TPH1_MOUSE
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 03-AUG-2022, entry version 177.
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; P17532; -.
DR PRIDE; P17532; -.
DR ProteomicsDB; 259165; -.
DR Antibodypedia; 4386; 623 antibodies from 43 providers.
DR DNASU; 21990; -.
DR Ensembl; ENSMUST00000049298; ENSMUSP00000037752; ENSMUSG00000040046.
DR Ensembl; ENSMUST00000107669; ENSMUSP00000103296; ENSMUSG00000040046.
DR GeneID; 21990; -.
DR KEGG; mmu:21990; -.
DR UCSC; uc009gyq.3; mouse.
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; VTCQEEC; -.
DR OrthoDB; 614557at2759; -.
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 74 CRISPR screens.
DR PRO; PR:P17532; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; P17532; protein.
DR Bgee; ENSMUSG00000040046; Expressed in pineal body and 67 other tissues.
DR ExpressionAtlas; P17532; baseline and differential.
DR Genevisible; P17532; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0043005; C:neuron projection; ISO:MGI.
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 family 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; -; 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; 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; 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 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
