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TY3H_CANLF
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   03-AUG-2022, entry version 92.
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       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; AB097058; BAC82588.1; -; mRNA.
DR   RefSeq; NP_001002966.1; NM_001002966.1.
DR   AlphaFoldDB; Q76IQ3; -.
DR   SMR; Q76IQ3; -.
DR   STRING; 9615.ENSCAFP00000014845; -.
DR   PaxDb; Q76IQ3; -.
DR   GeneID; 403444; -.
DR   KEGG; cfa:403444; -.
DR   CTD; 7054; -.
DR   eggNOG; KOG3820; Eukaryota.
DR   InParanoid; Q76IQ3; -.
DR   OrthoDB; 614557at2759; -.
DR   UniPathway; UPA00747; UER00733.
DR   Proteomes; UP000002254; Unplaced.
DR   GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR   GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
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; IEA:UniProtKB-EC.
DR   GO; GO:0009072; P:aromatic amino acid family metabolic process; IEA:InterPro.
DR   GO; GO:0042416; P:dopamine biosynthetic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:1990384; P:hyaloid vascular plexus regression; ISS:UniProtKB.
DR   GO; GO:0042136; P:neurotransmitter biosynthetic process; IEA:UniProtKB-KW.
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   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
 
 
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