FTId=VAR_001024.
FT   VARIANT     388    388       V -> L (in PKU).
FT                                /FTId=VAR_001025.
FT   VARIANT     388    388       V -> M (in PKU; haplotypes 1,4).
FT                                /FTId=VAR_001026.
FT   VARIANT     390    390       E -> G (in non-PKU HPA; haplotype 4).
FT                                /FTId=VAR_001027.
FT   VARIANT     394    394       D -> A (in PKU).
FT                                /FTId=VAR_001028.
FT   VARIANT     394    394       D -> H (in PKU).
FT                                /FTId=VAR_001029.
FT   VARIANT     395    395       A -> G (in PKU).
FT                                /FTId=VAR_001030.
FT   VARIANT     395    395       A -> P (in PKU; haplotype 1).
FT                                /FTId=VAR_001031.
FT   VARIANT     399    400       Missing (in PKU; haplotype 7).
FT                                /FTId=VAR_001032.
FT   VARIANT     403    403       A -> V (in non-PKU HPA and PKU; haplotype
FT                                43).
FT                                /FTId=VAR_001033.
FT   VARIANT     407    407       P -> S (in PKU).
FT                                /FTId=VAR_011576.
FT   VARIANT     408    408       R -> Q (in PKU; haplotypes 4,12).
FT                                /FTId=VAR_001034.
FT   VARIANT     408    408       R -> W (in PKU; haplotypes 1,2,4,5,13,34,
FT                                41,44; most common mutation).
FT                                /FTId=VAR_001035.
FT   VARIANT     410    410       F -> S (in PKU; mild).
FT                                /FTId=VAR_009249.
FT   VARIANT     413    413       R -> P (in non-PKU HPA and PKU; haplotype
FT                                4).
FT                                /FTId=VAR_001036.
FT   VARIANT     413    413       R -> S (in PKU; haplotype 1).
FT                                /FTId=VAR_001037.
FT   VARIANT     414    414       Y -> C (in PKU; haplotype 4).
FT                                /FTId=VAR_001038.
FT   VARIANT     415    415       D -> N (in non-PKU HPA; haplotype 1).
FT                                /FTId=VAR_001039.
FT   VARIANT     418    418       T -> P (in PKU; haplotype 4).
FT                                /FTId=VAR_001040.
FT   VARIANT     430    430       L -> P (in PKU).
FT                                /FTId=VAR_001041.
FT   VARIANT     447    447       A -> D (in PKU).
FT                                /FTId=VAR_001042.
FT   CONFLICT    183    183       E -> G (in Ref. 3; AAH26251).
FT   HELIX       125    133
FT   HELIX       140    142
FT   TURN        147    150
FT   HELIX       152    167
FT   HELIX       181    195
FT   HELIX       198    201
FT   HELIX       204    217
FT   HELIX       227    238
FT   STRAND      241    244
FT   HELIX       251    258
FT   TURN        259    261
FT   STRAND      262    265
FT   HELIX       283    289
FT   HELIX       291    294
FT   HELIX       297    310
FT   HELIX       315    327
FT   TURN        328    331
FT   STRAND      333    336
FT   STRAND      339    342
FT   HELIX       345    348
FT   HELIX       351    357
FT   STRAND      359    366
FT   HELIX       369    372
FT   STRAND      379    381
FT   STRAND      384    390
FT   HELIX       392    404
FT   STRAND      409    415
FT   TURN        416    419
FT   STRAND      420    424
FT   HELIX       428    450
SQ   SEQUENCE   452 AA;  51862 MW;  018F00EBBBDDCE2F CRC64;
     MSTAVLENPG LGRKLSDFGQ ETSYIEDNCN QNGAISLIFS LKEEVGALAK VLRLFEENDV
     NLTHIESRPS RLKKDEYEFF THLDKRSLPA LTNIIKILRH DIGATVHELS RDKKKDTVPW
     FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYM
     EEEKKTWGTV FKTLKSLYKT HACYEYNHIF PLLEKYCGFH EDNIPQLEDV SQFLQTCTGF
     RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
     QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKQGDSI KAYGAGLLSS FGELQYCLSE
     KPKLLPLELE KTAIQNYTVT EFQPLYYVAE SFNDAKEKVR NFAATIPRPF SVRYDPYTQR
     IEVLDNTQQL KILADSINSE IGILCSALQK IK
//
