PH4H_CAEEL
ID PH4H_CAEEL Reviewed; 457 AA.
AC P90925; I2HA98; Q9XYQ5;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 2.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Phenylalanine-4-hydroxylase {ECO:0000303|PubMed:10928216};
DE Short=PAH;
DE EC=1.14.16.1 {ECO:0000269|PubMed:10928216, ECO:0000269|PubMed:18460651};
DE EC=1.14.16.4 {ECO:0000269|PubMed:10928216};
DE AltName: Full=Biogenic amine synthesis protein 2;
DE AltName: Full=Phe-4-monooxygenase;
DE AltName: Full=Tryptophan 5-monooxygenase {ECO:0000305};
GN Name=pah-1 {ECO:0000312|WormBase:K08F8.4a};
GN Synonyms=bas-2 {ECO:0000312|WormBase:K08F8.4a};
GN ORFNames=K08F8.4 {ECO:0000312|WormBase:K08F8.4a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), FUNCTION, CATALYTIC ACTIVITY,
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=10928216; DOI=10.3109/01677069909083472;
RA Loer C.M., Davidson B., Mckerrow J.;
RT "A phenylalanine hydroxylase gene from the nematode C. elegans is expressed
RT in the hypodermis.";
RL J. Neurogenet. 13:157-180(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, SUBUNIT, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
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 [4]
RP DISRUPTION PHENOTYPE.
RX PubMed=18227072; DOI=10.1074/jbc.m708341200;
RA Fisher A.L., Page K.E., Lithgow G.J., Nash L.;
RT "The Caenorhabditis elegans K10C2.4 gene encodes a member of the
RT fumarylacetoacetate hydrolase family: a Caenorhabditis elegans model of
RT type I tyrosinemia.";
RL J. Biol. Chem. 283:9127-9135(2008).
CC -!- FUNCTION: Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine
CC (PubMed:18460651, PubMed:10928216). Catalyzes the hydroxylation of
CC tryptophan to 5-hydroxy-L-tryptophan (PubMed:10928216). Plays a role in
CC the biosynthesis of a melanin-like cuticle pigment (PubMed:18460651).
CC {ECO:0000269|PubMed:10928216, ECO:0000269|PubMed:18460651}.
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:10928216,
CC ECO:0000269|PubMed:18460651};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tryptophan + O2
CC = (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + 5-
CC hydroxy-L-tryptophan; Xref=Rhea:RHEA:16709, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:15642, ChEBI:CHEBI:57912, ChEBI:CHEBI:58266,
CC ChEBI:CHEBI:59560; EC=1.14.16.4;
CC Evidence={ECO:0000269|PubMed:10928216};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:P04176};
CC -!- ACTIVITY REGULATION: Inhibited by tetrahydrobiopterin. Unlike its
CC mammalian orthologs, pah-1 does not exhibit allosteric binding behavior
CC for phenylalanine. {ECO:0000269|PubMed:18460651}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=146 uM for L-phenylalanine (at 25 degrees Celsius)
CC {ECO:0000269|PubMed:18460651};
CC KM=33 uM for tetrahydrobiopterin (BH(4)) (at 25 degrees Celsius)
CC {ECO:0000269|PubMed:18460651};
CC Vmax=3.3 umol/min/mg enzyme towards L-phenylalanine (at 25 degrees
CC Celsius) {ECO:0000269|PubMed:18460651};
CC Vmax=3.22 umol/min/mg enzyme towards tetrahydrobiopterin (BH(4)) (at
CC 25 degrees Celsius) {ECO:0000269|PubMed:18460651};
CC -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation;
CC acetoacetate and fumarate from L-phenylalanine: step 1/6.
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:18460651}.
CC -!- INTERACTION:
CC P90925; O01869: rps-10; NbExp=3; IntAct=EBI-318020, EBI-314419;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10928216}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=a {ECO:0000312|WormBase:K08F8.4a};
CC IsoId=P90925-1; Sequence=Displayed;
CC Name=b {ECO:0000312|WormBase:K08F8.4b};
CC IsoId=P90925-2; Sequence=VSP_059801;
CC -!- TISSUE SPECIFICITY: Expressed in the seam cells of the lateral
CC hypodermis, in the ventral hypodermis and in the hyp7 hypodermal
CC syncytium, in hypodermal cells in the tail and in body wall muscle
CC cells (at protein level). {ECO:0000269|PubMed:10928216}.
CC -!- DEVELOPMENTAL STAGE: Expressed during all larval stages and in adult
CC animals (at protein level). {ECO:0000269|PubMed:10928216,
CC ECO:0000269|PubMed:18460651}.
CC -!- DISRUPTION PHENOTYPE: Reduced L-phenylalanine hydroxylation. Lack of a
CC yellow-orange pheomelanine-like pigment in the cuticle. Higher cuticle
CC resistance to physical or chemical disintegration factors or oxidizing
CC environments. Increase in superoxide dismutase activity. Increased life
CC span. In a bli-3(e767) mutant background, growth arrest in early larval
CC development, severe cuticle abnormalities with large blisters and
CC increased superoxide dismutase activity. RNAi-mediated knockdown
CC together with fah-1 RNAi partially rescues the impaired growth and
CC fertility defects in the single fah-1 RNAi mutant (PubMed:18227072).
CC {ECO:0000269|PubMed:18227072, ECO:0000269|PubMed:18460651}.
CC -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC hydroxylase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD31643.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF119388; AAD31643.1; ALT_FRAME; mRNA.
DR EMBL; Z66497; CAA91286.1; -; Genomic_DNA.
DR EMBL; BX284602; CCH63805.1; -; Genomic_DNA.
DR PIR; T23494; T23494.
DR RefSeq; NP_001254184.1; NM_001267255.1. [P90925-2]
DR RefSeq; NP_001254185.1; NM_001267256.1. [P90925-1]
DR AlphaFoldDB; P90925; -.
DR SMR; P90925; -.
DR BioGRID; 39728; 16.
DR DIP; DIP-25264N; -.
DR IntAct; P90925; 17.
DR STRING; 6239.K08F8.4a; -.
DR EPD; P90925; -.
DR PaxDb; P90925; -.
DR PeptideAtlas; P90925; -.
DR PRIDE; P90925; -.
DR EnsemblMetazoa; K08F8.4a.1; K08F8.4a.1; WBGene00000240. [P90925-1]
DR EnsemblMetazoa; K08F8.4b.1; K08F8.4b.1; WBGene00000240. [P90925-2]
DR GeneID; 174401; -.
DR KEGG; cel:CELE_K08F8.4; -.
DR UCSC; K08F8.4; c. elegans. [P90925-1]
DR CTD; 174401; -.
DR WormBase; K08F8.4a; CE21050; WBGene00000240; pah-1. [P90925-1]
DR WormBase; K08F8.4b; CE47563; WBGene00000240; pah-1. [P90925-2]
DR eggNOG; KOG3820; Eukaryota.
DR GeneTree; ENSGT00950000182885; -.
DR HOGENOM; CLU_023198_0_1_1; -.
DR InParanoid; P90925; -.
DR OMA; HAAQPLY; -.
DR OrthoDB; 614557at2759; -.
DR PhylomeDB; P90925; -.
DR BRENDA; 1.14.16.1; 1045.
DR Reactome; R-CEL-8964208; Phenylalanine metabolism.
DR UniPathway; UPA00139; UER00337.
DR PRO; PR:P90925; -.
DR Proteomes; UP000001940; Chromosome II.
DR Bgee; WBGene00000240; Expressed in larva and 3 other tissues.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; IDA:WormBase.
DR GO; GO:0004510; F:tryptophan 5-monooxygenase activity; IDA:WormBase.
DR GO; GO:0040002; P:collagen and cuticulin-based cuticle development; IGI:WormBase.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:WormBase.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; IDA:WormBase.
DR GO; GO:0042438; P:melanin biosynthetic process; IMP:WormBase.
DR GO; GO:0000003; P:reproduction; IMP:WormBase.
DR GO; GO:0006979; P:response to oxidative stress; IMP:WormBase.
DR GO; GO:0006569; P:tryptophan catabolic process; IDA:WormBase.
DR GO; GO:0006571; P:tyrosine biosynthetic process; IDA:WormBase.
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 Alternative splicing; Cytoplasm; Iron; Metal-binding; Monooxygenase;
KW Oxidoreductase; Phenylalanine catabolism; Reference proteome.
FT CHAIN 1..457
FT /note="Phenylalanine-4-hydroxylase"
FT /id="PRO_0000205551"
FT DOMAIN 31..108
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 VAR_SEQ 1..12
FT /note="MPPAGQDDLDFL -> MNIDEIRK (in isoform b)"
FT /id="VSP_059801"
FT CONFLICT 251
FT /note="S -> P (in Ref. 1; AAD31643)"
FT /evidence="ECO:0000305"
FT CONFLICT 258
FT /note="L -> W (in Ref. 1; AAD31643)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 457 AA; 52129 MW; 68365836DFEC8D4F CRC64;
MPPAGQDDLD FLKYAMESYV ADVNADIGKT TIVFTLREKA GALAETLKLF QAHDVNLSHI
ESRPSKTHEG CYEVLVEFAE AEDHRKIEGV IEHFQQKAEK KVLVQDWNTK NKQNKDSVPW
FPQKINDIDQ FANRILSYGA ELDADHPGFK DMTYRERRKF FADIAFNFKH GDKIPTITYT
DEEIATWRTV YNELTVMYPK NACQEFNYIF PLLQQNCGFG PDRIPQLQDV SDFLKDCTGY
TIRPVAGLLS SRDFLAGLAF RVFHSTQYIR HHSAPKYTPE PDICHELLGH VPLFADVEFA
QFSQEIGLAS LGAPDDVIEK LATLYWFTIE FGICQQDGEK KAYGAGLLSS FGELQYALSD
KPEVVDFDPA VCCVTKYPIT EYQPKYFLAE SFASAKNKLK SWAATINRPF QIRYNAYTQR
VEILDKVAAL QRLARDIRSD ISTLEEALGK VNNLKMK
