PH4H_HUMAN
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 03-AUG-2022, entry version 250.
DE RecName: Full=Phenylalanine-4-hydroxylase;
DE Short=PAH;
DE EC=1.14.16.1 {ECO:0000269|PubMed:18460651, ECO:0000269|PubMed:18835579};
DE AltName: Full=Phe-4-monooxygenase;
GN Name=PAH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX 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 amino
RT 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 131-144.
RX PubMed=2461704; DOI=10.1042/bj2550193;
RA Cotton R.G., McAdam W., Jennings I., Morgan F.J.;
RT "A monoclonal antibody to aromatic amino acid hydroxylases. Identification
RT of the epitope.";
RL Biochem. J. 255:193-196(1988).
RN [5]
RP PHOSPHORYLATION AT SER-16.
RX PubMed=12185072; DOI=10.1074/jbc.m112197200;
RA Miranda F.F., Teigen K., Thorolfsson M., Svebak R.M., Knappskog P.M.,
RA Flatmark T., Martinez A.;
RT "Phosphorylation and mutations of Ser(16) in human phenylalanine
RT hydroxylase. Kinetic and structural effects.";
RL J. Biol. Chem. 277:40937-40943(2002).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=18460651; DOI=10.1096/fj.08-108522;
RA Calvo A.C., Pey A.L., Ying M., Loer C.M., Martinez A.;
RT "Anabolic function of phenylalanine hydroxylase in Caenorhabditis
RT elegans.";
RL FASEB J. 22:3046-3058(2008).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND MUTAGENESIS OF ILE-283.
RX PubMed=18835579; DOI=10.1016/j.gene.2008.09.005;
RA Siltberg-Liberles J., Steen I.H., Svebak R.M., Martinez A.;
RT "The phylogeny of the aromatic amino acid hydroxylases revisited by
RT characterizing phenylalanine hydroxylase from Dictyostelium discoideum.";
RL Gene 427:86-92(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-16, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 117-424.
RX PubMed=9406548; DOI=10.1038/nsb1297-995;
RA Erlandsen H., Fusetti F., Martinez A., Hough E., Flatmark T., 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 [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 117-424.
RX PubMed=9843368; DOI=10.1021/bi9815290;
RA Erlandsen H., Flatmark T., Stevens R.C., Hough E.;
RT "Crystallographic analysis of the human phenylalanine hydroxylase catalytic
RT domain with bound catechol inhibitors at 2.0-A resolution.";
RL Biochemistry 37:15638-15646(1998).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 117-452, AND SUBUNIT.
RX 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 [13]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 118-424.
RX 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 [14]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 103-427.
RX 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 [15]
RP REVIEW ON PKU VARIANTS.
RX PubMed=1679029; DOI=10.1007/bf00197152;
RA Konecki D.S., Lichter-Konecki U.;
RT "The phenylketonuria locus: current knowledge about alleles and mutations
RT of the phenylalanine hydroxylase gene in various populations.";
RL Hum. Genet. 87:377-388(1991).
RN [16]
RP REVIEW ON PKU VARIANTS.
RX 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 [17]
RP REVIEW ON PKU VARIANTS.
RX PubMed=1301187; DOI=10.1002/humu.1380010104;
RA Eisensmith R.C., Woo S.L.C.;
RT "Molecular basis of phenylketonuria and related hyperphenylalaninemias:
RT mutations and polymorphisms in the human phenylalanine hydroxylase gene.";
RL Hum. Mutat. 1:13-22(1992).
RN [18]
RP DATABASE OF PKU VARIANTS.
RX 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 [19]
RP VARIANT PKU PRO-311.
RX 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 substitution
RT in an exon of the human phenylalanine hydroxylase gene.";
RL Biochemistry 27:2881-2885(1988).
RN [20]
RP VARIANT PKU LYS-280.
RX 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 deficiency.";
RL Am. J. Hum. Genet. 44:511-517(1989).
RN [21]
RP VARIANT PKU PRO-311.
RX PubMed=2615649;
RA Hofman K.J., Antonarakis S.E., Missiou-Tsangaraki S., Boehm C.D., 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 [22]
RP VARIANT PKU LEU-364 DEL.
RX PubMed=1975559; DOI=10.1007/bf00206750;
RA Svensson E., Andersson B., Hagenfeldt L.;
RT "Two mutations within the coding sequence of the phenylalanine hydroxylase
RT gene.";
RL Hum. Genet. 85:300-304(1990).
RN [23]
RP VARIANT PKU GLN-261.
RX 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 Italian
RT patients with phenylketonuria by using the chemical cleavage method: a new
RT splice mutation.";
RL Am. J. Hum. Genet. 48:631-635(1991).
RN [24]
RP VARIANT PKU SER-255.
RX PubMed=2014802;
RA Hofman K.J., Steel G., Kazazian H.H. Jr., Valle D.;
RT "Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine
RT hydroxylase gene.";
RL Am. J. Hum. Genet. 48:791-798(1991).
RN [25]
RP VARIANTS PKU TRP-252 AND LEU-281.
RX 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 [26]
RP VARIANT PKU LEU-281.
RX PubMed=1672290; DOI=10.1016/0888-7543(91)90238-a;
RA Dworniczak B., Grudda K., Stumper J., Bartholome K., Aulehla-Scholz C.,
RA Horst J.;
RT "Phenylalanine hydroxylase gene: novel missense mutation in exon 7 causing
RT severe phenylketonuria.";
RL Genomics 9:193-199(1991).
RN [27]
RP VARIANTS PKU SER-48 AND GLY-221.
RX PubMed=1679030; DOI=10.1007/bf00197153;
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 in a
RT Turkish patient with phenylketonuria.";
RL Hum. Genet. 87:389-393(1991).
RN [28]
RP VARIANT PKU ILE-94 DEL.
RX PubMed=1709636; DOI=10.1016/s0021-9258(18)92824-3;
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 [29]
RP VARIANTS NON-PKU HPA VAL-306 AND ASN-415.
RX 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 [30]
RP VARIANTS PKU GLN-408 AND TRP-408.
RX 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 [31]
RP VARIANT PKU 364-LEU--GLU-368 DEL.
RX 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 in
RT phenylketonuria.";
RL Hum. Mol. Genet. 1:763-764(1992).
RN [32]
RP VARIANT PKU LEU-244.
RX 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 [33]
RP VARIANTS PKU.
RX 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 mutations
RT detected by denaturing gradient gel electrophoresis.";
RL Genomics 17:141-146(1993).
RN [34]
RP VARIANT NON-PKU HPA GLY-390.
RX PubMed=8098245; DOI=10.1093/hmg/2.1.31;
RA Abadie V., Jaruzelska J., Lyonnet S., Millasseau P., Berthelon M., Rey F.,
RA 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 [35]
RP VARIANT NON-PKU HPA SER-98.
RX PubMed=8364546; DOI=10.1093/hmg/2.7.1061;
RA Guldberg P., Lou H.C., Henriksen K.F., Mikkelsen I., Olsen B., Holck B.,
RA Guettler F.;
RT "A novel missense mutation in the phenylalanine hydroxylase gene of a
RT homozygous Pakistani patient with non-PKU hyperphenylalaninemia.";
RL Hum. Mol. Genet. 2:1061-1062(1993).
RN [36]
RP VARIANT PKU VAL-276.
RX 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 [37]
RP VARIANTS NON-PKU HPA VAL-47; ARG-87; LEU-176 AND ALA-245.
RX 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 in 25
RT Danish patients.";
RL Genomics 21:453-455(1994).
RN [38]
RP VARIANTS PKU THR-164; ALA-171; SER-239; GLN-252 AND LEU-331.
RX PubMed=7833954; DOI=10.1002/humu.1380040311;
RA Benit P., Rey F., Melle D., Munnich A., Rey J.;
RT "Five novel missense mutations of the phenylalanine hydroxylase gene in
RT phenylketonuria.";
RL Hum. Mutat. 4:229-231(1994).
RN [39]
RP CHARACTERIZATION OF VARIANT PKU GLY-143.
RX PubMed=8889583;
RX DOI=10.1002/(sici)1098-1004(1996)8:3<236::aid-humu7>3.0.co;2-7;
RA Knappskog P.M., Eiken H.G., Martinez A., Bruland O., Apold J., Flatmark T.;
RT "PKU mutation (D143G) associated with an apparent high residual enzyme
RT activity: expression of a kinetic variant form of phenylalanine hydroxylase
RT in three different systems.";
RL Hum. Mutat. 8:236-246(1996).
RN [40]
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; HIS-394;
RP VAL-403; TRP-408 AND CYS-414.
RX PubMed=8889590;
RX DOI=10.1002/(sici)1098-1004(1996)8:3<276::aid-humu14>3.0.co;2-#;
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 [41]
RP VARIANTS PKU CYS-204 AND SER-207.
RX 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 [42]
RP VARIANTS PKU.
RX PubMed=9101291;
RX DOI=10.1002/(sici)1098-1004(1997)9:4<316::aid-humu3>3.0.co;2-3;
RA Byck S., Tyfield L., Carter K., Scriver C.R.;
RT "Prediction of multiple hypermutable codons in the human PAH gene: codon
RT 280 contains recurrent mutations in Quebec and other populations.";
RL Hum. Mutat. 9:316-321(1997).
RN [43]
RP CHARACTERIZATION OF VARIANTS.
RX PubMed=9450897;
RX DOI=10.1002/(sici)1098-1004(1998)11:1<4::aid-humu2>3.0.co;2-l;
RA Waters P.J., Parniak M.A., Nowacki P., Scriver C.R.;
RT "In vitro expression analysis of mutations in phenylalanine hydroxylase:
RT linking genotype to phenotype and structure to function.";
RL Hum. Mutat. 11:4-17(1998).
RN [44]
RP VARIANTS PKU SER-48; ASN-65; PRO-213 AND ASN-283, AND VARIANTS NON-PKU HPA
RP SER-48; LEU-55; TYR-201 AND LEU-269.
RX PubMed=9521426;
RX DOI=10.1002/(sici)1098-1004(1998)11:3<240::aid-humu9>3.0.co;2-l;
RA Bosco P., Cali F., Meli C., Mollica F., Zammarchi E., Cerone R., Vanni C.,
RA 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 [45]
RP VARIANTS PKU GLN-243; LEU-349 AND TRP-408.
RX PubMed=9600453;
RX DOI=10.1002/(sici)1098-1004(1998)11:5<354::aid-humu2>3.0.co;2-w;
RA de Lucca M., Perez B., Desviat L.R., Ugarte M.;
RT "Molecular basis of phenylketonuria in Venezuela: presence of two novel
RT null mutations.";
RL Hum. Mutat. 11:354-359(1998).
RN [46]
RP VARIANT PKU THR-362.
RX PubMed=10200057;
RX DOI=10.1002/(sici)1098-1004(1998)11:6<482::aid-humu15>3.0.co;2-e;
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 phenylketonuria.";
RL Hum. Mutat. 11:482-482(1998).
RN [47]
RP VARIANTS PKU HIS-53; ASP-207 AND LEU-388.
RX PubMed=9452061; DOI=10.1002/humu.1380110140;
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 [48]
RP VARIANTS PKU PHE-39 DEL; THR-65; GLN-158; ILE-167; ALA-190; CYS-241 AND
RP TRP-408.
RX PubMed=9452062; DOI=10.1002/humu.1380110141;
RA Michiels L., Francois B., Raus J., Vandevyver C.;
RT "Identification of seven new mutations in the phenylalanine hydroxylase
RT gene, associated with hyperphenylalaninemia in the Belgian population.";
RL Hum. Mutat. Suppl. 1:S123-S124(1998).
RN [49]
RP VARIANTS PKU.
RX 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 in 44
RT Romanian phenylketonuric alleles.";
RL Hum. Mutat. 12:314-319(1998).
RN [50]
RP CHARACTERIZATION OF VARIANTS PKU ASP-104 AND ASN-157.
RX PubMed=9792411;
RX DOI=10.1002/(sici)1098-1004(1998)12:5<344::aid-humu8>3.0.co;2-d;
RA Waters P.J., Parniak M.A., Hewson A.S., Scriver C.R.;
RT "Alterations in protein aggregation and degradation due to mild and severe
RT missense mutations (A104D, R157N) in the human phenylalanine hydroxylase
RT gene.";
RL Hum. Mutat. 12:344-354(1998).
RN [51]
RP VARIANTS NON-PKU HPA CYS-241; GLN-243 AND PRO-413.
RX PubMed=9852673; DOI=10.1007/s100380050079;
RA Kibayashi M., Nagao M., Chiba S.;
RT "Mutation analysis of the phenylalanine hydroxylase gene and its clinical
RT implications in two Japanese patients with non-phenylketonuria
RT hyperphenylalaninemia.";
RL J. Hum. Genet. 43:231-236(1998).
RN [52]
RP VARIANT PKU LEU-407.
RX PubMed=9950317; DOI=10.1007/s004310051018;
RA Corsello G., Bosco P., Cali F., Greco D., Cammarata M., Ciaccio M.,
RA Piccione M., Romano V.;
RT "Maternal phenylketonuria in two Sicilian families identified by maternal
RT blood phenylalanine level screening and identification of a new
RT phenylalanine hydroxylase gene mutation (P407L).";
RL Eur. J. Pediatr. 158:83-84(1999).
RN [53]
RP VARIANTS PKU.
RX PubMed=10679941;
RX DOI=10.1002/(sici)1098-1004(200003)15:3<254::aid-humu6>3.0.co;2-w;
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 [54]
RP CHARACTERIZATION OF VARIANTS PKU.
RX 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 [55]
RP VARIANTS PKU.
RX 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 [56]
RP VARIANTS PKU, AND VARIANTS HPA.
RX 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 [57]
RP VARIANTS PKU TRP-252 AND THR-318, AND VARIANT GLU-274.
RX 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 for
RT molecular diagnostics.";
RL Mol. Genet. Metab. 73:280-284(2001).
RN [58]
RP VARIANT NON-PKU HPA GLY-76.
RX PubMed=11935335; DOI=10.1007/s00439-002-0677-7;
RA Chen K.J., Chao H.K., Hsiao K.J., Su T.S.;
RT "Identification and characterization of a novel liver-specific enhancer of
RT the human phenylalanine hydroxylase gene.";
RL Hum. Genet. 110:235-243(2002).
RN [59]
RP VARIANTS HPA LEU-39; LEU-55; VAL-65; MET-177; ALA-245; GLN-261; TYR-310;
RP SER-314; VAL-403; TRP-408; CYS-414 AND ASN-415, AND VARIANTS PKU SER-48;
RP ASP-61; SER-65; THR-65; VAL-65; GLN-158; GLN-170; GLN-261; LEU-275;
RP LEU-281; SER-300; GLY-390; TRP-408; PRO-413; CYS-414 AND HIS-417.
RX PubMed=12501224; DOI=10.1056/nejmoa021654;
RA Muntau A.C., Roschinger W., Habich M., Demmelmair H., Hoffmann B.,
RA Sommerhoff C.P., Roscher A.A.;
RT "Tetrahydrobiopterin as an alternative treatment for mild
RT phenylketonuria.";
RL N. Engl. J. Med. 347:2122-2132(2002).
RN [60]
RP CHARACTERIZATION OF VARIANTS PKU LEU-55; SER-65; GLN-170; LEU-275; SER-300;
RP TYR-310; SER-314; TRP-408; CYS-414 AND HIS-417.
RX PubMed=18538294; DOI=10.1016/j.ajhg.2008.05.013;
RA Gersting S.W., Kemter K.F., Staudigl M., Messing D.D., Danecka M.K.,
RA Lagler F.B., Sommerhoff C.P., Roscher A.A., Muntau A.C.;
RT "Loss of function in phenylketonuria is caused by impaired molecular
RT motions and conformational instability.";
RL Am. J. Hum. Genet. 83:5-17(2008).
RN [61]
RP VARIANTS HPA PHE-39 DEL; LEU-121; TYR-196; TYR-201; ILE-230; SER-300;
RP VAL-306; MET-380; GLY-390 AND VAL-403, AND VARIANTS PKU VAL-65; TRP-252;
RP GLN-261 AND TRP-408.
RX PubMed=23792259; DOI=10.1016/j.clinbiochem.2013.06.009;
RA Trunzo R., Santacroce R., D'Andrea G., Longo V., De Girolamo G.,
RA Dimatteo C., Leccese A., Lillo V., Papadia F., Margaglione M.;
RT "Mutation analysis in Hyperphenylalaninemia patients from South Italy.";
RL Clin. Biochem. 46:1896-1898(2013).
RN [62]
RP VARIANTS PKU TYR-290; VAL-322 AND SER-421.
RX PubMed=22526846; DOI=10.1007/s10545-012-9485-y;
RA Sterl E., Paul K., Paschke E., Zschocke J., Brunner-Krainz M., Windisch E.,
RA Konstantopoulou V., Moslinger D., Karall D., Scholl-Burgi S., Sperl W.,
RA Lagler F., Plecko B.;
RT "Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian
RT patients with PAH deficiency: comprehensive results from molecular analysis
RT in 147 patients.";
RL J. Inherit. Metab. Dis. 36:7-13(2013).
RN [63]
RP VARIANTS PKU ALA-45; SER-48; PRO-62; SER-157; GLN-158; LEU-177; GLY-178;
RP ALA-190; HIS-226; ALA-245; TRP-252; GLN-261; LYS-280; LEU-281; SER-300;
RP PRO-349; GLY-390; VAL-403; TRP-408 AND ASN-415.
RX PubMed=22513348; DOI=10.1016/j.ymgme.2012.03.015;
RA Groselj U., Tansek M.Z., Kovac J., Hovnik T., Podkrajsek K.T.,
RA Battelino T.;
RT "Five novel mutations and two large deletions in a population analysis of
RT the phenylalanine hydroxylase gene.";
RL Mol. Genet. Metab. 106:142-148(2012).
CC -!- FUNCTION: Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.
CC {ECO:0000269|PubMed:18460651, ECO:0000269|PubMed:18835579}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-phenylalanine +
CC O2 = (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + L-
CC tyrosine; Xref=Rhea:RHEA:20273, ChEBI:CHEBI:15379, ChEBI:CHEBI:15642,
CC ChEBI:CHEBI:58095, ChEBI:CHEBI:58315, ChEBI:CHEBI:59560;
CC EC=1.14.16.1; Evidence={ECO:0000269|PubMed:18460651,
CC ECO:0000269|PubMed:18835579};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:P04176};
CC -!- ACTIVITY 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 domain
CC in the C-terminal portion of the molecule.
CC {ECO:0000269|PubMed:18460651, ECO:0000269|PubMed:18835579}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=150 uM for L-phenylalanine {ECO:0000269|PubMed:18835579};
CC KM=154 uM for L-phenylalanine (at 25 degrees Celsius)
CC {ECO:0000269|PubMed:18460651};
CC KM=30 uM for tetrahydrobiopterin (BH(4))
CC {ECO:0000269|PubMed:18835579};
CC KM=36 uM for tetrahydrobiopterin (BH(4)) (at 25 degrees Celsius)
CC {ECO:0000269|PubMed:18460651};
CC Vmax=3500 nmol/min/mg enzyme towards L-phenylalanine (at 25 degrees
CC Celsius) {ECO:0000269|PubMed:18460651};
CC Vmax=3600 nmol/min/mg enzyme towards tetrahydrobiopterin (BH(4)) (at
CC 25 degrees Celsius) {ECO:0000269|PubMed:18460651};
CC Vmax=3640 nmol/min/mg enzyme towards L-phenylalanine (preincubated
CC with L-Phe) {ECO:0000269|PubMed:18835579};
CC Vmax=1230 nmol/min/mg enzyme towards L-phenylalanine (preincubated
CC with BH(4)) {ECO:0000269|PubMed:18835579};
CC Temperature dependence:
CC Optimum temperature is 50 degrees Celsius.
CC {ECO:0000269|PubMed:18835579};
CC -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation;
CC acetoacetate and fumarate from L-phenylalanine: step 1/6.
CC -!- SUBUNIT: Homodimer and homotetramer. {ECO:0000269|PubMed:9642259}.
CC -!- PTM: Phosphorylation at Ser-16 increases basal activity and facilitates
CC activation by the substrate phenylalanine.
CC {ECO:0000269|PubMed:12185072}.
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: Phenylketonuria (PKU) [MIM:261600]: Autosomal recessive inborn
CC error of phenylalanine metabolism, due to severe phenylalanine
CC hydroxylase deficiency. It is characterized by blood concentrations of
CC phenylalanine persistently above 1200 mumol (normal concentration 100
CC mumol) which usually causes intellectual disability (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 {ECO:0000269|PubMed:10200057, ECO:0000269|PubMed:10679941,
CC ECO:0000269|PubMed:11180595, ECO:0000269|PubMed:11326337,
CC ECO:0000269|PubMed:11385716, ECO:0000269|PubMed:11461196,
CC ECO:0000269|PubMed:12501224, ECO:0000269|PubMed:1355066,
CC ECO:0000269|PubMed:1363837, ECO:0000269|PubMed:1363838,
CC ECO:0000269|PubMed:1671810, ECO:0000269|PubMed:1672290,
CC ECO:0000269|PubMed:1672294, ECO:0000269|PubMed:1679030,
CC ECO:0000269|PubMed:1709636, ECO:0000269|PubMed:18538294,
CC ECO:0000269|PubMed:1975559, ECO:0000269|PubMed:2014802,
CC ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:22526846,
CC ECO:0000269|PubMed:23792259, ECO:0000269|PubMed:2564729,
CC ECO:0000269|PubMed:2615649, ECO:0000269|PubMed:2840952,
CC ECO:0000269|PubMed:7833954, ECO:0000269|PubMed:8068076,
CC ECO:0000269|PubMed:8406445, ECO:0000269|PubMed:8889583,
CC ECO:0000269|PubMed:8889590, ECO:0000269|PubMed:9048935,
CC ECO:0000269|PubMed:9101291, ECO:0000269|PubMed:9452061,
CC ECO:0000269|PubMed:9452062, ECO:0000269|PubMed:9521426,
CC ECO:0000269|PubMed:9600453, ECO:0000269|PubMed:9792407,
CC ECO:0000269|PubMed:9792411, ECO:0000269|PubMed:9950317}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA)
CC [MIM:261600]: Mild form of phenylalanine hydroxylase deficiency
CC characterized by phenylalanine levels persistently below 600 mumol,
CC which allows normal intellectual and behavioral development without
CC treatment. Non-PKU HPA is usually caused by the combined effect of a
CC mild hyperphenylalaninemia mutation and a severe one.
CC {ECO:0000269|PubMed:1358789, ECO:0000269|PubMed:8088845,
CC ECO:0000269|PubMed:8098245, ECO:0000269|PubMed:9521426,
CC ECO:0000269|PubMed:9852673}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hyperphenylalaninemia (HPA) [MIM:261600]: Mildest form of
CC phenylalanine hydroxylase deficiency. {ECO:0000269|PubMed:11385716,
CC ECO:0000269|PubMed:11935335, ECO:0000269|PubMed:12501224,
CC ECO:0000269|PubMed:1358789, ECO:0000269|PubMed:23792259,
CC ECO:0000269|PubMed:8088845, ECO:0000269|PubMed:8098245,
CC ECO:0000269|PubMed:9521426, ECO:0000269|PubMed:9852673}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC hydroxylase family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Phenylalanine hydroxylase entry;
CC URL="https://en.wikipedia.org/wiki/Phenylalanine_hydroxylase";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
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 CCDS; CCDS9092.1; -.
DR PIR; A00508; WHHUF.
DR RefSeq; NP_000268.1; NM_000277.1.
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; 4ANP; X-ray; 2.11 A; A=104-427.
DR PDB; 4PAH; X-ray; 2.00 A; A=117-424.
DR PDB; 5FII; X-ray; 1.80 A; A/B/C/D=19-118.
DR PDB; 5PAH; X-ray; 2.10 A; A=117-424.
DR PDB; 6HPO; X-ray; 1.67 A; A=1-452.
DR PDB; 6HYC; X-ray; 3.18 A; A/B/C/D=1-452.
DR PDB; 6N1K; X-ray; 3.06 A; A/B/C/D=2-452.
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; 4ANP; -.
DR PDBsum; 4PAH; -.
DR PDBsum; 5FII; -.
DR PDBsum; 5PAH; -.
DR PDBsum; 6HPO; -.
DR PDBsum; 6HYC; -.
DR PDBsum; 6N1K; -.
DR PDBsum; 6PAH; -.
DR AlphaFoldDB; P00439; -.
DR SASBDB; P00439; -.
DR SMR; P00439; -.
DR BioGRID; 111090; 6.
DR DIP; DIP-58927N; -.
DR IntAct; P00439; 5.
DR MINT; P00439; -.
DR STRING; 9606.ENSP00000448059; -.
DR BindingDB; P00439; -.
DR ChEMBL; CHEMBL3076; -.
DR DrugBank; DB03673; beta-2-Thienyl-L-alanine.
DR DrugBank; DB04339; Carbocisteine.
DR DrugBank; DB06778; Cupric sulfate.
DR DrugBank; DB04419; D-norleucine.
DR DrugBank; DB06262; Droxidopa.
DR DrugBank; DB04400; L-erythro-7,8-dihydrobiopterin.
DR DrugBank; DB00368; Norepinephrine.
DR DrugBank; DB00120; Phenylalanine.
DR DrugBank; DB02562; Quinonoid 7,8-Tetrahydrobiopterin.
DR DrugBank; DB00360; Sapropterin.
DR DrugCentral; P00439; -.
DR GuidetoPHARMACOLOGY; 1240; -.
DR iPTMnet; P00439; -.
DR PhosphoSitePlus; P00439; -.
DR BioMuta; PAH; -.
DR DMDM; 129973; -.
DR UCD-2DPAGE; P00439; -.
DR EPD; P00439; -.
DR MassIVE; P00439; -.
DR MaxQB; P00439; -.
DR PaxDb; P00439; -.
DR PeptideAtlas; P00439; -.
DR PRIDE; P00439; -.
DR ProteomicsDB; 51249; -.
DR Antibodypedia; 30481; 287 antibodies from 32 providers.
DR DNASU; 5053; -.
DR Ensembl; ENST00000553106.6; ENSP00000448059.1; ENSG00000171759.10.
DR GeneID; 5053; -.
DR KEGG; hsa:5053; -.
DR MANE-Select; ENST00000553106.6; ENSP00000448059.1; NM_000277.3; NP_000268.1.
DR UCSC; uc001tjq.2; human.
DR CTD; 5053; -.
DR DisGeNET; 5053; -.
DR GeneCards; PAH; -.
DR GeneReviews; PAH; -.
DR HGNC; HGNC:8582; PAH.
DR HPA; ENSG00000171759; Group enriched (kidney, liver).
DR MalaCards; PAH; -.
DR MIM; 261600; phenotype.
DR MIM; 612349; gene.
DR neXtProt; NX_P00439; -.
DR OpenTargets; ENSG00000171759; -.
DR Orphanet; 79254; Classic phenylketonuria.
DR Orphanet; 2209; Maternal phenylketonuria.
DR Orphanet; 79651; Mild hyperphenylalaninemia.
DR Orphanet; 79253; Mild phenylketonuria.
DR Orphanet; 293284; Tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria.
DR PharmGKB; PA32911; -.
DR VEuPathDB; HostDB:ENSG00000171759; -.
DR eggNOG; KOG3820; Eukaryota.
DR GeneTree; ENSGT00950000182885; -.
DR HOGENOM; CLU_023198_0_1_1; -.
DR InParanoid; P00439; -.
DR OMA; HAAQPLY; -.
DR OrthoDB; 614557at2759; -.
DR PhylomeDB; P00439; -.
DR TreeFam; TF313327; -.
DR BioCyc; MetaCyc:HS10374-MON; -.
DR BRENDA; 1.14.16.1; 2681.
DR PathwayCommons; P00439; -.
DR Reactome; R-HSA-2160456; Phenylketonuria.
DR Reactome; R-HSA-8964208; Phenylalanine metabolism.
DR SABIO-RK; P00439; -.
DR SignaLink; P00439; -.
DR SIGNOR; P00439; -.
DR UniPathway; UPA00139; UER00337.
DR BioGRID-ORCS; 5053; 8 hits in 1073 CRISPR screens.
DR ChiTaRS; PAH; human.
DR EvolutionaryTrace; P00439; -.
DR GeneWiki; Phenylalanine_hydroxylase; -.
DR GenomeRNAi; 5053; -.
DR Pharos; P00439; Tclin.
DR PRO; PR:P00439; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; P00439; protein.
DR Bgee; ENSG00000171759; Expressed in right lobe of liver and 122 other tissues.
DR ExpressionAtlas; P00439; baseline and differential.
DR Genevisible; P00439; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; IDA:CACAO.
DR GO; GO:0042423; P:catecholamine biosynthetic process; NAS:BHF-UCL.
DR GO; GO:0008652; P:cellular amino acid biosynthetic process; TAS:ProtInc.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0042136; P:neurotransmitter biosynthetic process; NAS:BHF-UCL.
DR GO; GO:0006571; P:tyrosine biosynthetic process; IBA:GO_Central.
DR CDD; cd03347; eu_PheOH; 1.
DR Gene3D; 1.10.800.10; -; 1.
DR InterPro; IPR045865; ACT-like_dom_sf.
DR InterPro; IPR002912; ACT_dom.
DR InterPro; IPR001273; ArAA_hydroxylase.
DR InterPro; IPR018301; ArAA_hydroxylase_Fe/CU_BS.
DR InterPro; IPR036951; ArAA_hydroxylase_sf.
DR InterPro; IPR036329; Aro-AA_hydroxylase_C_sf.
DR InterPro; IPR019774; Aromatic-AA_hydroxylase_C.
DR InterPro; IPR041912; Euk_PheOH_cat.
DR InterPro; IPR005961; Phe-4-hydroxylase_tetra.
DR InterPro; IPR019773; Tyrosine_3-monooxygenase-like.
DR PANTHER; PTHR11473; PTHR11473; 1.
DR Pfam; PF01842; ACT; 1.
DR Pfam; PF00351; Biopterin_H; 1.
DR PIRSF; PIRSF000336; TH; 1.
DR PRINTS; PR00372; FYWHYDRXLASE.
DR SUPFAM; SSF55021; SSF55021; 1.
DR SUPFAM; SSF56534; SSF56534; 1.
DR TIGRFAMs; TIGR01268; Phe4hydrox_tetr; 1.
DR PROSITE; PS51671; ACT; 1.
DR PROSITE; PS00367; BH4_AAA_HYDROXYL_1; 1.
DR PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Direct protein sequencing;
KW Disease variant; Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW Phenylalanine catabolism; Phenylketonuria; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..452
FT /note="Phenylalanine-4-hydroxylase"
FT /id="PRO_0000205548"
FT DOMAIN 36..114
FT /note="ACT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01007"
FT BINDING 285
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04176"
FT BINDING 290
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04176"
FT BINDING 330
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04176"
FT MOD_RES 16
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:12185072,
FT ECO:0007744|PubMed:24275569"
FT VARIANT 16
FT /note="S -> P (in PKU; dbSNP:rs62642946)"
FT /id="VAR_000869"
FT VARIANT 20
FT /note="Q -> L (in HPA; dbSNP:rs199475662)"
FT /id="VAR_009239"
FT VARIANT 39
FT /note="F -> L (in HPA and PKU; haplotype 1;
FT dbSNP:rs62642926)"
FT /evidence="ECO:0000269|PubMed:12501224"
FT /id="VAR_000870"
FT VARIANT 39
FT /note="Missing (in PKU; haplotypes 9,21)"
FT /evidence="ECO:0000269|PubMed:23792259,
FT ECO:0000269|PubMed:9452062"
FT /id="VAR_000871"
FT VARIANT 40
FT /note="S -> L (in PKU; dbSNP:rs62642938)"
FT /evidence="ECO:0000269|PubMed:8889590"
FT /id="VAR_000872"
FT VARIANT 41
FT /note="L -> F (in PKU; dbSNP:rs62642928)"
FT /id="VAR_000873"
FT VARIANT 41
FT /note="L -> P (in PKU; mild; dbSNP:rs62642916)"
FT /id="VAR_009240"
FT VARIANT 42
FT /note="K -> I (in PKU; haplotype 21; dbSNP:rs62635346)"
FT /id="VAR_000874"
FT VARIANT 45
FT /note="V -> A (in PKU; dbSNP:rs1592988883)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_067994"
FT VARIANT 46
FT /note="G -> S (in PKU; haplotype 5; significantly reduces
FT phenylalanine binding; dbSNP:rs74603784)"
FT /evidence="ECO:0000269|PubMed:8889590"
FT /id="VAR_000875"
FT VARIANT 47
FT /note="A -> V (in non-PKU HPA; haplotype 4; significantly
FT reduces phenylalanine binding; dbSNP:rs118203925)"
FT /evidence="ECO:0000269|PubMed:8088845"
FT /id="VAR_000876"
FT VARIANT 48
FT /note="L -> S (in PKU; mild; haplotypes 3,4;
FT dbSNP:rs5030841)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:1679030, ECO:0000269|PubMed:22513348,
FT ECO:0000269|PubMed:8889590, ECO:0000269|PubMed:9521426"
FT /id="VAR_000877"
FT VARIANT 53
FT /note="R -> H (in PKU; dbSNP:rs118092776)"
FT /evidence="ECO:0000269|PubMed:9452061"
FT /id="VAR_000878"
FT VARIANT 55
FT /note="F -> L (in HPA and PKU; does not affect
FT oligomerization; results in loss of substrate activation;
FT dbSNP:rs199475598)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294, ECO:0000269|PubMed:9521426"
FT /id="VAR_000879"
FT VARIANT 56
FT /note="E -> D (in PKU; haplotype 10; dbSNP:rs199475567)"
FT /id="VAR_000880"
FT VARIANT 61
FT /note="N -> D (in PKU; dbSNP:rs199475651)"
FT /evidence="ECO:0000269|PubMed:12501224"
FT /id="VAR_067995"
FT VARIANT 62
FT /note="L -> P (in PKU)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_067996"
FT VARIANT 63..64
FT /note="TH -> PN (in PKU; haplotype 1; abolishes
FT phenylalanine binding)"
FT /id="VAR_000881"
FT VARIANT 65
FT /note="I -> N (in PKU; dbSNP:rs75193786)"
FT /evidence="ECO:0000269|PubMed:9521426"
FT /id="VAR_000882"
FT VARIANT 65
FT /note="I -> S (in PKU; results in disturbed
FT oligomerization; results in loss of substrate activation;
FT dbSNP:rs75193786)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294"
FT /id="VAR_067997"
FT VARIANT 65
FT /note="I -> T (in PKU; haplotypes 1,5,9,21,B; abolishes
FT phenylalanine binding; dbSNP:rs75193786)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:8889590, ECO:0000269|PubMed:9452062"
FT /id="VAR_000883"
FT VARIANT 65
FT /note="I -> V (in HPA and PKU; dbSNP:rs199475643)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:23792259"
FT /id="VAR_067998"
FT VARIANT 67
FT /note="S -> P (in PKU; haplotype 4; dbSNP:rs5030842)"
FT /id="VAR_000884"
FT VARIANT 68
FT /note="R -> S (in PKU; haplotype 1; dbSNP:rs76394784)"
FT /evidence="ECO:0000269|PubMed:8889590"
FT /id="VAR_000885"
FT VARIANT 76
FT /note="E -> A (in PKU; dbSNP:rs62507347)"
FT /id="VAR_000886"
FT VARIANT 76
FT /note="E -> G (in non-PKU HPA; dbSNP:rs62507347)"
FT /evidence="ECO:0000269|PubMed:11935335"
FT /id="VAR_067999"
FT VARIANT 84
FT /note="D -> Y (in PKU; haplotype 4; dbSNP:rs62514902)"
FT /id="VAR_000887"
FT VARIANT 87
FT /note="S -> R (in non-PKU HPA; haplotype 1;
FT dbSNP:rs62516151)"
FT /evidence="ECO:0000269|PubMed:8088845"
FT /id="VAR_000888"
FT VARIANT 92
FT /note="T -> I (in PKU; dbSNP:rs62514903)"
FT /id="VAR_000889"
FT VARIANT 94
FT /note="Missing (in PKU; mild; haplotype 2)"
FT /evidence="ECO:0000269|PubMed:1709636"
FT /id="VAR_000890"
FT VARIANT 98
FT /note="L -> S (in non-PKU HPA; dbSNP:rs62517167)"
FT /evidence="ECO:0000269|PubMed:8364546"
FT /id="VAR_000891"
FT VARIANT 104
FT /note="A -> D (in PKU; mild; haplotype 1;
FT dbSNP:rs62642929)"
FT /evidence="ECO:0000269|PubMed:9792411"
FT /id="VAR_000892"
FT VARIANT 110
FT /note="S -> C (in HPA)"
FT /id="VAR_009241"
FT VARIANT 121
FT /note="F -> L (in HPA)"
FT /evidence="ECO:0000269|PubMed:23792259"
FT /id="VAR_069776"
FT VARIANT 124
FT /note="T -> I (in PKU; haplotype 28; dbSNP:rs199475571)"
FT /id="VAR_000893"
FT VARIANT 129
FT /note="D -> Y (in PKU; dbSNP:rs199475606)"
FT /id="VAR_000894"
FT VARIANT 143
FT /note="D -> G (in PKU; haplotype 11; dbSNP:rs199475572)"
FT /evidence="ECO:0000269|PubMed:8889583"
FT /id="VAR_000895"
FT VARIANT 145
FT /note="D -> V (in PKU; dbSNP:rs140175796)"
FT /id="VAR_011566"
FT VARIANT 146
FT /note="H -> Y (in PKU; dbSNP:rs199475599)"
FT /id="VAR_000896"
FT VARIANT 148
FT /note="G -> S (in PKU; haplotypes 1,2,7; dbSNP:rs80297647)"
FT /id="VAR_000897"
FT VARIANT 151
FT /note="D -> H (in PKU; haplotypes 1,8; dbSNP:rs199475597)"
FT /id="VAR_000898"
FT VARIANT 154
FT /note="Y -> N (in PKU; dbSNP:rs199475587)"
FT /id="VAR_000899"
FT VARIANT 155
FT /note="R -> P (in PKU; dbSNP:rs199475663)"
FT /id="VAR_009242"
FT VARIANT 157
FT /note="R -> N (in PKU; severe; 5% activity; requires 2
FT nucleotide substitutions; dbSNP:rs1565853495)"
FT /evidence="ECO:0000269|PubMed:9792411"
FT /id="VAR_000900"
FT VARIANT 157
FT /note="R -> S (in PKU; dbSNP:rs199475612)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_068000"
FT VARIANT 158
FT /note="R -> Q (in PKU; haplotypes 1,2,4,7,16, 28;
FT dbSNP:rs5030843)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:9452062"
FT /id="VAR_000901"
FT VARIANT 158
FT /note="R -> W (in PKU; dbSNP:rs75166491)"
FT /id="VAR_000902"
FT VARIANT 160
FT /note="Q -> P (in PKU; dbSNP:rs199475601)"
FT /id="VAR_000903"
FT VARIANT 161
FT /note="F -> S (in PKU; haplotype 4; dbSNP:rs79635844)"
FT /id="VAR_000904"
FT VARIANT 164
FT /note="I -> T (in PKU; haplotype 1; dbSNP:rs199475595)"
FT /evidence="ECO:0000269|PubMed:7833954"
FT /id="VAR_000905"
FT VARIANT 167
FT /note="N -> I (in PKU; dbSNP:rs77554925)"
FT /evidence="ECO:0000269|PubMed:9452062"
FT /id="VAR_000906"
FT VARIANT 167
FT /note="N -> S (in HPA; dbSNP:rs77554925)"
FT /id="VAR_011567"
FT VARIANT 169
FT /note="R -> H (in PKU; dbSNP:rs199475679)"
FT /id="VAR_011568"
FT VARIANT 170
FT /note="H -> D (in HPA; dbSNP:rs199475655)"
FT /id="VAR_011569"
FT VARIANT 170
FT /note="H -> Q (in PKU; does not affect oligomerization;
FT dbSNP:rs199475652)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294"
FT /id="VAR_068001"
FT VARIANT 170
FT /note="H -> R (in PKU; dbSNP:rs199475573)"
FT /id="VAR_000907"
FT VARIANT 171
FT /note="G -> A (in PKU; haplotype 1; dbSNP:rs199475596)"
FT /evidence="ECO:0000269|PubMed:7833954"
FT /id="VAR_000908"
FT VARIANT 171
FT /note="G -> R (in PKU; dbSNP:rs199475613)"
FT /id="VAR_000909"
FT VARIANT 173
FT /note="P -> T (in PKU; haplotype 4; dbSNP:rs199475574)"
FT /id="VAR_000910"
FT VARIANT 174
FT /note="I -> T (in PKU; haplotype 1; dbSNP:rs138809906)"
FT /id="VAR_000911"
FT VARIANT 174
FT /note="I -> V (in PKU; dbSNP:rs199475632)"
FT /id="VAR_011570"
FT VARIANT 175
FT /note="P -> A (in PKU; dbSNP:rs199475604)"
FT /id="VAR_000912"
FT VARIANT 176
FT /note="R -> L (in non-PKU HPA; dbSNP:rs74486803)"
FT /evidence="ECO:0000269|PubMed:8088845"
FT /id="VAR_000913"
FT VARIANT 176
FT /note="R -> P (in PKU; dbSNP:rs74486803)"
FT /id="VAR_000914"
FT VARIANT 177
FT /note="V -> L (in PKU; haplotype 6; dbSNP:rs199475602)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_000915"
FT VARIANT 177
FT /note="V -> M (in HPA; dbSNP:rs199475602)"
FT /evidence="ECO:0000269|PubMed:12501224"
FT /id="VAR_068002"
FT VARIANT 178
FT /note="E -> G (in non-PKU HPA; dbSNP:rs77958223)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_000916"
FT VARIANT 183
FT /note="E -> Q (in PKU; dbSNP:rs199475664)"
FT /id="VAR_009243"
FT VARIANT 190
FT /note="V -> A (in PKU; haplotype 3; dbSNP:rs62514919)"
FT /evidence="ECO:0000269|PubMed:22513348,
FT ECO:0000269|PubMed:9452062"
FT /id="VAR_000917"
FT VARIANT 194
FT /note="L -> P (in PKU; dbSNP:rs5030844)"
FT /id="VAR_000918"
FT VARIANT 194
FT /note="Missing (in PKU)"
FT /id="VAR_000919"
FT VARIANT 196
FT /note="S -> Y (in HPA; dbSNP:rs865899394)"
FT /evidence="ECO:0000269|PubMed:23792259"
FT /id="VAR_069777"
FT VARIANT 197
FT /note="Missing (in PKU)"
FT /id="VAR_000920"
FT VARIANT 198
FT /note="Missing (in PKU; haplotype 2)"
FT /id="VAR_000921"
FT VARIANT 201
FT /note="H -> R (in PKU; dbSNP:rs62517180)"
FT /id="VAR_000922"
FT VARIANT 201
FT /note="H -> Y (in non-PKU HPA; haplotype 1;
FT dbSNP:rs62517205)"
FT /evidence="ECO:0000269|PubMed:23792259,
FT ECO:0000269|PubMed:9521426"
FT /id="VAR_000923"
FT VARIANT 204
FT /note="Y -> C (in PKU; mild; haplotypes 3,4;
FT dbSNP:rs62514927)"
FT /evidence="ECO:0000269|PubMed:9048935"
FT /id="VAR_000924"
FT VARIANT 205
FT /note="E -> A (in PKU; dbSNP:rs62508593)"
FT /id="VAR_011571"
FT VARIANT 206
FT /note="Y -> D (in PKU; dbSNP:rs62517170)"
FT /id="VAR_000925"
FT VARIANT 207
FT /note="N -> D (in PKU; dbSNP:rs62508572)"
FT /evidence="ECO:0000269|PubMed:9452061"
FT /id="VAR_000926"
FT VARIANT 207
FT /note="N -> S (in PKU; severe; haplotype 4;
FT dbSNP:rs62508721)"
FT /evidence="ECO:0000269|PubMed:9048935"
FT /id="VAR_000927"
FT VARIANT 211
FT /note="P -> T (in PKU; haplotype 4; dbSNP:rs62514931)"
FT /id="VAR_000928"
FT VARIANT 212
FT /note="L -> P (in PKU; dbSNP:rs62517198)"
FT /id="VAR_000929"
FT VARIANT 213
FT /note="L -> P (in PKU; severe; dbSNP:rs62516109)"
FT /evidence="ECO:0000269|PubMed:9521426"
FT /id="VAR_000930"
FT VARIANT 217
FT /note="C -> G (in PKU; dbSNP:rs62508718)"
FT /id="VAR_000931"
FT VARIANT 218
FT /note="G -> V (in PKU; haplotypes 1,2; dbSNP:rs62514933)"
FT /id="VAR_000932"
FT VARIANT 221
FT /note="E -> G (in PKU; haplotype 4; dbSNP:rs62514934)"
FT /evidence="ECO:0000269|PubMed:1679030"
FT /id="VAR_000933"
FT VARIANT 222
FT /note="D -> V (in PKU; haplotypes 3,4; dbSNP:rs62507319)"
FT /id="VAR_000934"
FT VARIANT 224
FT /note="I -> M (in PKU; haplotype 4; dbSNP:rs199475576)"
FT /id="VAR_000935"
FT VARIANT 225
FT /note="P -> R (in PKU; dbSNP:rs62517204)"
FT /id="VAR_000936"
FT VARIANT 225
FT /note="P -> T (in PKU; haplotype 1; dbSNP:rs199475589)"
FT /id="VAR_000937"
FT VARIANT 226
FT /note="Q -> H (in PKU; dbSNP:rs62508615)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_068003"
FT VARIANT 230
FT /note="V -> I (in non-PKU HPA; haplotype 4;
FT dbSNP:rs62516152)"
FT /evidence="ECO:0000269|PubMed:23792259"
FT /id="VAR_000938"
FT VARIANT 231
FT /note="S -> F (in PKU; dbSNP:rs62508577)"
FT /id="VAR_009244"
FT VARIANT 231
FT /note="S -> P (in PKU; dbSNP:rs5030845)"
FT /id="VAR_000939"
FT VARIANT 233
FT /note="F -> L (in PKU; haplotypes 2,3; dbSNP:rs62517208)"
FT /id="VAR_000940"
FT VARIANT 238
FT /note="T -> P (in PKU; haplotype 4; dbSNP:rs199475577)"
FT /id="VAR_000941"
FT VARIANT 239
FT /note="G -> S (in PKU; dbSNP:rs62517178)"
FT /evidence="ECO:0000269|PubMed:7833954"
FT /id="VAR_000942"
FT VARIANT 240
FT /note="F -> S (in PKU; dbSNP:rs62508594)"
FT /id="VAR_011572"
FT VARIANT 241
FT /note="R -> C (in non-PKU HPA and PKU; haplotype 34;
FT dbSNP:rs76687508)"
FT /evidence="ECO:0000269|PubMed:8889590,
FT ECO:0000269|PubMed:9452062, ECO:0000269|PubMed:9852673"
FT /id="VAR_000943"
FT VARIANT 241
FT /note="R -> H (in PKU; haplotypes 1,5; dbSNP:rs62508730)"
FT /id="VAR_000944"
FT VARIANT 241
FT /note="R -> L (in PKU; dbSNP:rs62508730)"
FT /id="VAR_000945"
FT VARIANT 242
FT /note="L -> F (in PKU; dbSNP:rs199475578)"
FT /id="VAR_000946"
FT VARIANT 243
FT /note="R -> Q (in non-PKU HPA and PKU; haplotypes 4,7,9;
FT dbSNP:rs62508588)"
FT /evidence="ECO:0000269|PubMed:9600453,
FT ECO:0000269|PubMed:9852673"
FT /id="VAR_000947"
FT VARIANT 244
FT /note="P -> L (in PKU; haplotype 12; dbSNP:rs118203923)"
FT /evidence="ECO:0000269|PubMed:1363838"
FT /id="VAR_000948"
FT VARIANT 245
FT /note="V -> A (in PKU, HPA and non-PKU HPA; haplotypes 3,7;
FT dbSNP:rs796052017)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:8088845,
FT ECO:0000269|PubMed:8889590"
FT /id="VAR_000949"
FT VARIANT 245
FT /note="V -> E (in PKU; haplotype 11; dbSNP:rs76212747)"
FT /id="VAR_000950"
FT VARIANT 245
FT /note="V -> L (in PKU; dbSNP:rs62508694)"
FT /id="VAR_000951"
FT VARIANT 246
FT /note="A -> D (in PKU; dbSNP:rs199475610)"
FT /id="VAR_000952"
FT VARIANT 247
FT /note="G -> V (in PKU; haplotype 4; dbSNP:rs199475579)"
FT /id="VAR_000953"
FT VARIANT 248
FT /note="L -> P (in PKU; dbSNP:rs62507340)"
FT /id="VAR_000954"
FT VARIANT 249
FT /note="L -> F (in PKU; haplotype 1; dbSNP:rs74503222)"
FT /id="VAR_000955"
FT VARIANT 252
FT /note="R -> G (in PKU; haplotype 7; dbSNP:rs5030847)"
FT /id="VAR_000956"
FT VARIANT 252
FT /note="R -> Q (in PKU; haplotype 1; dbSNP:rs62644503)"
FT /evidence="ECO:0000269|PubMed:7833954"
FT /id="VAR_000957"
FT VARIANT 252
FT /note="R -> W (in PKU; haplotypes 1,6,7,8,42, 69; complete
FT loss of activity; dbSNP:rs5030847)"
FT /evidence="ECO:0000269|PubMed:11461196,
FT ECO:0000269|PubMed:1672294, ECO:0000269|PubMed:22513348,
FT ECO:0000269|PubMed:23792259"
FT /id="VAR_000958"
FT VARIANT 255
FT /note="L -> S (in PKU; haplotype 36; dbSNP:rs62642930)"
FT /evidence="ECO:0000269|PubMed:2014802"
FT /id="VAR_000960"
FT VARIANT 255
FT /note="L -> V (in PKU; haplotypes 18,21; dbSNP:rs62642931)"
FT /id="VAR_000959"
FT VARIANT 257
FT /note="G -> C (in PKU; dbSNP:rs5030848)"
FT /id="VAR_000961"
FT VARIANT 259
FT /note="A -> T (in PKU; haplotype 3; dbSNP:rs62642932)"
FT /id="VAR_000962"
FT VARIANT 259
FT /note="A -> V (in PKU; haplotypes 7,42; dbSNP:rs118203921)"
FT /id="VAR_000963"
FT VARIANT 261
FT /note="R -> P (in PKU; dbSNP:rs5030849)"
FT /id="VAR_000964"
FT VARIANT 261
FT /note="R -> Q (in HPA and PKU; mild; haplotypes 1,2,4,22,
FT 24,28; dbSNP:rs5030849)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:1671810, ECO:0000269|PubMed:22513348,
FT ECO:0000269|PubMed:23792259, ECO:0000269|PubMed:8889590"
FT /id="VAR_000965"
FT VARIANT 263
FT /note="F -> L (in PKU; dbSNP:rs62642944)"
FT /id="VAR_000966"
FT VARIANT 264
FT /note="H -> L (in PKU; dbSNP:rs199475580)"
FT /id="VAR_000967"
FT VARIANT 265
FT /note="C -> G (in PKU; dbSNP:rs62517181)"
FT /id="VAR_000968"
FT VARIANT 269
FT /note="I -> L (in non-PKU HPA; dbSNP:rs62508692)"
FT /evidence="ECO:0000269|PubMed:9521426"
FT /id="VAR_000969"
FT VARIANT 270
FT /note="R -> K (in PKU; dbSNP:rs62514950)"
FT /id="VAR_000970"
FT VARIANT 270
FT /note="R -> S (in PKU; haplotype 1; dbSNP:rs62514951)"
FT /id="VAR_000971"
FT VARIANT 271
FT /note="H -> Y (in PKU; dbSNP:rs62517164)"
FT /id="VAR_000972"
FT VARIANT 273
FT /note="S -> F (in PKU; haplotype 7; dbSNP:rs62514953)"
FT /id="VAR_000973"
FT VARIANT 274
FT /note="K -> E (in dbSNP:rs142934616)"
FT /evidence="ECO:0000269|PubMed:11461196"
FT /id="VAR_011573"
FT VARIANT 275
FT /note="P -> L (in PKU; reduced activity; increased affinity
FT for the substrate; mildly reduced substrate activation;
FT decreased cofactor affinity; dbSNP:rs62508715)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294"
FT /id="VAR_068004"
FT VARIANT 276
FT /note="M -> I (in PKU; dbSNP:rs62514954)"
FT /id="VAR_000974"
FT VARIANT 276
FT /note="M -> V (in PKU; haplotype 4; dbSNP:rs62516149)"
FT /evidence="ECO:0000269|PubMed:8068076"
FT /id="VAR_000975"
FT VARIANT 277
FT /note="Y -> C (in PKU; dbSNP:rs62516155)"
FT /id="VAR_000976"
FT VARIANT 277
FT /note="Y -> D (in PKU; haplotype 2; dbSNP:rs78655458)"
FT /id="VAR_000977"
FT VARIANT 278
FT /note="T -> A (in PKU; dbSNP:rs62516156)"
FT /id="VAR_000978"
FT VARIANT 278
FT /note="T -> N (in PKU; dbSNP:rs62507262)"
FT /id="VAR_000979"
FT VARIANT 280
FT /note="E -> K (in PKU; haplotypes 1,2,4,16,38; partial
FT residual activity; dbSNP:rs62508698)"
FT /evidence="ECO:0000269|PubMed:22513348,
FT ECO:0000269|PubMed:2564729, ECO:0000269|PubMed:8889590"
FT /id="VAR_000980"
FT VARIANT 281
FT /note="P -> L (in PKU; haplotypes 1,4; dbSNP:rs5030851)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:1672290, ECO:0000269|PubMed:1672294,
FT ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:8889590"
FT /id="VAR_000981"
FT VARIANT 282
FT /note="D -> N (in PKU; haplotype 1; dbSNP:rs199475582)"
FT /id="VAR_000982"
FT VARIANT 283
FT /note="I -> F (in PKU; haplotype 21; dbSNP:rs62517168)"
FT /id="VAR_000983"
FT VARIANT 283
FT /note="I -> N (in PKU; severe; dbSNP:rs62508693)"
FT /evidence="ECO:0000269|PubMed:9521426"
FT /id="VAR_000984"
FT VARIANT 290
FT /note="H -> Y (in PKU; dbSNP:rs1486763160)"
FT /evidence="ECO:0000269|PubMed:22526846"
FT /id="VAR_067758"
FT VARIANT 297
FT /note="R -> C (in PKU; haplotype 4; dbSNP:rs62642945)"
FT /id="VAR_000985"
FT VARIANT 297
FT /note="R -> H (in PKU; dbSNP:rs62642939)"
FT /id="VAR_000986"
FT VARIANT 299
FT /note="F -> C (in PKU; haplotype 8; dbSNP:rs62642933)"
FT /evidence="ECO:0000269|PubMed:8889590"
FT /id="VAR_000987"
FT VARIANT 300
FT /note="A -> S (in PKU and HPA; haplotype 1; does not affect
FT oligomerization; reduction in activity is probably due to a
FT global conformational change in the protein that reduces
FT allostery; dbSNP:rs5030853)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294, ECO:0000269|PubMed:22513348,
FT ECO:0000269|PubMed:23792259"
FT /id="VAR_000988"
FT VARIANT 300
FT /note="A -> V (in PKU; dbSNP:rs199475609)"
FT /id="VAR_000989"
FT VARIANT 303
FT /note="S -> P (in PKU; haplotype 5; dbSNP:rs199475608)"
FT /id="VAR_000990"
FT VARIANT 304
FT /note="Q -> R (in PKU; dbSNP:rs199475592)"
FT /id="VAR_000991"
FT VARIANT 306
FT /note="I -> V (in non-PKU HPA; haplotype 4;
FT dbSNP:rs62642934)"
FT /evidence="ECO:0000269|PubMed:1358789,
FT ECO:0000269|PubMed:23792259"
FT /id="VAR_000992"
FT VARIANT 309
FT /note="A -> D (in PKU; haplotype 7; dbSNP:rs62642935)"
FT /id="VAR_000993"
FT VARIANT 309
FT /note="A -> V (in PKU; dbSNP:rs62642935)"
FT /id="VAR_000994"
FT VARIANT 310
FT /note="S -> F (in PKU; haplotype 7; dbSNP:rs62642913)"
FT /id="VAR_000995"
FT VARIANT 310
FT /note="S -> Y (in HPA; reduction in activity is probably
FT due to a global conformational change in the protein that
FT reduces allostery; dbSNP:rs62642913)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294"
FT /id="VAR_068005"
FT VARIANT 311
FT /note="L -> P (in PKU; haplotypes 1,7,10;
FT dbSNP:rs62642936)"
FT /evidence="ECO:0000269|PubMed:2615649,
FT ECO:0000269|PubMed:2840952"
FT /id="VAR_000996"
FT VARIANT 314
FT /note="P -> H (in PKU; dbSNP:rs62642940)"
FT /id="VAR_000997"
FT VARIANT 314
FT /note="P -> S (in HPA; does not affect oligomerization;
FT reduction in activity is probably due to a global
FT conformational change in the protein that reduces
FT allostery; dbSNP:rs199475650)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294"
FT /id="VAR_068006"
FT VARIANT 318
FT /note="I -> T (in PKU; partial loss of activity;
FT dbSNP:rs62642918)"
FT /evidence="ECO:0000269|PubMed:11461196"
FT /id="VAR_011574"
FT VARIANT 322
FT /note="A -> G (in PKU; haplotype 12; dbSNP:rs62514958)"
FT /id="VAR_000998"
FT VARIANT 322
FT /note="A -> T (in PKU; haplotype 1; dbSNP:rs62514957)"
FT /id="VAR_000999"
FT VARIANT 322
FT /note="A -> V (in PKU; dbSNP:rs62514958)"
FT /evidence="ECO:0000269|PubMed:22526846"
FT /id="VAR_067759"
FT VARIANT 325
FT /note="Y -> C (in PKU; dbSNP:rs62508578)"
FT /id="VAR_009245"
FT VARIANT 330
FT /note="E -> D (in PKU; dbSNP:rs62508580)"
FT /id="VAR_009246"
FT VARIANT 331
FT /note="F -> L (in PKU; haplotype 1; dbSNP:rs62517179)"
FT /evidence="ECO:0000269|PubMed:7833954"
FT /id="VAR_001000"
FT VARIANT 333
FT /note="L -> F (in PKU; dbSNP:rs62516060)"
FT /id="VAR_001001"
FT VARIANT 334
FT /note="C -> S (in PKU; dbSNP:rs62517174)"
FT /id="VAR_001002"
FT VARIANT 337
FT /note="G -> V (in PKU; dbSNP:rs62517206)"
FT /id="VAR_001003"
FT VARIANT 338
FT /note="D -> Y (in PKU; haplotype 4; dbSNP:rs62516150)"
FT /id="VAR_001004"
FT VARIANT 341
FT /note="K -> R (in PKU; dbSNP:rs62516153)"
FT /id="VAR_001005"
FT VARIANT 341
FT /note="K -> T (in PKU; dbSNP:rs62516153)"
FT /id="VAR_001006"
FT VARIANT 342
FT /note="A -> T (in PKU; haplotype 5; dbSNP:rs62507282)"
FT /id="VAR_001007"
FT VARIANT 343
FT /note="Y -> C (in PKU; dbSNP:rs62507265)"
FT /id="VAR_001008"
FT VARIANT 344
FT /note="G -> R (in PKU; dbSNP:rs62508679)"
FT /id="VAR_009247"
FT VARIANT 344
FT /note="G -> V (in PKU; dbSNP:rs62508582)"
FT /id="VAR_009248"
FT VARIANT 345
FT /note="A -> S (in PKU; dbSNP:rs62516062)"
FT /id="VAR_001009"
FT VARIANT 345
FT /note="A -> T (in PKU; haplotype 7; dbSNP:rs62516062)"
FT /id="VAR_001010"
FT VARIANT 347
FT /note="L -> F (in PKU; dbSNP:rs62516154)"
FT /id="VAR_001011"
FT VARIANT 348
FT /note="L -> V (in PKU; mild haplotype 9; dbSNP:rs62516092)"
FT /id="VAR_001012"
FT VARIANT 349
FT /note="S -> L (in PKU; severe; dbSNP:rs62507279)"
FT /evidence="ECO:0000269|PubMed:9600453"
FT /id="VAR_001013"
FT VARIANT 349
FT /note="S -> P (in PKU; haplotypes 1,4; dbSNP:rs62508646)"
FT /evidence="ECO:0000269|PubMed:22513348"
FT /id="VAR_001014"
FT VARIANT 350
FT /note="S -> T (in PKU; haplotype 2; dbSNP:rs62517183)"
FT /id="VAR_001015"
FT VARIANT 357
FT /note="C -> G (in PKU; dbSNP:rs62508595)"
FT /id="VAR_011575"
FT VARIANT 362
FT /note="P -> T (in PKU; dbSNP:rs62507329)"
FT /evidence="ECO:0000269|PubMed:10200057"
FT /id="VAR_001016"
FT VARIANT 364..368
FT /note="Missing (in PKU; dbSNP:rs62516096)"
FT /evidence="ECO:0000269|PubMed:1363837"
FT /id="VAR_001018"
FT VARIANT 364
FT /note="Missing (in PKU; haplotype 5; dbSNP:rs62516096)"
FT /evidence="ECO:0000269|PubMed:1975559"
FT /id="VAR_001017"
FT VARIANT 366
FT /note="P -> H (in PKU; dbSNP:rs62516098)"
FT /id="VAR_001019"
FT VARIANT 372
FT /note="T -> S (in PKU; dbSNP:rs62517163)"
FT /id="VAR_001020"
FT VARIANT 377
FT /note="Y -> C (in PKU; haplotype 4; dbSNP:rs62642942)"
FT /id="VAR_001021"
FT VARIANT 380
FT /note="T -> M (in non-PKU HPA; haplotype 4;
FT dbSNP:rs62642937)"
FT /evidence="ECO:0000269|PubMed:23792259"
FT /id="VAR_001022"
FT VARIANT 386
FT /note="Y -> C (in PKU; common mutation; dbSNP:rs62516141)"
FT /id="VAR_001023"
FT VARIANT 387
FT /note="Y -> H (in PKU; haplotype 1; dbSNP:rs62517194)"
FT /id="VAR_001024"
FT VARIANT 388
FT /note="V -> L (in PKU; dbSNP:rs62516101)"
FT /evidence="ECO:0000269|PubMed:9452061"
FT /id="VAR_001025"
FT VARIANT 388
FT /note="V -> M (in PKU; haplotypes 1,4; dbSNP:rs62516101)"
FT /id="VAR_001026"
FT VARIANT 390
FT /note="E -> G (in PKU and non-PKU HPA; haplotype 4;
FT dbSNP:rs5030856)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:23792259,
FT ECO:0000269|PubMed:8098245, ECO:0000269|PubMed:8889590"
FT /id="VAR_001027"
FT VARIANT 394
FT /note="D -> A (in PKU; dbSNP:rs62516102)"
FT /id="VAR_001028"
FT VARIANT 394
FT /note="D -> H (in PKU; dbSNP:rs62516142)"
FT /evidence="ECO:0000269|PubMed:8889590"
FT /id="VAR_001029"
FT VARIANT 395
FT /note="A -> G (in PKU; dbSNP:rs62508736)"
FT /id="VAR_001030"
FT VARIANT 395
FT /note="A -> P (in PKU; haplotype 1; dbSNP:rs62516103)"
FT /id="VAR_001031"
FT VARIANT 399..400
FT /note="Missing (in PKU; haplotype 7)"
FT /id="VAR_001032"
FT VARIANT 403
FT /note="A -> V (in non-PKU HPA and PKU; haplotype 43;
FT dbSNP:rs5030857)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:23792259,
FT ECO:0000269|PubMed:8889590"
FT /id="VAR_001033"
FT VARIANT 407
FT /note="P -> L (in PKU; dbSNP:rs62644473)"
FT /evidence="ECO:0000269|PubMed:9950317"
FT /id="VAR_068007"
FT VARIANT 407
FT /note="P -> S (in PKU; dbSNP:rs62644465)"
FT /id="VAR_011576"
FT VARIANT 408
FT /note="R -> Q (in PKU; haplotypes 4,12; dbSNP:rs5030859)"
FT /evidence="ECO:0000269|PubMed:1355066"
FT /id="VAR_001034"
FT VARIANT 408
FT /note="R -> W (in HPA and PKU; haplotypes 1,2,4,5,13,34,
FT 41,44; most common mutation; reduction in activity is
FT probably due to a global conformational change in the
FT protein that reduces allostery; dbSNP:rs5030858)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:1355066, ECO:0000269|PubMed:18538294,
FT ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:23792259,
FT ECO:0000269|PubMed:8889590, ECO:0000269|PubMed:9452062,
FT ECO:0000269|PubMed:9600453"
FT /id="VAR_001035"
FT VARIANT 410
FT /note="F -> S (in PKU; mild; dbSNP:rs62644475)"
FT /id="VAR_009249"
FT VARIANT 413
FT /note="R -> P (in non-PKU HPA and PKU; haplotype 4;
FT dbSNP:rs79931499)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:9852673"
FT /id="VAR_001036"
FT VARIANT 413
FT /note="R -> S (in PKU; haplotype 1; dbSNP:rs62644467)"
FT /id="VAR_001037"
FT VARIANT 414
FT /note="Y -> C (in HPA and PKU; haplotype 4; does not affect
FT oligomerization; reduction in activity is probably due to a
FT global conformational change in the protein that reduces
FT allostery; dbSNP:rs5030860)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294, ECO:0000269|PubMed:8889590"
FT /id="VAR_001038"
FT VARIANT 415
FT /note="D -> N (in PKU, HPA and non-PKU HPA; haplotype 1;
FT dbSNP:rs62644499)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:1358789, ECO:0000269|PubMed:22513348"
FT /id="VAR_001039"
FT VARIANT 417
FT /note="Y -> H (in PKU; reduction in activity is probably
FT due to a global conformational change in the protein that
FT reduces allostery; dbSNP:rs62644471)"
FT /evidence="ECO:0000269|PubMed:12501224,
FT ECO:0000269|PubMed:18538294"
FT /id="VAR_068008"
FT VARIANT 418
FT /note="T -> P (in PKU; haplotype 4; dbSNP:rs62644501)"
FT /id="VAR_001040"
FT VARIANT 421
FT /note="I -> S (in PKU; dbSNP:rs199475696)"
FT /evidence="ECO:0000269|PubMed:22526846"
FT /id="VAR_067760"
FT VARIANT 430
FT /note="L -> P (in PKU; dbSNP:rs199475607)"
FT /id="VAR_001041"
FT VARIANT 447
FT /note="A -> D (in PKU; dbSNP:rs76542238)"
FT /id="VAR_001042"
FT MUTAGEN 283
FT /note="I->C: Loss of positive cooperativity and reduction
FT of fold-activation by L-Phe preincubation."
FT /evidence="ECO:0000269|PubMed:18835579"
FT CONFLICT 183
FT /note="E -> G (in Ref. 3; AAH26251)"
FT /evidence="ECO:0000305"
FT STRAND 35..42
FT /evidence="ECO:0007829|PDB:5FII"
FT HELIX 47..57
FT /evidence="ECO:0007829|PDB:5FII"
FT STRAND 62..69
FT /evidence="ECO:0007829|PDB:5FII"
FT STRAND 71..73
FT /evidence="ECO:0007829|PDB:6HYC"
FT STRAND 76..83
FT /evidence="ECO:0007829|PDB:5FII"
FT HELIX 85..90
FT /evidence="ECO:0007829|PDB:5FII"
FT HELIX 91..102
FT /evidence="ECO:0007829|PDB:5FII"
FT STRAND 105..108
FT /evidence="ECO:0007829|PDB:5FII"
FT HELIX 125..133
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 135..138
FT /evidence="ECO:0007829|PDB:1PAH"
FT HELIX 140..142
FT /evidence="ECO:0007829|PDB:1J8U"
FT TURN 147..150
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 152..167
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 170..172
FT /evidence="ECO:0007829|PDB:6N1K"
FT HELIX 181..201
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 204..217
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 227..238
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 241..244
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 246..248
FT /evidence="ECO:0007829|PDB:1MMT"
FT HELIX 251..259
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 262..265
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 283..289
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 291..294
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 297..310
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 315..327
FT /evidence="ECO:0007829|PDB:1J8U"
FT TURN 328..331
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 333..336
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 339..342
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 345..348
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 351..357
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 359..366
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 369..372
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 379..381
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 384..390
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 392..403
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 409..415
FT /evidence="ECO:0007829|PDB:1J8U"
FT TURN 416..419
FT /evidence="ECO:0007829|PDB:1J8U"
FT STRAND 420..424
FT /evidence="ECO:0007829|PDB:1J8U"
FT HELIX 428..439
FT /evidence="ECO:0007829|PDB:6N1K"
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
