TH

Function

Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of cathecolamines, dopamine, noradrenaline, and adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to L-Dopa (PubMed:15287903, PubMed:1680128, PubMed:17391063, PubMed:24753243, PubMed:34922205, PubMed:8528210, Ref.18). In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity (By similarity). Positively regulates the regression of retinal hyaloid vessels during postnatal development (By similarity).

Isoform 5

Lacks catalytic activity.

Isoform 6

Lacks catalytic activity.

Involvement in disease

Segawa syndrome autosomal recessive

ARSEGS

A form of DOPA-responsive dystonia presenting in infancy or early childhood. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Some cases present with parkinsonian symptoms in infancy. Unlike all other forms of dystonia, it is an eminently treatable condition, due to a favorable response to L-DOPA.

None

The disease is caused by variants affecting the gene represented in this entry.

May play a role in the pathogenesis of Parkinson disease (PD). A genome-wide copy number variation analysis has identified a 34 kilobase deletion over the TH gene in a PD patient but not in any controls.

Pathway

Catecholamine biosynthesis; dopamine biosynthesis; dopamine from L-tyrosine: step 1/2.

Post-translational modifications

Phosphorylated on Ser-19, Ser-62 and Ser-71 by several protein kinases with different site specificities. Phosphorylation at Ser-62 and Ser-71 leads to an increase of TH activity (PubMed:7901013). Phosphorylation at Ser-71 activates the enzyme and also counteracts the feedback inhibition of TH by catecholamines (PubMed:15287903). Phosphorylation of Ser-19 and Ser-62 triggers the proteasomal degradation of TH through the ubiquitin-proteasome pathway (By similarity). Phosphorylation at Ser-62 facilitates transport of TH from the soma to the nerve terminals via the microtubule network (PubMed:28637871). Phosphorylation at Ser-19 induces the high-affinity binding to the 14-3-3 protein YWHAG; this interaction may influence the phosphorylation and dephosphorylation of other sites (PubMed:24947669). Ser-19 increases the phosphorylation at Ser-71 in a hierarchical manner, leading to increased activity (By similarity).

Sequence similarities

Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.

Tissue specificity

Mainly expressed in the brain and adrenal glands.

Cellular localization

• Cytoplasm
• Perinuclear region
• Nucleus
• Cell projection
• Axon
• Cytoplasm
• Cytoplasmic vesicle
• Secretory vesicle
• Synaptic vesicle
• When phosphorylated at Ser-19 shows a nuclear distribution and when phosphorylated at Ser-31 as well at Ser-40 shows a cytosolic distribution (By similarity). Expressed in dopaminergic axons and axon terminals.

Alternative names

• TYH
• TH
• TYH
• Tyrosine 3-monooxygenase
• Tyrosine 3-hydroxylase
• TH

Database links

• entrezGene:7054
• omim:191290
• swissprot:P07101

Target type

Proteins

Primary research area

Neuroscience

Molecular weight

58600Da