PH4H_RAT
ID PH4H_RAT Reviewed; 453 AA.
AC P04176;
DT 20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 174.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2869038; DOI=10.1016/s0021-9258(17)35638-7;
RA Dahl H.-H.M., Mercer J.F.B.;
RT "Isolation and sequence of a cDNA clone which contains the complete coding
RT region of rat phenylalanine hydroxylase. Structural homology with tyrosine
RT hydroxylase, glucocorticoid regulation, and use of alternate
RT polyadenylation sites.";
RL J. Biol. Chem. 261:4148-4153(1986).
RN [2]
RP PROTEIN SEQUENCE OF 12-21, AND PHOSPHORYLATION AT SER-16.
RC TISSUE=Liver;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 208-453.
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 [4]
RP SUBUNIT.
RX PubMed=7407194; DOI=10.1016/0005-2744(80)90221-1;
RA Nakata H., Fujisawa H.;
RT "Purification and characterization of phenylalanine 4-monooxygenase from
RT rat liver.";
RL Biochim. Biophys. Acta 614:313-327(1980).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-16, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [6] {ECO:0007744|PDB:1PHZ, ECO:0007744|PDB:2PHM}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1-429 IN COMPLEX WITH IRON, AND
RP COFACTOR.
RX PubMed=10331871; DOI=10.1038/8247;
RA Kobe B., Jennings I.G., House C.M., Michell B.J., Goodwill K.E.,
RA Santarsiero B.D., Stevens R.C., Cotton R.G., Kemp B.E.;
RT "Structural basis of autoregulation of phenylalanine hydroxylase.";
RL Nat. Struct. Biol. 6:442-448(1999).
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:0000269|PubMed:10331871};
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:0000269|PubMed:7407194}.
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; M12337; AAA41843.1; -; mRNA.
DR EMBL; K02599; AAA41794.1; -; mRNA.
DR PIR; A25321; WHRTF.
DR PDB; 1PHZ; X-ray; 2.20 A; A=1-429.
DR PDB; 2PHM; X-ray; 2.60 A; A=1-429.
DR PDB; 5DEN; X-ray; 2.90 A; A/B/C/D=1-453.
DR PDB; 5EGQ; X-ray; 2.50 A; A/B/C/D=1-453.
DR PDB; 5FGJ; X-ray; 3.60 A; A/B/C/D=1-453.
DR PDBsum; 1PHZ; -.
DR PDBsum; 2PHM; -.
DR PDBsum; 5DEN; -.
DR PDBsum; 5EGQ; -.
DR PDBsum; 5FGJ; -.
DR AlphaFoldDB; P04176; -.
DR SMR; P04176; -.
DR STRING; 10116.ENSRNOP00000005844; -.
DR BindingDB; P04176; -.
DR ChEMBL; CHEMBL3077; -.
DR iPTMnet; P04176; -.
DR PhosphoSitePlus; P04176; -.
DR PaxDb; P04176; -.
DR PRIDE; P04176; -.
DR UCSC; RGD:3248; rat.
DR RGD; 3248; Pah.
DR eggNOG; KOG3820; Eukaryota.
DR InParanoid; P04176; -.
DR PhylomeDB; P04176; -.
DR BRENDA; 1.14.16.1; 5301.
DR Reactome; R-RNO-8964208; Phenylalanine metabolism.
DR SABIO-RK; P04176; -.
DR UniPathway; UPA00139; UER00337.
DR EvolutionaryTrace; P04176; -.
DR PRO; PR:P04176; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0016597; F:amino acid binding; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; IPI:RGD.
DR GO; GO:0005506; F:iron ion binding; IDA:RGD.
DR GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; IDA:RGD.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006558; P:L-phenylalanine metabolic process; IDA:RGD.
DR GO; GO:0018126; P:protein hydroxylation; IDA:RGD.
DR GO; GO:0006571; P:tyrosine biosynthetic process; IDA:RGD.
DR GO; GO:0019293; P:tyrosine biosynthetic process, by oxidation of phenylalanine; IDA:RGD.
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; Acetylation; Allosteric enzyme; Direct protein sequencing;
KW Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW Phenylalanine catabolism; Phosphoprotein; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P16331"
FT CHAIN 2..453
FT /note="Phenylalanine-4-hydroxylase"
FT /id="PRO_0000205550"
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:0000269|PubMed:10331871,
FT ECO:0007744|PDB:1PHZ, ECO:0007744|PDB:2PHM"
FT BINDING 290
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000269|PubMed:10331871,
FT ECO:0007744|PDB:1PHZ, ECO:0007744|PDB:2PHM"
FT BINDING 330
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000269|PubMed:10331871,
FT ECO:0007744|PDB:1PHZ, ECO:0007744|PDB:2PHM"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P16331"
FT MOD_RES 16
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:7387651,
FT ECO:0007744|PubMed:22673903"
FT STRAND 35..42
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 47..56
FT /evidence="ECO:0007829|PDB:1PHZ"
FT TURN 57..59
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 64..69
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 76..81
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 85..87
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 88..100
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 106..110
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 117..119
FT /evidence="ECO:0007829|PDB:5EGQ"
FT HELIX 125..129
FT /evidence="ECO:0007829|PDB:1PHZ"
FT TURN 130..133
FT /evidence="ECO:0007829|PDB:1PHZ"
FT TURN 147..150
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 152..166
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 181..201
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 204..216
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 227..238
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 241..244
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 251..258
FT /evidence="ECO:0007829|PDB:1PHZ"
FT TURN 259..261
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 262..265
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 283..289
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 291..294
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 297..310
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 315..326
FT /evidence="ECO:0007829|PDB:1PHZ"
FT TURN 327..331
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 333..336
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 339..342
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 345..348
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 351..357
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 359..366
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 369..372
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 379..382
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 384..390
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 392..403
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 409..415
FT /evidence="ECO:0007829|PDB:1PHZ"
FT TURN 416..419
FT /evidence="ECO:0007829|PDB:1PHZ"
FT STRAND 420..424
FT /evidence="ECO:0007829|PDB:1PHZ"
FT HELIX 426..448
FT /evidence="ECO:0007829|PDB:5EGQ"
SQ SEQUENCE 453 AA; 51822 MW; 365D9E8A7E498D52 CRC64;
MAAVVLENGV LSRKLSDFGQ ETSYIEDNSN QNGAISLIFS LKEEVGALAK VLRLFEENDI
NLTHIESRPS RLNKDEYEFF TYLDKRTKPV LGSIIKSLRN DIGATVHELS RDKEKNTVPW
FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYT
EEEKQTWGTV FRTLKALYKT HACYEHNHIF PLLEKYCGFR EDNIPQLEDV SQFLQTCTGF
RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKEGDSI KAYGAGLLSS FGELQYCLSD
KPKLLPLELE KTACQEYSVT EFQPLYYVAE SFSDAKEKVR TFAATIPRPF SVRYDPYTQR
VEVLDNTQQL KILADSINSE VGILCNALQK IKS
