TY3H_BOVIN
ID TY3H_BOVIN Reviewed; 491 AA.
AC P17289;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 5.
DT 03-AUG-2022, entry version 145.
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 Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2898537; DOI=10.1002/jnr.490190408;
RA D'Mello S.R., Weisberg E.P., Stachowiak M.K., Turzai L.M., Gioio A.E.,
RA Kaplan B.B.;
RT "Isolation and nucleotide sequence of a cDNA clone encoding bovine adrenal
RT tyrosine hydroxylase: comparative analysis of tyrosine hydroxylase gene
RT products.";
RL J. Neurosci. Res. 19:440-449(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2899135; DOI=10.1111/j.1471-4159.1988.tb01077.x;
RA Saadat S., Stehle A.D., Lamouroux A., Mallet J., Thoenen H.;
RT "Predicted amino acid sequence of bovine tyrosine hydroxylase and its
RT similarity to tyrosine hydroxylases from other species.";
RL J. Neurochem. 51:572-578(1988).
RN [3]
RP PROTEIN SEQUENCE OF 154-170.
RX PubMed=2895648; DOI=10.1016/s0006-291x(88)80524-2;
RA Abate C., Smith J.A., Joh T.H.;
RT "Characterization of the catalytic domain of bovine adrenal tyrosine
RT hydroxylase.";
RL Biochem. Biophys. Res. Commun. 151:1446-1453(1988).
RN [4]
RP PROTEIN SEQUENCE OF 2-28.
RC TISSUE=Adrenal medulla;
RX PubMed=2894860; DOI=10.1016/0167-4838(88)90019-2;
RA Haavik J., Andersson K.K., Petersson L., Flatmark T.;
RT "Soluble tyrosine hydroxylase (tyrosine 3-monooxygenase) from bovine
RT adrenal medulla: large-scale purification and physicochemical properties.";
RL Biochim. Biophys. Acta 953:142-156(1988).
RN [5]
RP PHOSPHORYLATION AT SER-19; SER-31 AND SER-40.
RX PubMed=8096628; DOI=10.1007/bf00966919;
RA Haycock J.W.;
RT "Multiple signaling pathways in bovine chromaffin cells regulate tyrosine
RT hydroxylase phosphorylation at Ser19, Ser31, and Ser40.";
RL Neurochem. Res. 18:15-26(1993).
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-170.
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 phsphorylated 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}.
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DR EMBL; M36794; AAA30779.1; -; mRNA.
DR EMBL; M36705; AAA30798.1; -; mRNA.
DR PIR; I45983; I45983.
DR PIR; JL0039; JL0039.
DR RefSeq; NP_776309.1; NM_173884.2.
DR AlphaFoldDB; P17289; -.
DR SMR; P17289; -.
DR STRING; 9913.ENSBTAP00000038050; -.
DR BindingDB; P17289; -.
DR ChEMBL; CHEMBL3713; -.
DR iPTMnet; P17289; -.
DR PaxDb; P17289; -.
DR GeneID; 280707; -.
DR KEGG; bta:280707; -.
DR CTD; 7054; -.
DR eggNOG; KOG3820; Eukaryota.
DR InParanoid; P17289; -.
DR OrthoDB; 614557at2759; -.
DR SABIO-RK; P17289; -.
DR UniPathway; UPA00747; UER00733.
DR PRO; PR:P17289; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
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:0042136; P:neurotransmitter biosynthetic process; IEA:UniProtKB-KW.
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; 1.10.800.10; -; 1.
DR InterPro; IPR045865; ACT-like_dom_sf.
DR InterPro; IPR001273; ArAA_hydroxylase.
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; 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 INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:2894860"
FT CHAIN 2..491
FT /note="Tyrosine 3-monooxygenase"
FT /id="PRO_0000205560"
FT BINDING 324
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT BINDING 329
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT BINDING 369
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT SITE 418
FT /note="Important for substrate specificity"
FT /evidence="ECO:0000250|UniProtKB:P04177"
FT MOD_RES 19
FT /note="Phosphoserine; by CaMK2"
FT /evidence="ECO:0000269|PubMed:8096628"
FT MOD_RES 31
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:8096628"
FT MOD_RES 40
FT /note="Phosphoserine; by CaMK2 and PKA"
FT /evidence="ECO:0000269|PubMed:8096628"
FT MOD_RES 465
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P24529"
FT CONFLICT 65..68
FT /note="AAWL -> GSLV (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 73
FT /note="E -> K (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 83
FT /note="P -> R (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 86
FT /note="R -> K (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 284
FT /note="A -> V (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 321
FT /note="E -> D (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 328..330
FT /note="GHV -> AHG (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 380
FT /note="K -> N (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
FT CONFLICT 471
FT /note="H -> R (in Ref. 2; AAA30798)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 491 AA; 55123 MW; 86707712238F12F2 CRC64;
MPTPNAASPQ AKGFRRAVSE LDAKQAEAIM SPRFVGRRQS LIQDARKERE KAEAAASSSE
SAEAAAWLER DGEAVLTLLF ALPPTRPPAL TRAIKVFETF EAHLHHLETR PAQPLRAGSP
PLECFVRCEV PGPVVPALLS ALRRVAEDVR AAGESKVLWF PRKVSELDKC HHLVTKFDPD
LDLDHPGFSD QAYRQRRKLI AEIAFQYKQG DPIPHVEYTA EETATWKEVY STLRGLYPTH
ACREHLEAFE LLERFCGYRE DRIPQLEDVS RFLKERTGFQ LRPAAGLLSA RDFLASLAFR
VFQCTQYIRH ASSPMHSPEP ECCHELLGHV PMLADRTFAQ FSQDIGLASL GVSDEEIEKL
STLYWFTVEF GLCKQNGEVK AYGAGLLSSY GELLHSLSEE PEIRAFDPDA AAVQPYQDQT
YQPVYFVSES FSDAKDKLRS YASRIQRPFS VKFDPYTLAI DVLDSPHAIR HALDGVQDEM
QALAHALNAI S
