TY3H_MOUSE
ID TY3H_MOUSE Reviewed; 498 AA.
AC P24529;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Tyrosine 3-monooxygenase;
DE EC=1.14.16.2 {ECO:0000250|UniProtKB:P07101};
DE AltName: Full=Tyrosine 3-hydroxylase;
DE Short=TH;
GN Name=Th;
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], AND TISSUE SPECIFICITY.
RX PubMed=1674869; DOI=10.1016/0006-291x(91)90472-j;
RA Ichikawa S., Sasaoka T., Nagatsu T.;
RT "Primary structure of mouse tyrosine hydroxylase deduced from its cDNA.";
RL Biochem. Biophys. Res. Commun. 176:1610-1616(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-30.
RC STRAIN=BALB/cJ;
RA Morgan W.W., Bermudez J., Sharp Z.D.;
RL Submitted (APR-1992) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 78-90.
RC TISSUE=Brain;
RA Lubec G., Yang J.W., Zigmond M.;
RL Submitted (JUL-2007) to UniProtKB.
RN [4]
RP DISRUPTION PHENOTYPE.
RX PubMed=7715703; DOI=10.1038/374640a0;
RA Zhou Q.Y., Quaife C.J., Palmiter R.D.;
RT "Targeted disruption of the tyrosine hydroxylase gene reveals that
RT catecholamines are required for mouse fetal development.";
RL Nature 374:640-643(1995).
RN [5]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17296554; DOI=10.1016/j.neuron.2007.01.019;
RA Ihara M., Yamasaki N., Hagiwara A., Tanigaki A., Kitano A., Hikawa R.,
RA Tomimoto H., Noda M., Takanashi M., Mori H., Hattori N., Miyakawa T.,
RA Kinoshita M.;
RT "Sept4, a component of presynaptic scaffold and Lewy bodies, is required
RT for the suppression of alpha-synuclein neurotoxicity.";
RL Neuron 53:519-533(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19; SER-31 AND SER-472, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Brown adipose tissue;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE,
RP AND DISRUPTION PHENOTYPE.
RX PubMed=30936473; DOI=10.1038/s41556-019-0301-x;
RA Nguyen M.T., Vemaraju S., Nayak G., Odaka Y., Buhr E.D., Alonzo N.,
RA Tran U., Batie M., Upton B.A., Darvas M., Kozmik Z., Rao S., Hegde R.S.,
RA Iuvone P.M., Van Gelder R.N., Lang R.A.;
RT "An opsin 5-dopamine pathway mediates light-dependent vascular development
RT in the eye.";
RL Nat. Cell Biol. 21:420-429(2019).
CC -!- FUNCTION: Catalyzes the conversion of L-tyrosine to L-
CC dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the
CC biosynthesis of cathecolamines, dopamine, noradrenaline, and
CC adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert
CC tyrosine to L-Dopa (By similarity). In addition to tyrosine, is able to
CC catalyze the hydroxylation of phenylalanine and tryptophan with lower
CC specificity (By similarity). Positively regulates the regression of
CC retinal hyaloid vessels during postnatal development(PubMed:30936473).
CC {ECO:0000250|UniProtKB:P04177, ECO:0000250|UniProtKB:P07101,
CC ECO:0000269|PubMed:30936473}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tyrosine + O2 =
CC (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + L-dopa;
CC Xref=Rhea:RHEA:18201, ChEBI:CHEBI:15379, ChEBI:CHEBI:15642,
CC ChEBI:CHEBI:57504, ChEBI:CHEBI:58315, ChEBI:CHEBI:59560;
CC EC=1.14.16.2; Evidence={ECO:0000250|UniProtKB:P07101};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:18202;
CC Evidence={ECO:0000250|UniProtKB:P07101};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:P04177};
CC -!- ACTIVITY REGULATION: Inhibited in feedback fashion by the catecholamine
CC neurotransmitters, especially by dopamine in competition with
CC tetrahydrobiopterin. Phosphorylation of several Ser/Thr residues in the
CC N-terminus regulates the catalytic activity. Ser-31 and Ser-40 are
CC readily phosphorylated to activate the catalytic activity. A Cysteine
CC modification induced by N-ethylmaleimide (NEM), inhibits tyrosine 3-
CC monooxygenase activity through the modification of the Cys-177.
CC {ECO:0000250|UniProtKB:P07101}.
CC -!- PATHWAY: Catecholamine biosynthesis; dopamine biosynthesis; dopamine
CC from L-tyrosine: step 1/2. {ECO:0000250|UniProtKB:P07101}.
CC -!- SUBUNIT: Homotetramer. Interacts (when phosphorylated at Ser-19) with
CC YWHAG; one YWHAG dimer bounds to one TH tetramer this interaction may
CC influence the phosphorylation and dephosphorylation of other sites.
CC {ECO:0000250|UniProtKB:P07101}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:30936473}. Nucleus {ECO:0000250|UniProtKB:P04177}.
CC Cell projection, axon {ECO:0000269|PubMed:17296554}. Cytoplasm
CC {ECO:0000250|UniProtKB:P04177}. Cytoplasmic vesicle, secretory vesicle,
CC synaptic vesicle {ECO:0000250|UniProtKB:P04177}. Note=When
CC phosphorylated at Ser-19 shows a nuclear distribution and when
CC phsphorylated at Ser-31 as well at Ser-40 shows a cytosolic
CC distribution (By similarity). Expressed in dopaminergic axons and axon
CC terminals (PubMed:17296554). {ECO:0000250|UniProtKB:P04177,
CC ECO:0000269|PubMed:17296554}.
CC -!- TISSUE SPECIFICITY: Expressed in the adrenal gland (PubMed:1674869).
CC Expressed in the retina (PubMed:30936473). Expressed in the in the
CC striatum (at protein level) (PubMed:17296554).
CC {ECO:0000269|PubMed:1674869, ECO:0000269|PubMed:17296554,
CC ECO:0000269|PubMed:30936473}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the retinal inner nuclear layer and
CC outer nuclear layer at postnatal day 8 (P8) (PubMed:30936473).
CC Expressed in retinal dopaminergic amacrine cells in the retina at P8
CC and P15 (PubMed:30936473). {ECO:0000269|PubMed:30936473}.
CC -!- PTM: Phosphorylated on Ser-19, Ser-31 and Ser-40 by several protein
CC kinases with different site specificities. Phosphorylation at Ser-31
CC and Ser-40 leads to an increase of TH activity. Phosphorylation at Ser-
CC 40 activates the enzyme and also counteracts the feedback inhibition of
CC TH by catecholamines (By similarity). Phosphorylation of Ser-19 and
CC Ser-31 triggers the proteasomal degradation of TH through the
CC ubiquitin-proteasome pathway (By similarity). Phosphorylation at Ser-31
CC facilitates transport of TH from the soma to the nerve terminals via
CC the microtubule network (By similarity). Phosphorylation at Ser-19
CC induces the high-affinity binding to the 14-3-3 protein YWHAG; this
CC interaction may influence the phosphorylation and dephosphorylation of
CC other sites (By similarity). Ser-19 increases the phosphorylation at
CC Ser-40 in a hierarchical manner, leading to increased activity (By
CC similarity). {ECO:0000250|UniProtKB:P04177,
CC ECO:0000250|UniProtKB:P07101}.
CC -!- DISRUPTION PHENOTYPE: Homozygotes deficient mice are deficient in
CC catecholamines, and usually die around embryonic day 11.5-15.5 due to
CC cardiac failure (PubMed:7715703). Increased number of persisting
CC retinal hyaloid vessels due to loss of hyaloid vessel regression at P8
CC (PubMed:30936473). {ECO:0000269|PubMed:30936473,
CC ECO:0000269|PubMed:7715703}.
CC -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC hydroxylase family. {ECO:0000305}.
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DR EMBL; M69200; AAA40434.1; -; mRNA.
DR EMBL; X53503; CAA37580.1; -; Genomic_DNA.
DR CCDS; CCDS22036.1; -.
DR PIR; JN0068; JN0068.
DR RefSeq; NP_033403.1; NM_009377.1.
DR AlphaFoldDB; P24529; -.
DR BMRB; P24529; -.
DR SMR; P24529; -.
DR BioGRID; 204173; 3.
DR STRING; 10090.ENSMUSP00000000219; -.
DR iPTMnet; P24529; -.
DR PhosphoSitePlus; P24529; -.
DR MaxQB; P24529; -.
DR PaxDb; P24529; -.
DR PeptideAtlas; P24529; -.
DR PRIDE; P24529; -.
DR ProteomicsDB; 298442; -.
DR Antibodypedia; 3748; 1700 antibodies from 51 providers.
DR DNASU; 21823; -.
DR Ensembl; ENSMUST00000000219; ENSMUSP00000000219; ENSMUSG00000000214.
DR GeneID; 21823; -.
DR KEGG; mmu:21823; -.
DR UCSC; uc009koi.1; mouse.
DR CTD; 7054; -.
DR MGI; MGI:98735; Th.
DR VEuPathDB; HostDB:ENSMUSG00000000214; -.
DR eggNOG; KOG3820; Eukaryota.
DR GeneTree; ENSGT00950000182885; -.
DR HOGENOM; CLU_023198_3_0_1; -.
DR InParanoid; P24529; -.
DR OMA; PELDMNH; -.
DR OrthoDB; 614557at2759; -.
DR PhylomeDB; P24529; -.
DR TreeFam; TF313327; -.
DR BRENDA; 1.14.16.2; 3474.
DR Reactome; R-MMU-209905; Catecholamine biosynthesis.
DR UniPathway; UPA00747; UER00733.
DR BioGRID-ORCS; 21823; 1 hit in 74 CRISPR screens.
DR ChiTaRS; Th; mouse.
DR PRO; PR:P24529; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; P24529; protein.
DR Bgee; ENSMUSG00000000214; Expressed in superior cervical ganglion and 88 other tissues.
DR ExpressionAtlas; P24529; baseline and differential.
DR Genevisible; P24529; MM.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISO:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISO:MGI.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0030425; C:dendrite; ISO:MGI.
DR GO; GO:0033162; C:melanosome membrane; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0043005; C:neuron projection; IDA:MGI.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0043204; C:perikaryon; IDA:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005790; C:smooth endoplasmic reticulum; ISO:MGI.
DR GO; GO:0008021; C:synaptic vesicle; ISO:MGI.
DR GO; GO:0043195; C:terminal bouton; ISO:MGI.
DR GO; GO:0016597; F:amino acid binding; ISO:MGI.
DR GO; GO:0035240; F:dopamine binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0008199; F:ferric iron binding; ISO:MGI.
DR GO; GO:0008198; F:ferrous iron binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004497; F:monooxygenase activity; ISO:MGI.
DR GO; GO:0019825; F:oxygen binding; ISO:MGI.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0034617; F:tetrahydrobiopterin binding; ISO:MGI.
DR GO; GO:0004511; F:tyrosine 3-monooxygenase activity; ISO:MGI.
DR GO; GO:0015842; P:aminergic neurotransmitter loading into synaptic vesicle; ISO:MGI.
DR GO; GO:0009887; P:animal organ morphogenesis; IMP:MGI.
DR GO; GO:0042423; P:catecholamine biosynthetic process; ISO:MGI.
DR GO; GO:0071312; P:cellular response to alkaloid; IEA:Ensembl.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
DR GO; GO:0071316; P:cellular response to nicotine; IEA:Ensembl.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0042745; P:circadian sleep/wake cycle; IEA:Ensembl.
DR GO; GO:0042416; P:dopamine biosynthetic process; ISO:MGI.
DR GO; GO:0006585; P:dopamine biosynthetic process from tyrosine; IDA:MGI.
DR GO; GO:0042755; P:eating behavior; IMP:MGI.
DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; IMP:BHF-UCL.
DR GO; GO:0042418; P:epinephrine biosynthetic process; ISO:MGI.
DR GO; GO:0042462; P:eye photoreceptor cell development; IMP:BHF-UCL.
DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl.
DR GO; GO:0016137; P:glycoside metabolic process; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:1990384; P:hyaloid vascular plexus regression; IMP:UniProtKB.
DR GO; GO:0033076; P:isoquinoline alkaloid metabolic process; IEA:Ensembl.
DR GO; GO:0007612; P:learning; IMP:MGI.
DR GO; GO:0007626; P:locomotory behavior; IMP:MGI.
DR GO; GO:0007617; P:mating behavior; IMP:MGI.
DR GO; GO:0007613; P:memory; IMP:MGI.
DR GO; GO:0010259; P:multicellular organism aging; IEA:Ensembl.
DR GO; GO:0042136; P:neurotransmitter biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0042421; P:norepinephrine biosynthetic process; ISO:MGI.
DR GO; GO:0018963; P:phthalate metabolic process; IEA:Ensembl.
DR GO; GO:0052314; P:phytoalexin metabolic process; IEA:Ensembl.
DR GO; GO:0008016; P:regulation of heart contraction; IMP:MGI.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl.
DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl.
DR GO; GO:0051602; P:response to electrical stimulus; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; ISO:MGI.
DR GO; GO:0045472; P:response to ether; IEA:Ensembl.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; ISO:MGI.
DR GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR GO; GO:0035900; P:response to isolation stress; IEA:Ensembl.
DR GO; GO:0009416; P:response to light stimulus; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl.
DR GO; GO:0046684; P:response to pyrethroid; IEA:Ensembl.
DR GO; GO:0009651; P:response to salt stress; IEA:Ensembl.
DR GO; GO:0009414; P:response to water deprivation; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0007605; P:sensory perception of sound; IEA:Ensembl.
DR GO; GO:0035176; P:social behavior; IEA:Ensembl.
DR GO; GO:0006665; P:sphingolipid metabolic process; IEA:Ensembl.
DR GO; GO:0001963; P:synaptic transmission, dopaminergic; IMP:MGI.
DR GO; GO:0042214; P:terpene metabolic process; IEA:Ensembl.
DR GO; GO:0007601; P:visual perception; IMP:BHF-UCL.
DR CDD; cd03345; eu_TyrOH; 1.
DR Gene3D; 1.10.800.10; -; 1.
DR InterPro; IPR045865; ACT-like_dom_sf.
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; IPR041903; Eu_TyrOH_cat.
DR InterPro; IPR005962; Tyr_3_mOase.
DR InterPro; IPR019773; Tyrosine_3-monooxygenase-like.
DR InterPro; IPR021164; Tyrosine_hydroxylase_CS.
DR PANTHER; PTHR11473; PTHR11473; 1.
DR Pfam; PF00351; Biopterin_H; 1.
DR Pfam; PF12549; TOH_N; 2.
DR PIRSF; PIRSF000336; TH; 1.
DR PRINTS; PR00372; FYWHYDRXLASE.
DR SUPFAM; SSF55021; SSF55021; 1.
DR SUPFAM; SSF56534; SSF56534; 1.
DR TIGRFAMs; TIGR01269; Tyr_3_monoox; 1.
DR PROSITE; PS00367; BH4_AAA_HYDROXYL_1; 1.
DR PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1.
PE 1: Evidence at protein level;
KW Catecholamine biosynthesis; Cell projection; Cytoplasm;
KW Cytoplasmic vesicle; Direct protein sequencing; Iron; Metal-binding;
KW Monooxygenase; Neurotransmitter biosynthesis; Nucleus; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Synapse.
FT CHAIN 1..498
FT /note="Tyrosine 3-monooxygenase"
FT /id="PRO_0000205562"
FT REGION 1..33
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 331
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P07101"
FT BINDING 336
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P07101"
FT BINDING 376
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P07101"
FT SITE 425
FT /note="Important for substrate specificity"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT MOD_RES 19
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 31
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 40
FT /note="Phosphoserine; by CaMK2 and PKA"
FT /evidence="ECO:0000250|UniProtKB:P07101"
FT MOD_RES 472
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
SQ SEQUENCE 498 AA; 55993 MW; 62790179664F6DC6 CRC64;
MPTPSASSPQ PKGFRRAVSE QDTKQAEAVT SPRFIGRRQS LIEDARKERE AAAAAAAAAV
ASAEPGNPLE AVVFEERDGN AVLNLLFSLR GTKPSSLSRA LKVFETFEAK IHHLETRPAQ
RPLAGSPHLE YFVRFEVPSG DLAALLSSVR RVSDDVRSAR EDKVPWFPRK VSELDKCHHL
VTKFDPDLDL DHPGFSDQAY RQRRKLIAEI AFQYKQGEPI PHVEYTKEEI ATWKEVYATL
KGLYATHACR EHLEAFQLLE RYCGYREDSI PQLEDVSHFL KERTGFQLRP VAGLLSARDF
LASLAFRVFQ CTQYIRHASS PMHSPEPDCC HELLGHVPML ADRTFAQFSQ DIGLASLGAS
DEEIEKLSTV YWFTVEFGLC KQNGELKAYG AGLLSSYGEL LHSLSEEPEV RAFDPDTAAV
QPYQDQTYQP VYFVSESFSD AKDKLRNYAS RIQRPFSVKF DPYTLAIDVL DSPHTIRRSL
EGVQDELHTL TQALSAIS
