ID   PH4H_MOUSE              Reviewed;         453 AA.
AC   P16331; Q91WV1;
DT   01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 4.
DT   27-MAR-2024, entry version 204.
DE   RecName: Full=Phenylalanine-4-hydroxylase;
DE            Short=PAH;
DE            EC=1.14.16.1 {ECO:0000250|UniProtKB:P00439};
DE   AltName: Full=Phe-4-monooxygenase;
GN   Name=Pah;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Liver;
RX   PubMed=2334400; DOI=10.1042/bj2670399;
RA   Ledley F.D., Grenett H.E., Dunbar B.S., Woo S.L.C.;
RT   "Mouse phenylalanine hydroxylase. Homology and divergence from human
RT   phenylalanine hydroxylase.";
RL   Biochem. J. 267:399-406(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA   Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA   Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA   Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA   Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA   Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA   Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of the
RT   mouse.";
RL   PLoS Biol. 7:E1000112-E1000112(2009).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=FVB/N; TISSUE=Kidney;
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 2-13; 54-68; 160-169 AND 253-261, CLEAVAGE OF INITIATOR
RP   METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   STRAIN=C57BL/6J; TISSUE=Liver;
RA   Bienvenut W.V.;
RL   Submitted (JUL-2005) to UniProtKB.
RN   [5]
RP   PROTEIN SEQUENCE OF 12-21.
RX   PubMed=7387651; DOI=10.1016/0006-291x(80)91091-8;
RA   Wretborn M., Humble E., Ragnarsson U., Engstrom L.;
RT   "Amino acid sequence at the phosphorylated site of rat liver phenylalanine
RT   hydroxylase and phosphorylation of a corresponding synthetic peptide.";
RL   Biochem. Biophys. Res. Commun. 93:403-408(1980).
RN   [6]
RP   PROTEIN SEQUENCE OF 277-294.
RX   PubMed=6098294; DOI=10.1021/bi00319a001;
RA   Robson K.J.H., Beattie W., James R.J., Cotton R.C.H., Morgan F.J.,
RA   Woo S.L.C.;
RT   "Sequence comparison of rat liver phenylalanine hydroxylase and its cDNA
RT   clones.";
RL   Biochemistry 23:5671-5675(1984).
RN   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-16, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Kidney, Liver, and Pancreas;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [8]
RP   MUTAGENESIS OF VAL-106 AND PHE-263.
RX   PubMed=9119379; DOI=10.1006/geno.1996.4508;
RA   McDonald J.D., Charlton C.K.;
RT   "Characterization of mutations at the mouse phenylalanine hydroxylase
RT   locus.";
RL   Genomics 39:402-405(1997).
CC   -!- FUNCTION: Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.
CC       {ECO:0000250|UniProtKB:P00439}.
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:0000250|UniProtKB:P00439};
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:0000250|UniProtKB:P00439}.
CC   -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation;
CC       acetoacetate and fumarate from L-phenylalanine: step 1/6.
CC   -!- SUBUNIT: Homodimer and homotetramer. {ECO:0000250|UniProtKB:P04176}.
CC   -!- PTM: Phosphorylation at Ser-16 increases basal activity and facilitates
CC       activation by the substrate phenylalanine.
CC       {ECO:0000250|UniProtKB:P00439}.
CC   -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC       hydroxylase family. {ECO:0000305}.
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DR   EMBL; X51942; CAA36205.1; -; mRNA.
DR   EMBL; AC122360; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC013458; AAH13458.1; -; mRNA.
DR   CCDS; CCDS24102.1; -.
DR   PIR; S15758; S15758.
DR   RefSeq; NP_032803.2; NM_008777.3.
DR   AlphaFoldDB; P16331; -.
DR   SMR; P16331; -.
DR   STRING; 10090.ENSMUSP00000020241; -.
DR   iPTMnet; P16331; -.
DR   PhosphoSitePlus; P16331; -.
DR   SwissPalm; P16331; -.
DR   jPOST; P16331; -.
DR   MaxQB; P16331; -.
DR   PaxDb; 10090-ENSMUSP00000020241; -.
DR   PeptideAtlas; P16331; -.
DR   ProteomicsDB; 301807; -.
DR   Antibodypedia; 30481; 331 antibodies from 32 providers.
DR   DNASU; 18478; -.
DR   Ensembl; ENSMUST00000020241.17; ENSMUSP00000020241.8; ENSMUSG00000020051.18.
DR   GeneID; 18478; -.
DR   KEGG; mmu:18478; -.
DR   UCSC; uc007gqt.2; mouse.
DR   AGR; MGI:97473; -.
DR   CTD; 5053; -.
DR   MGI; MGI:97473; Pah.
DR   VEuPathDB; HostDB:ENSMUSG00000020051; -.
DR   eggNOG; KOG3820; Eukaryota.
DR   GeneTree; ENSGT00950000182885; -.
DR   HOGENOM; CLU_023198_0_1_1; -.
DR   InParanoid; P16331; -.
DR   OMA; FHDEVYR; -.
DR   OrthoDB; 275463at2759; -.
DR   PhylomeDB; P16331; -.
DR   TreeFam; TF313327; -.
DR   Reactome; R-MMU-8964208; Phenylalanine metabolism.
DR   UniPathway; UPA00139; UER00337.
DR   BioGRID-ORCS; 18478; 2 hits in 80 CRISPR screens.
DR   ChiTaRS; Pah; mouse.
DR   PRO; PR:P16331; -.
DR   Proteomes; UP000000589; Chromosome 10.
DR   RNAct; P16331; Protein.
DR   Bgee; ENSMUSG00000020051; Expressed in adult mammalian kidney and 67 other cell types or tissues.
DR   ExpressionAtlas; P16331; baseline and differential.
DR   GO; GO:0016597; F:amino acid binding; ISO:MGI.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0005506; F:iron ion binding; ISO:MGI.
DR   GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; IMP:MGI.
DR   GO; GO:0006559; P:L-phenylalanine catabolic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0006558; P:L-phenylalanine metabolic process; ISO:MGI.
DR   GO; GO:0006571; P:tyrosine biosynthetic process; ISO:MGI.
DR   GO; GO:0019293; P:tyrosine biosynthetic process, by oxidation of phenylalanine; ISO:MGI.
DR   CDD; cd04931; ACT_PAH; 1.
DR   CDD; cd03347; eu_PheOH; 1.
DR   Gene3D; 1.10.800.10; Aromatic amino acid hydroxylase; 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   NCBIfam; TIGR01268; Phe4hydrox_tetr; 1.
DR   PANTHER; PTHR11473; AROMATIC AMINO ACID HYDROXYLASE; 1.
DR   PANTHER; PTHR11473:SF24; PHENYLALANINE-4-HYDROXYLASE; 1.
DR   Pfam; PF01842; ACT; 1.
DR   Pfam; PF00351; Biopterin_H; 1.
DR   PIRSF; PIRSF000336; TH; 1.
DR   PRINTS; PR00372; FYWHYDRXLASE.
DR   SUPFAM; SSF55021; ACT-like; 1.
DR   SUPFAM; SSF56534; Aromatic aminoacid monoxygenases, catalytic and oligomerization domains; 1.
DR   PROSITE; PS51671; ACT; 1.
DR   PROSITE; PS00367; BH4_AAA_HYDROXYL_1; 1.
DR   PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1.
DR   Genevisible; P16331; MM.
PE   1: Evidence at protein level;
KW   Acetylation; Allosteric enzyme; Direct protein sequencing; Disease variant;
KW   Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW   Phenylalanine catabolism; Phosphoprotein; Reference proteome.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|Ref.4"
FT   CHAIN           2..453
FT                   /note="Phenylalanine-4-hydroxylase"
FT                   /id="PRO_0000205549"
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         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000269|Ref.4"
FT   MOD_RES         16
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MUTAGEN         106
FT                   /note="V->A: Mutant mice have mild features of
FT                   phenylketonuria."
FT                   /evidence="ECO:0000269|PubMed:9119379"
FT   MUTAGEN         263
FT                   /note="F->S: Mutant mice have features of phenylketonuria."
FT                   /evidence="ECO:0000269|PubMed:9119379"
FT   CONFLICT        383
FT                   /note="Q -> R (in Ref. 1; CAA36205)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        432
FT                   /note="I -> N (in Ref. 1; CAA36205)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   453 AA;  51900 MW;  551F181FA59DEA5B CRC64;
     MAAVVLENGV LSRKLSDFGQ ETSYIEDNSN QNGAVSLIFS LKEEVGALAK VLRLFEENEI
     NLTHIESRPS RLNKDEYEFF TYLDKRSKPV LGSIIKSLRN DIGATVHELS RDKEKNTVPW
     FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYT
     EEERKTWGTV FRTLKALYKT HACYEHNHIF PLLEKYCGFR EDNIPQLEDV SQFLQTCTGF
     RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
     QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKEGDSI KAYGAGLLSS FGELQYCLSD
     KPKLLPLELE KTACQEYTVT EFQPLYYVAE SFNDAKEKVR TFAATIPRPF SVRYDPYTQR
     VEVLDNTQQL KILADSINSE VGILCHALQK IKS
//