PH4H_DROME
ID PH4H_DROME Reviewed; 452 AA.
AC P17276; O46110; Q27599; Q27600;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 3.
DT 03-AUG-2022, entry version 203.
DE RecName: Full=Protein henna;
DE EC=1.14.16.1;
DE EC=1.14.16.4;
DE AltName: Full=Phe-4-monooxygenase;
DE AltName: Full=Phenylalanine-4-hydroxylase;
DE Short=PAH;
DE AltName: Full=Tryptophan 5-hydroxylase;
DE Short=TRH;
DE AltName: Full=Tryptophan 5-monooxygenase;
GN Name=Hn; Synonyms=pah, Tph; ORFNames=CG7399;
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=Canton-S, and Oregon-R; TISSUE=Embryo, and Head;
RX PubMed=1371286; DOI=10.1016/s0021-9258(19)50648-2;
RA Neckameyer W.S., White K.;
RT "A single locus encodes both phenylalanine hydroxylase and tryptophan
RT hydroxylase activities in Drosophila.";
RL J. Biol. Chem. 267:4199-4206(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2121612; DOI=10.1016/0378-1119(90)90227-i;
RA Morales G., Requena J.M., Jimenez-Ruiz A., Lopez M.C., Ugarte M.,
RA Alonso C.;
RT "Sequence and expression of the Drosophila phenylalanine hydroxylase
RT mRNA.";
RL Gene 93:213-219(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Canton-S;
RX PubMed=8769124; DOI=10.1006/bbrc.1996.1160;
RA Ruiz-Vazquez P., Moulard M., Silva F.J.;
RT "Structure of the phenylalanine hydroxylase gene in Drosophila melanogaster
RT and evidence of alternative promoter usage.";
RL Biochem. Biophys. Res. Commun. 225:238-242(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [5]
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley; TISSUE=Head;
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 5-93 AND 161-412 (MUTANT
RP HN-R3).
RX PubMed=10333570; DOI=10.1016/s0965-1748(99)00002-8;
RA Ruiz-Vazquez P., Silva F.J.;
RT "Aberrant splicing of the Drosophila melanogaster phenylalanine hydroxylase
RT pre-mRNA caused by the insertion of a B104/roo transposable element in the
RT Henna locus.";
RL Insect Biochem. Mol. Biol. 29:311-318(1999).
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;
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 -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
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 -!- PATHWAY: Amino-acid degradation; L-phenylalanine degradation;
CC acetoacetate and fumarate from L-phenylalanine: step 1/6.
CC -!- TISSUE SPECIFICITY: Phenylalanine hydrolase activity is found in yolk
CC granules of embryos, and female abdomen and fat body tissues.
CC Tryptophan hydroxylase is expressed in serotonergic neurons. Both
CC enzymes are present in cuticular tissues.
CC -!- MISCELLANEOUS: In Drosophila, the 2 enzymes, PAH and TRH are found to
CC be encoded by the same gene. Preference for the substrate is probably
CC due to post-translational modifications such as phosphorylation, or by
CC changes in the N-terminal regulatory domain.
CC -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC hydroxylase family. {ECO:0000305}.
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DR EMBL; M81833; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR EMBL; M32802; AAA69513.1; -; mRNA.
DR EMBL; X98116; CAA66797.1; -; Genomic_DNA.
DR EMBL; X98116; CAA66798.1; -; Genomic_DNA.
DR EMBL; AE014296; AAF50517.1; -; Genomic_DNA.
DR EMBL; AY069306; AAL39451.1; -; mRNA.
DR EMBL; AJ001718; CAA04950.1; -; Genomic_DNA.
DR EMBL; AJ001719; CAB51601.1; -; Genomic_DNA.
DR EMBL; AJ001720; CAB51601.1; JOINED; Genomic_DNA.
DR EMBL; AJ001722; CAB51599.1; -; mRNA.
DR EMBL; AJ001723; CAB51597.1; -; mRNA.
DR PIR; A42271; A42271.
DR PIR; JC4888; JC4888.
DR PIR; JQ0766; JQ0766.
DR RefSeq; NP_001014573.1; NM_001014573.2.
DR RefSeq; NP_001261542.1; NM_001274613.1.
DR RefSeq; NP_523963.2; NM_079239.4.
DR AlphaFoldDB; P17276; -.
DR SMR; P17276; -.
DR BioGRID; 64301; 42.
DR DIP; DIP-20514N; -.
DR IntAct; P17276; 14.
DR STRING; 7227.FBpp0076523; -.
DR PaxDb; P17276; -.
DR DNASU; 38871; -.
DR EnsemblMetazoa; FBtr0076811; FBpp0076523; FBgn0001208.
DR EnsemblMetazoa; FBtr0334645; FBpp0306707; FBgn0001208.
DR GeneID; 38871; -.
DR KEGG; dme:Dmel_CG7399; -.
DR CTD; 38871; -.
DR FlyBase; FBgn0001208; Hn.
DR VEuPathDB; VectorBase:FBgn0001208; -.
DR eggNOG; KOG3820; Eukaryota.
DR GeneTree; ENSGT00950000182885; -.
DR InParanoid; P17276; -.
DR PhylomeDB; P17276; -.
DR Reactome; R-DME-8964208; Phenylalanine metabolism.
DR SignaLink; P17276; -.
DR UniPathway; UPA00139; UER00337.
DR BioGRID-ORCS; 38871; 0 hits in 3 CRISPR screens.
DR ChiTaRS; Hn; fly.
DR GenomeRNAi; 38871; -.
DR PRO; PR:P17276; -.
DR Proteomes; UP000000803; Chromosome 3L.
DR Bgee; FBgn0001208; Expressed in head capsule and 19 other tissues.
DR ExpressionAtlas; P17276; baseline and differential.
DR Genevisible; P17276; DM.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; IDA:FlyBase.
DR GO; GO:0004510; F:tryptophan 5-monooxygenase activity; IEA:UniProtKB-EC.
DR GO; GO:0006726; P:eye pigment biosynthetic process; IDA:FlyBase.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; IMP:FlyBase.
DR GO; GO:0007616; P:long-term memory; IGI:FlyBase.
DR GO; GO:0042427; P:serotonin biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006571; P:tyrosine biosynthetic process; IBA:GO_Central.
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; 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 2: Evidence at transcript level;
KW Allosteric enzyme; Iron; Metal-binding; Monooxygenase; Oxidoreductase;
KW Phenylalanine catabolism; Phosphoprotein; Reference proteome;
KW Serotonin biosynthesis.
FT CHAIN 1..452
FT /note="Protein henna"
FT /id="PRO_0000205552"
FT DOMAIN 36..107
FT /note="ACT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01007"
FT BINDING 284
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250"
FT BINDING 289
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250"
FT BINDING 329
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250"
FT MOD_RES 272
FT /note="Phosphoserine; by CaMK2"
FT /evidence="ECO:0000250"
FT CONFLICT 28
FT /note="E -> A (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 39..47
FT /note="KDSSLSSGA -> RIRRCPAEL (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 55..56
FT /note="FK -> LR (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 63..71
FT /note="VHIESRSSL -> CILSRILAPWF (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 74..114
FT /note="PGYEFFVEADGKSGALGKAIEDVKEQCSYFNIISRDYKDNA -> SSCFWRR
FT MENRSLGKSHRGCEGAMLATLTSSCRELQGVMP (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 154
FT /note="R -> A (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 164
FT /note="A -> G (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 171
FT /note="E -> Q (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 264
FT /note="S -> C (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 297
FT /note="A -> S (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 332
FT /note="V -> L (in Ref. 1; M81833 and 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 333..335
FT /note="CRQ -> LAK (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 370
FT /note="V -> S (in Ref. 2; AAA69513)"
FT /evidence="ECO:0000305"
FT CONFLICT 449..452
FT /note="KLRV -> NCASE (in Ref. 1; M81833)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 452 AA; 51660 MW; 990F554150056867 CRC64;
MYQRQVSFDK PTRVEDSAYI VEGVDIKEAR NTCLLFSPKD SSLSSGALAN ILAIFKKHDI
NLVHIESRSS LRVPGYEFFV EADGKSGALG KAIEDVKEQC SYFNIISRDY KDNATAVPWF
PRRIRDLDRF ANQILSYGSE LDADHPGFTD PEYRKRRKYF ADIAYNYKHG EPLPHVDYTK
EEIETWGIIF RNLTKLYKTH ACREYNHVFP LLVDNCGFRE DNIPQLEDVS NFLRDCTGFT
LRPVAGLLSS RDFLAGLAFR VFHSTQYIRH PSKPMYTPEP DVCHELMGHV PLFADPAFAQ
FSQEIGLASL GAPDDYIEKL STIFWFTVEY GVCRQEGELK AYGAGLLSSY GELEYCLTDK
PQLKDFEPEV TGVTKYPITQ FQPLYYVADS FETAKEKTIK FANSIPRPFG VRYNAYTQSV
EVLDSKPQIS NLMDNINSEF QILQNAVAKL RV
