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FLASH GENE

Symbol

TH

contributors: mct/npt - updated : 20-04-2020

HGNC name	tyrosine hydroxylase
HGNC id	11782

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	10.15 kb     14 Exon(s)    1 Copie(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor   HRE
text structure	potential recognition sites for NR4A2, HNF-3beta, HOXA4 and HOXA5
	four bicoid binding elements (for the transcription factor Pitx3)
	novel species-specific transcriptional regulation of the TH promoter by PARK7
	a glucocorticoid-responsive element in a 7 bp AP-1-like motif in the promoter region at -7.24 kb of the human TH gene
	in TH promoter, three consensus elements for NR4A2 binding: NBRE-A, -B, and -C

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	see PTH PTH ,INS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_199292 14 - 1910 NP_954986 - 528 - 2019 30361782 isoform a NM_199293 14 - 1898 NP_954987 - 524 - 2019 30361782 isoform c NM_000360 13 - 1817 NP_000351 - 497 - 2019 30361782 isoform b variant 5 - - - isoform 5 - - in neuroblastoma and adrenal glands 2019 30361782 also called TH isoforms Delta2,8,9 variant 4 - - - isoform 4 - - in neuroblastoma and adrenal glands 2019 30361782 also called Delta1b,2,8,9

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     highly Endocrine adrenal gland       highly   pancreas       highly Nervous brain diencephalon hypothalamus nucleus accumbens   Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

N-terminal sequence (residues 1-43), which corresponds to an extension to the TH regulatory domain, interacts with negatively charged membranes, is a conformationally versatile motif, and binds 14-3-3 proteins and membranes ; phosphorylation of the N-terminal portion of TH regulates the degradation of this enzyme by the ubiquitin-proteasome pathway

mono polymer

tetramer

HOMOLOGY

interspecies

homolog to murine Th

Homologene

FAMILY

biopterin-dependent aromatic amino acid hydroxylase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,nucleus

basic FUNCTION	tyrosine 3-monooxygenase
	potentially associated with longevity in the male
	catalyzes the rate limiting step in the biosynthesis of catecholamines in the central and peripheral nervous system
	the promoter is able to direct GFP expression to TH+ neurons of substantia nigra
	POU3F4 and TH synergistically promote the differentiation of neural stem cells into dopaminergic neurons
	rate-limiting enzyme in catecholamine biosynthesis, and the regulation of its transcription is critical for the specification and maintenance of catecholaminergic neuron phenotypes
	could represent a pathomechanism whereby obesity contributes to periodontitis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

catecholamines

a component

is a tetramer composed of regulatory, catalytic and tetramerization domains

INTERACTION

DNA

RNA

small molecule	cofactor,
	ferrous ion

protein	up-regulating retinal genes (OPN1MW, OPN1LW, TIMP3, RP1L1, GNGT2, CRX, ARR3, GUCA1A, IMPDH1, and PDE6C) (Liu 2007)
	down-regulating retinal genes GNGT1 and GNB3 (Liu 2007)
	role for MTA1 as an upstream coactivator of TH
	during dopaminergic (DA) neurogenesis, NR4A2 directly targets human tyrosine hydroxylase (TH)
	NR4A2 represses TH expression via SIRT1 in human neural stem cells
	SLC6A3 expression affects TH expression and phosphorylation largely in Dopamine (DA) terminal field compartments
	CTCF is a novel regulator of TH transcription in the forebrain
	TH induced mitochondrial biogenesis, fission, and mitophagy in an ESRRA-dependent manner
	NR4A2 is an orphan transcription factor that influences the expression of several key proteins of dopaminergic (DA) neurons, including tyrosine hydroxylase (TH), dopamine transporter (SLC6A3), and vesicular monoamine transporter (SLC18A1)

cell & other

REGULATION

Other	catalytic activity increased by phosphorylation
	TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail, and Ser-31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably toward the projection terminals
	expression of TH is epigenetically regulated in neural stem cells

ASSOCIATED DISORDERS

corresponding disease(s)

DPDV

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       in schizophrenia, bipolar disorder and alcoholism constitutional     --over   obesity-associated stimuli induce a TH upregulation in periodontal cells and tissues tumoral germinal mutation       in familial isolated pituitary adenoma

Susceptibility

to alterations in autonomic activity and blood pressure

Variant & Polymorphism SNP	common genetic variants in the proximal TH promoter, especially at C-824T and A-581G, are associated to alterations in autonomic activity and blood pressure

Candidate gene
Marker	tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma is a marker of worse outcome
	in high-risk metastatic Neuroblastoma, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses
Therapy target

ANIMAL & CELL MODELS