ID   TPH1_MOUSE              Reviewed;         447 AA.
AC   P17532;
DT   01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1990, sequence version 1.
DT   27-MAR-2024, entry version 185.
DE   RecName: Full=Tryptophan 5-hydroxylase 1 {ECO:0000305};
DE            EC=1.14.16.4 {ECO:0000305|PubMed:2110547};
DE   AltName: Full=Tryptophan 5-monooxygenase 1;
GN   Name=Tph1 {ECO:0000303|PubMed:14697203, ECO:0000312|MGI:MGI:98796};
GN   Synonyms=Tph;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=2110547; DOI=10.1016/0888-7543(90)90522-v;
RA   Stoll J., Kozak C.A., Goldman D.;
RT   "Characterization and chromosomal mapping of a cDNA encoding tryptophan
RT   hydroxylase from a mouse mastocytoma cell line.";
RL   Genomics 7:88-96(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Brain;
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   [3]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=14697203; DOI=10.1016/s0092-8674(03)01014-6;
RA   Walther D.J., Peter J.U., Winter S., Hoeltje M., Paulmann N., Grohmann M.,
RA   Vowinckel J., Alamo-Bethencourt V., Wilhelm C.S., Ahnert-Hilger G.,
RA   Bader M.;
RT   "Serotonylation of small GTPases is a signal transduction pathway that
RT   triggers platelet alpha-granule release.";
RL   Cell 115:851-862(2003).
CC   -!- FUNCTION: Oxidizes L-tryptophan to 5-hydroxy-l-tryptophan in the rate-
CC       determining step of serotonin biosynthesis.
CC       {ECO:0000269|PubMed:14697203, ECO:0000305|PubMed:2110547}.
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:0000305|PubMed:2110547};
CC   -!- COFACTOR:
CC       Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC         Evidence={ECO:0000250|UniProtKB:P17752};
CC   -!- PATHWAY: Aromatic compound metabolism; serotonin biosynthesis;
CC       serotonin from L-tryptophan: step 1/2. {ECO:0000305|PubMed:2110547}.
CC   -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P70080}.
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   -!- DISRUPTION PHENOTYPE: Mice display impaired hemostasis, resulting in a
CC       reduced risk of thrombosis and thromboembolism, although the
CC       ultrastructure of the platelets is not affected (PubMed:14697203).
CC       Blood platelet counts are normal (PubMed:14697203). Defects are caused
CC       by inability to inability to mediate protein serotonylation of small
CC       GTPases during activation and aggregation of platelets
CC       (PubMed:14697203). {ECO:0000269|PubMed:14697203}.
CC   -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC       hydroxylase family. {ECO:0000305}.
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DR   EMBL; J04758; AAA63401.1; -; mRNA.
DR   EMBL; BC072582; AAH72582.1; -; mRNA.
DR   CCDS; CCDS21280.1; -.
DR   PIR; A34582; A34582.
DR   RefSeq; NP_001129556.1; NM_001136084.2.
DR   RefSeq; NP_033440.1; NM_009414.3.
DR   AlphaFoldDB; P17532; -.
DR   SMR; P17532; -.
DR   STRING; 10090.ENSMUSP00000037752; -.
DR   iPTMnet; P17532; -.
DR   PhosphoSitePlus; P17532; -.
DR   PaxDb; 10090-ENSMUSP00000037752; -.
DR   ProteomicsDB; 259165; -.
DR   Antibodypedia; 4386; 671 antibodies from 43 providers.
DR   DNASU; 21990; -.
DR   Ensembl; ENSMUST00000049298.15; ENSMUSP00000037752.8; ENSMUSG00000040046.15.
DR   Ensembl; ENSMUST00000107669.9; ENSMUSP00000103296.3; ENSMUSG00000040046.15.
DR   GeneID; 21990; -.
DR   KEGG; mmu:21990; -.
DR   UCSC; uc009gyq.3; mouse.
DR   AGR; MGI:98796; -.
DR   CTD; 7166; -.
DR   MGI; MGI:98796; Tph1.
DR   VEuPathDB; HostDB:ENSMUSG00000040046; -.
DR   eggNOG; KOG3820; Eukaryota.
DR   GeneTree; ENSGT00950000182885; -.
DR   HOGENOM; CLU_023198_0_1_1; -.
DR   InParanoid; P17532; -.
DR   OMA; SEVDMPW; -.
DR   OrthoDB; 275463at2759; -.
DR   PhylomeDB; P17532; -.
DR   TreeFam; TF313327; -.
DR   BRENDA; 1.14.16.4; 3474.
DR   Reactome; R-MMU-209931; Serotonin and melatonin biosynthesis.
DR   UniPathway; UPA00846; UER00799.
DR   BioGRID-ORCS; 21990; 2 hits in 79 CRISPR screens.
DR   PRO; PR:P17532; -.
DR   Proteomes; UP000000589; Chromosome 7.
DR   RNAct; P17532; Protein.
DR   Bgee; ENSMUSG00000040046; Expressed in pineal body and 69 other cell types or tissues.
DR   ExpressionAtlas; P17532; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:MGI.
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; IDA:MGI.
DR   GO; GO:0009072; P:aromatic amino acid metabolic process; IEA:InterPro.
DR   GO; GO:0046849; P:bone remodeling; IGI:MGI.
DR   GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR   GO; GO:0060749; P:mammary gland alveolus development; IMP:MGI.
DR   GO; GO:0030279; P:negative regulation of ossification; ISO:MGI.
DR   GO; GO:0002576; P:platelet degranulation; IMP:UniProtKB.
DR   GO; GO:0045600; P:positive regulation of fat cell differentiation; IMP:MGI.
DR   GO; GO:1900046; P:regulation of hemostasis; IMP:UniProtKB.
DR   GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR   GO; GO:0042427; P:serotonin biosynthetic process; IMP:UniProtKB.
DR   CDD; cd03346; eu_TrpOH; 1.
DR   Gene3D; 1.10.800.10; Aromatic amino acid hydroxylase; 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   NCBIfam; TIGR01270; Trp_5_monoox; 1.
DR   PANTHER; PTHR11473; AROMATIC AMINO ACID HYDROXYLASE; 1.
DR   PANTHER; PTHR11473:SF23; TRYPTOPHAN 5-HYDROXYLASE 1; 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   PROSITE; PS51671; ACT; 1.
DR   PROSITE; PS00367; BH4_AAA_HYDROXYL_1; 1.
DR   PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1.
DR   Genevisible; P17532; MM.
PE   1: Evidence at protein level;
KW   Iron; Metal-binding; Monooxygenase; Oxidoreductase; Phosphoprotein;
KW   Reference proteome; Serotonin biosynthesis; Ubl conjugation.
FT   CHAIN           1..447
FT                   /note="Tryptophan 5-hydroxylase 1"
FT                   /id="PRO_0000205569"
FT   DOMAIN          22..97
FT                   /note="ACT"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01007"
FT   BINDING         238
FT                   /ligand="L-tryptophan"
FT                   /ligand_id="ChEBI:CHEBI:57912"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         260
FT                   /ligand="L-tryptophan"
FT                   /ligand_id="ChEBI:CHEBI:57912"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         268
FT                   /ligand="L-tryptophan"
FT                   /ligand_id="ChEBI:CHEBI:57912"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         275
FT                   /ligand="Fe cation"
FT                   /ligand_id="ChEBI:CHEBI:24875"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         280
FT                   /ligand="Fe cation"
FT                   /ligand_id="ChEBI:CHEBI:24875"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         320
FT                   /ligand="Fe cation"
FT                   /ligand_id="ChEBI:CHEBI:24875"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         339
FT                   /ligand="L-tryptophan"
FT                   /ligand_id="ChEBI:CHEBI:57912"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   BINDING         369
FT                   /ligand="L-tryptophan"
FT                   /ligand_id="ChEBI:CHEBI:57912"
FT                   /evidence="ECO:0000250|UniProtKB:P70080"
FT   MOD_RES         61
FT                   /note="Phosphoserine; by PKA"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   447 AA;  51343 MW;  16C839F22A138BCA CRC64;
     MIEDNKENKE NKDHSSERGR VTLIFSLENE VGGLIKVLKI FQENHVSLLH IESRKSKQRN
     SEFEIFVDCD ISREQLNDIF PLLKSHATVL SVDSPDQLTA KEDVMETVPW FPKKISDLDF
     CANRVLLYGS ELDADHPGFK DNVYRRRRKY FAELAMNYKH GDPIPKIEFT EEEIKTWGTI
     FRELNKLYPT HACREYLRNL PLLSKYCGYR EDNIPQLEDV SNFLKERTGF SIRPVAGYLS
     PRDFLSGLAF RVFHCTQYVR HSSDPLYTPE PDTCHELLGH VPLLAEPSFA QFSQEIGLAS
     LGASEETVQK LATCYFFTVE FGLCKQDGQL RVFGAGLLSS ISELKHALSG HAKVKPFDPK
     IACKQECLIT SFQDVYFVSE SFEDAKEKMR EFAKTVKRPF GLKYNPYTQS VQVLRDTKSI
     TSAMNELRYD LDVISDALAR VTRWPSV
//