TPH1_HUMAN
ID TPH1_HUMAN Reviewed; 444 AA.
AC P17752; D3DQX6; O95188; O95189; Q16736; Q3KPG8;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 4.
DT 03-AUG-2022, entry version 205.
DE RecName: Full=Tryptophan 5-hydroxylase 1;
DE EC=1.14.16.4 {ECO:0000250|UniProtKB:P17532};
DE AltName: Full=Tryptophan 5-monooxygenase 1;
GN Name=TPH1; Synonyms=TPH, TPRH, TRPH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Carcinoma;
RX PubMed=2377472; DOI=10.1093/nar/18.14.4257;
RA Boulalard S., Darmon M.C., Ganem Y., Launay J.-M., Mallet J.;
RT "Complete coding sequence of human tryptophan hydroxylase.";
RL Nucleic Acids Res. 18:4257-4257(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7986090; DOI=10.1006/abbi.1994.1523;
RA Tipper J.P., Citron B.A., Ribeiro P., Kaufman S.;
RT "Cloning and expression of rabbit and human brain tryptophan hydroxylase
RT cDNA in Escherichia coli.";
RL Arch. Biochem. Biophys. 315:445-453(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 388-444 (ISOFORMS 1 AND 2), AND TISSUE
RP SPECIFICITY.
RX PubMed=9751214; DOI=10.1046/j.1471-4159.1998.71041769.x;
RA Wang G.A., Coon S.L., Kaufman S.;
RT "Alternative splicing at the 3'-cDNA of human tryptophan hydroxylase.";
RL J. Neurochem. 71:1769-1772(1998).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 102-402 IN COMPLEX WITH IRON, AND
RP COFACTOR.
RX PubMed=12379098; DOI=10.1021/bi026561f;
RA Wang L., Erlandsen H., Haavik J., Knappskog P.M., Stevens R.C.;
RT "Three-dimensional structure of human tryptophan hydroxylase and its
RT implications for the biosynthesis of the neurotransmitters serotonin and
RT melatonin.";
RL Biochemistry 41:12569-12574(2002).
CC -!- FUNCTION: Oxidizes L-tryptophan to 5-hydroxy-l-tryptophan in the rate-
CC determining step of serotonin biosynthesis.
CC {ECO:0000250|UniProtKB:P17532}.
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:0000250|UniProtKB:P17532};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000269|PubMed:12379098};
CC -!- PATHWAY: Aromatic compound metabolism; serotonin biosynthesis;
CC serotonin from L-tryptophan: step 1/2. {ECO:0000250|UniProtKB:P17532}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P70080}.
CC -!- INTERACTION:
CC P17752; Q14457: BECN1; NbExp=3; IntAct=EBI-3956833, EBI-949378;
CC P17752; Q96IK1-2: BOD1; NbExp=3; IntAct=EBI-3956833, EBI-18924329;
CC P17752; Q9H8Y8: GORASP2; NbExp=5; IntAct=EBI-3956833, EBI-739467;
CC P17752; O43586: PSTPIP1; NbExp=3; IntAct=EBI-3956833, EBI-1050964;
CC P17752; O95789-4: ZMYM6; NbExp=3; IntAct=EBI-3956833, EBI-12949277;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P17752-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P17752-2; Sequence=VSP_000546;
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Seems to be less widely expressed than
CC isoform 1. {ECO:0000269|PubMed:9751214}.
CC -!- PTM: Ubiquitinated, leading to its degradation by the proteasome.
CC Ubiquitinated is triggered by phosphorylation.
CC {ECO:0000250|UniProtKB:P09810}.
CC -!- PTM: Phosphorylated; triggering degradation by the proteasome.
CC {ECO:0000250|UniProtKB:P09810}.
CC -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC hydroxylase family. {ECO:0000305}.
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DR EMBL; X52836; CAA37018.1; -; mRNA.
DR EMBL; L29306; AAA67050.1; -; mRNA.
DR EMBL; CH471064; EAW68421.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68422.1; -; Genomic_DNA.
DR EMBL; BC106739; AAI06740.1; -; mRNA.
DR EMBL; AF057280; AAC69458.1; -; Genomic_DNA.
DR EMBL; AF057280; AAC69459.1; -; Genomic_DNA.
DR CCDS; CCDS7829.1; -. [P17752-1]
DR PIR; S10489; S10489.
DR RefSeq; NP_004170.1; NM_004179.2. [P17752-1]
DR PDB; 1MLW; X-ray; 1.71 A; A=102-402.
DR PDB; 3HF6; X-ray; 1.80 A; A=105-393.
DR PDB; 3HF8; X-ray; 1.85 A; A=105-393.
DR PDB; 3HFB; X-ray; 1.92 A; A=104-393.
DR PDB; 5J6D; X-ray; 1.90 A; A/B=102-402.
DR PDB; 5L01; X-ray; 1.90 A; A=1-444.
DR PDB; 5TPG; X-ray; 1.50 A; A=104-402.
DR PDBsum; 1MLW; -.
DR PDBsum; 3HF6; -.
DR PDBsum; 3HF8; -.
DR PDBsum; 3HFB; -.
DR PDBsum; 5J6D; -.
DR PDBsum; 5L01; -.
DR PDBsum; 5TPG; -.
DR AlphaFoldDB; P17752; -.
DR SMR; P17752; -.
DR BioGRID; 113019; 12.
DR IntAct; P17752; 11.
DR STRING; 9606.ENSP00000250018; -.
DR BindingDB; P17752; -.
DR ChEMBL; CHEMBL5689; -.
DR DrugBank; DB05199; LX1031.
DR DrugBank; DB00360; Sapropterin.
DR DrugBank; DB12095; Telotristat ethyl.
DR DrugBank; DB00150; Tryptophan.
DR DrugCentral; P17752; -.
DR GuidetoPHARMACOLOGY; 1241; -.
DR iPTMnet; P17752; -.
DR PhosphoSitePlus; P17752; -.
DR BioMuta; TPH1; -.
DR DMDM; 116242823; -.
DR jPOST; P17752; -.
DR MassIVE; P17752; -.
DR PaxDb; P17752; -.
DR PeptideAtlas; P17752; -.
DR PRIDE; P17752; -.
DR ProteomicsDB; 53513; -. [P17752-1]
DR ProteomicsDB; 53514; -. [P17752-2]
DR Antibodypedia; 4386; 623 antibodies from 43 providers.
DR DNASU; 7166; -.
DR Ensembl; ENST00000250018.6; ENSP00000250018.2; ENSG00000129167.10. [P17752-1]
DR Ensembl; ENST00000682019.1; ENSP00000508368.1; ENSG00000129167.10. [P17752-1]
DR GeneID; 7166; -.
DR KEGG; hsa:7166; -.
DR MANE-Select; ENST00000682019.1; ENSP00000508368.1; NM_004179.3; NP_004170.1.
DR UCSC; uc001mnp.3; human. [P17752-1]
DR CTD; 7166; -.
DR DisGeNET; 7166; -.
DR GeneCards; TPH1; -.
DR HGNC; HGNC:12008; TPH1.
DR HPA; ENSG00000129167; Group enriched (brain, intestine, stomach).
DR MIM; 191060; gene.
DR neXtProt; NX_P17752; -.
DR OpenTargets; ENSG00000129167; -.
DR PharmGKB; PA355; -.
DR VEuPathDB; HostDB:ENSG00000129167; -.
DR eggNOG; KOG3820; Eukaryota.
DR GeneTree; ENSGT00950000182885; -.
DR HOGENOM; CLU_023198_0_0_1; -.
DR InParanoid; P17752; -.
DR OMA; VTCQEEC; -.
DR OrthoDB; 614557at2759; -.
DR PhylomeDB; P17752; -.
DR TreeFam; TF313327; -.
DR BioCyc; MetaCyc:HS05250-MON; -.
DR BRENDA; 1.14.16.4; 2681.
DR PathwayCommons; P17752; -.
DR Reactome; R-HSA-209931; Serotonin and melatonin biosynthesis.
DR Reactome; R-HSA-9031628; NGF-stimulated transcription.
DR SABIO-RK; P17752; -.
DR SignaLink; P17752; -.
DR SIGNOR; P17752; -.
DR UniPathway; UPA00846; UER00799.
DR BioGRID-ORCS; 7166; 19 hits in 1074 CRISPR screens.
DR ChiTaRS; TPH1; human.
DR EvolutionaryTrace; P17752; -.
DR GeneWiki; TPH1; -.
DR GenomeRNAi; 7166; -.
DR Pharos; P17752; Tclin.
DR PRO; PR:P17752; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P17752; protein.
DR Bgee; ENSG00000129167; Expressed in buccal mucosa cell and 102 other tissues.
DR ExpressionAtlas; P17752; baseline and differential.
DR Genevisible; P17752; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043005; C:neuron projection; IBA:GO_Central.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004510; F:tryptophan 5-monooxygenase activity; IBA:GO_Central.
DR GO; GO:0009072; P:aromatic amino acid family metabolic process; IEA:InterPro.
DR GO; GO:0046849; P:bone remodeling; IEA:Ensembl.
DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR GO; GO:0060749; P:mammary gland alveolus development; IEA:Ensembl.
DR GO; GO:0030279; P:negative regulation of ossification; IEA:Ensembl.
DR GO; GO:0002576; P:platelet degranulation; ISS:UniProtKB.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; IEA:Ensembl.
DR GO; GO:1900046; P:regulation of hemostasis; ISS:UniProtKB.
DR GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR GO; GO:0042427; P:serotonin biosynthetic process; ISS:UniProtKB.
DR CDD; cd03346; eu_TrpOH; 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; IPR005963; Trp_5_mOase.
DR InterPro; IPR041904; TrpOH_cat.
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; TIGR01270; Trp_5_monoox; 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; Alternative splicing; Iron; Metal-binding; Monooxygenase;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Serotonin biosynthesis;
KW Ubl conjugation.
FT CHAIN 1..444
FT /note="Tryptophan 5-hydroxylase 1"
FT /id="PRO_0000205568"
FT DOMAIN 19..94
FT /note="ACT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01007"
FT BINDING 235
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P70080"
FT BINDING 257
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P70080"
FT BINDING 265
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P70080"
FT BINDING 272
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000269|PubMed:12379098,
FT ECO:0007744|PDB:1MLW"
FT BINDING 277
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000269|PubMed:12379098,
FT ECO:0007744|PDB:1MLW"
FT BINDING 317
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000269|PubMed:12379098,
FT ECO:0007744|PDB:1MLW"
FT BINDING 336
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P70080"
FT BINDING 366
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P70080"
FT MOD_RES 58
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000255"
FT VAR_SEQ 438..444
FT /note="VSRKPSI -> SLNEDVLQVSVFALLLFLPSLHGECHPDT (in isoform
FT 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_000546"
FT CONFLICT 19
FT /note="S -> T (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 68
FT /note="I -> T (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 90..91
FT /note="NL -> TP (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 97
FT /note="L -> M (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 100
FT /note="D -> E (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 104
FT /note="T -> S (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 151
FT /note="L -> S (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 154
FT /note="N -> S (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 157
FT /note="H -> Y (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 179
FT /note="Q -> R (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 207
FT /note="R -> Q (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 217
FT /note="V -> I (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 344
FT /note="A -> V (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 414
FT /note="T -> A (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 419
FT /note="S -> N (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 425
FT /note="Q -> R (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT CONFLICT 436
FT /note="A -> G (in Ref. 2; AAA67050)"
FT /evidence="ECO:0000305"
FT HELIX 112..117
FT /evidence="ECO:0007829|PDB:5TPG"
FT TURN 118..120
FT /evidence="ECO:0007829|PDB:1MLW"
FT TURN 126..128
FT /evidence="ECO:0007829|PDB:5J6D"
FT TURN 134..137
FT /evidence="ECO:0007829|PDB:1MLW"
FT HELIX 140..154
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 168..188
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 191..204
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 214..225
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 228..231
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:1MLW"
FT HELIX 238..246
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 249..252
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 270..276
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 278..281
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 284..297
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 302..313
FT /evidence="ECO:0007829|PDB:5TPG"
FT TURN 314..318
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 320..323
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 326..329
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 332..335
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 338..344
FT /evidence="ECO:0007829|PDB:5TPG"
FT TURN 345..347
FT /evidence="ECO:0007829|PDB:3HF6"
FT STRAND 349..353
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 356..359
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 367..369
FT /evidence="ECO:0007829|PDB:5TPG"
FT STRAND 371..377
FT /evidence="ECO:0007829|PDB:5TPG"
FT HELIX 379..392
FT /evidence="ECO:0007829|PDB:5TPG"
SQ SEQUENCE 444 AA; 50985 MW; DFAD501446953A91 CRC64;
MIEDNKENKD HSLERGRASL IFSLKNEVGG LIKALKIFQE KHVNLLHIES RKSKRRNSEF
EIFVDCDINR EQLNDIFHLL KSHTNVLSVN LPDNFTLKED GMETVPWFPK KISDLDHCAN
RVLMYGSELD ADHPGFKDNV YRKRRKYFAD LAMNYKHGDP IPKVEFTEEE IKTWGTVFQE
LNKLYPTHAC REYLKNLPLL SKYCGYREDN IPQLEDVSNF LKERTGFSIR PVAGYLSPRD
FLSGLAFRVF HCTQYVRHSS DPFYTPEPDT CHELLGHVPL LAEPSFAQFS QEIGLASLGA
SEEAVQKLAT CYFFTVEFGL CKQDGQLRVF GAGLLSSISE LKHALSGHAK VKPFDPKITC
KQECLITTFQ DVYFVSESFE DAKEKMREFT KTIKRPFGVK YNPYTRSIQI LKDTKSITSA
MNELQHDLDV VSDALAKVSR KPSI
