ID TY3H_CANLF Reviewed; 495 AA.
AC Q76IQ3;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 27-MAR-2024, entry version 100.
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 Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT CYS-33.
RC STRAIN=Beagle; TISSUE=Brain;
RX PubMed=16210796; DOI=10.1292/jvms.67.861;
RA Takeuchi Y., Hashizume C., Chon E.M.H., Momozawa Y., Masuda K., Kikusui T.,
RA Mori Y.;
RT "Canine tyrosine hydroxylase (TH) gene and dopamine beta-hydroxylase (DBH)
RT gene: their sequences, genetic polymorphisms, and diversities among five
RT different dog breeds.";
RL J. Vet. Med. Sci. 67:861-867(2005).
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 (By similarity).
CC {ECO:0000250|UniProtKB:P04177, ECO:0000250|UniProtKB:P07101,
CC ECO:0000250|UniProtKB:P24529}.
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-174.
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 (By similarity). Interacts (when phosphorylated
CC at Ser-19) with YWHAG; one YWHAG dimer bounds to one TH tetramer this
CC interaction may influence the phosphorylation and dephosphorylation of
CC other sites (By similarity). {ECO:0000250|UniProtKB:P07101}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:P24529}. Nucleus {ECO:0000250|UniProtKB:P04177}.
CC Cell projection, axon {ECO:0000250|UniProtKB:P24529}. 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 phosphorylated at Ser-31 as well at Ser-40 shows a cytosolic
CC distribution (By similarity). Expressed in dopaminergic axons and axon
CC terminals (By similarity). {ECO:0000250|UniProtKB:P04177,
CC ECO:0000250|UniProtKB:P07101}.
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 -!- SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid
CC hydroxylase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB097058; BAC82588.1; -; mRNA.
DR RefSeq; NP_001002966.1; NM_001002966.1.
DR AlphaFoldDB; Q76IQ3; -.
DR SMR; Q76IQ3; -.
DR STRING; 9615.ENSCAFP00000014845; -.
DR PaxDb; 9612-ENSCAFP00000014845; -.
DR GeneID; 403444; -.
DR KEGG; cfa:403444; -.
DR CTD; 7054; -.
DR eggNOG; KOG3820; Eukaryota.
DR InParanoid; Q76IQ3; -.
DR OrthoDB; 275463at2759; -.
DR UniPathway; UPA00747; UER00733.
DR Proteomes; UP000002254; Unplaced.
DR Proteomes; UP000694429; Unplaced.
DR Proteomes; UP000694542; Unplaced.
DR Proteomes; UP000805418; Unplaced.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IBA:GO_Central.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004511; F:tyrosine 3-monooxygenase activity; IBA:GO_Central.
DR GO; GO:0006585; P:dopamine biosynthetic process from tyrosine; IBA:GO_Central.
DR GO; GO:0007507; P:heart development; IBA:GO_Central.
DR GO; GO:1990384; P:hyaloid vascular plexus regression; ISS:UniProtKB.
DR GO; GO:0045471; P:response to ethanol; IBA:GO_Central.
DR GO; GO:0001666; P:response to hypoxia; IBA:GO_Central.
DR CDD; cd03345; eu_TyrOH; 1.
DR Gene3D; 3.30.70.260; -; 1.
DR Gene3D; 1.10.800.10; Aromatic amino acid hydroxylase; 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; IPR049321; TH_ACT.
DR InterPro; IPR005962; Tyr_3_mOase.
DR InterPro; IPR019773; Tyrosine_3-monooxygenase-like.
DR InterPro; IPR021164; Tyrosine_hydroxylase_CS.
DR NCBIfam; TIGR01269; Tyr_3_monoox; 1.
DR PANTHER; PTHR11473; AROMATIC AMINO ACID HYDROXYLASE; 1.
DR PANTHER; PTHR11473:SF18; TYROSINE 3-MONOOXYGENASE; 1.
DR Pfam; PF00351; Biopterin_H; 1.
DR Pfam; PF21417; TH_ACT; 1.
DR Pfam; PF12549; TOH_N; 2.
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; PS00367; BH4_AAA_HYDROXYL_1; 1.
DR PROSITE; PS51410; BH4_AAA_HYDROXYL_2; 1.
PE 2: Evidence at transcript level;
KW Catecholamine biosynthesis; Cell projection; Cytoplasm;
KW Cytoplasmic vesicle; Iron; Metal-binding; Monooxygenase;
KW Neurotransmitter biosynthesis; Nucleus; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Synapse.
FT CHAIN 1..495
FT /note="Tyrosine 3-monooxygenase"
FT /id="PRO_0000289577"
FT REGION 41..65
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 41..55
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 328
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT BINDING 333
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT BINDING 373
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT SITE 422
FT /note="Important for substrate specificity"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT MOD_RES 19
FT /note="Phosphoserine; by CaMK2"
FT /evidence="ECO:0000250|UniProtKB:P07101"
FT MOD_RES 31
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P24529"
FT MOD_RES 40
FT /note="Phosphoserine; by CaMK2 and PKA"
FT /evidence="ECO:0000250|UniProtKB:P07101"
FT MOD_RES 469
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P24529"
FT VARIANT 33
FT /note="R -> C"
FT /evidence="ECO:0000269|PubMed:16210796"
SQ SEQUENCE 495 AA; 55679 MW; D02E3C7784336C7B CRC64;
MPTPNTASPQ AKGFRRAVSE LDAKQAEAIM SPRFIGRRQS LIEDARKERE KAEAASAASS
EPGDLLEAAV SKEKDGKAML NLLFTLRGAK TSSLSRAVKA FETFEAQIHH LETRPVQRPR
AGGPHLEYFV RCEVPSADLP ALLSSVRRVA EDVRGAGENK VLWFPRKVSE LDKCHHLVTK
FDPDLDLDHP GFSDQVYRQR RKLIAEIAFQ YKHGDPIPRV EYTAEEIATW KEVYTTLKSL
YVTHACREHL EAFQLLERFS GYREDSIPQL EDVSRFLKER TGFQLRPVAG LLSARDFLAS
LAFRVFQCTQ YIRHASSPMH SPEPDCCHEL LGHVPMLADR TFAQFSQDIG LASLGASDEE
IEKLSTLYWF TVEFGLCKQN GEVKAYGAGL LSSYGELLHS LSEEPEIRAF DPDAAAVQPY
QDQTYQSVYF VSESFSDAKD KLRNYASRIQ RPFSVKFDPY TLAIDVLDSP HAIRRSLEGV
QDELHTLAHA LSAIG
//
