PH4H_MOUSE
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 03-AUG-2022, entry version 196.
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 VARIANTS PAH-ENU1 ALA-106 AND PAH-ENU2 SER-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 -!- DISEASE: Note=Mouse strains deficient in phenylalanine hydroxylase
CC (Pah) were created as models of phenylketonuria (PKU).
CC {ECO:0000269|PubMed:9119379}.
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; P16331; -.
DR PeptideAtlas; P16331; -.
DR PRIDE; P16331; -.
DR ProteomicsDB; 301807; -.
DR Antibodypedia; 30481; 287 antibodies from 32 providers.
DR DNASU; 18478; -.
DR Ensembl; ENSMUST00000020241; ENSMUSP00000020241; ENSMUSG00000020051.
DR GeneID; 18478; -.
DR KEGG; mmu:18478; -.
DR UCSC; uc007gqt.2; mouse.
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; HAAQPLY; -.
DR OrthoDB; 614557at2759; -.
DR PhylomeDB; P16331; -.
DR TreeFam; TF313327; -.
DR Reactome; R-MMU-8964208; Phenylalanine metabolism.
DR UniPathway; UPA00139; UER00337.
DR BioGRID-ORCS; 18478; 2 hits in 75 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 tissues.
DR ExpressionAtlas; P16331; baseline and differential.
DR Genevisible; P16331; MM.
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:0018126; P:protein hydroxylation; 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; 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 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 VARIANT 106
FT /note="V -> A (in PAH-ENU1; mild PKU phenotype)"
FT /evidence="ECO:0000269|PubMed:9119379"
FT VARIANT 263
FT /note="F -> S (in PAH-ENU2; severe PKU phenotype)"
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
