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 14-DEC-2022, entry version 163. 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}; 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; 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; 17. DR DIP; DIP-25264N; -. DR IntAct; P90925; 17. DR STRING; 6239.K08F8.4a; -. DR EPD; P90925; -. DR PaxDb; P90925; -. DR PeptideAtlas; 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 AGR; WB:WBGene00000240; -. 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; AROMATIC AMINO ACID 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 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 //