Tyrosine hydroxylase

Enzyme found in Homo sapiens that converts l tyrosine to l dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3 monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L tyrosine to L 3,4 dihydroxyphenylalanine (L DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene,

The AAAHs converts the cofactor 5,6,7,8 tetrahydrobiopterin (BH4) into tetrahydrobiopterin 4a carbinolamine (4a BH4). Under physiological conditions, 4a BH4 is dehydrated to quinonoid dihydrobiopterin (q BH2) by the enzyme pterin 4a carbinolamine dehydrase (PCD) and a water molecule is released in this reaction. Then, the NAD(P)H dependent enzyme dihydropteridine reductase (DHPR) converts q BH2 back to BH4. The product of the enzymatic reaction, L DOPA, can be transformed to dopamine by the enzyme DOPA decarboxylase. Dopamine may be converted into norepinephrine by the enzyme dopamine β hydroxylase, which can be further modified by the enzyme phenylethanol N methyltransferase to obtain epinephrine. Since L DOPA is the precursor for the neurotransmitters dopamine, noradrenaline and adrenaline, tyrosine hydroxylase is therefore found in the cytosol of all cells containing these catecholamines. This initial reaction catalyzed by tyrosine hydroxylase has been shown to be the rate limiting step in the production of catecholamines. The enzyme can then further catalyze L tyrosine to form L DOPA. Tyrosine hydroxylase may also be involved in other reactions as well, such as oxidizing L DOPA to form 5 S cysteinyl DOPA or other L DOPA derivatives.

Tyrosine hydroxylase is a tetramer of four identical subunits (homotetramer). Each subunit consists of three domains. At the carboxyl terminal of the peptide chain there's a short alpha helix domain that allows tetramerization. The central ~300 amino acids make up a catalytic core, in which all the residues necessary for catalysis are located, along with a non covalently bound iron atom. The amino terminal ~150 amino acids make up a regulatory domain, thought to control access of substrates to the active site. In humans there are thought to be four different versions of this regulatory domain, and thus four versions of the enzyme, depending on alternative splicing, though none of their structures have yet been properly determined. It has been suggested that this domain might be an intrinsically unstructured protein, which has no clearly defined tertiary structure, but so far no evidence has been presented supporting this claim. As for the tetramerization and catalytic domains their structure was found with rat tyrosine hydroxylase using X ray crystallography. This has shown how its structure is very similar to that of phenylalanine hydroxylase and tryptophan hydroxylase; together the three make up a family of homologous aromatic amino acid hydroxylases.

Tyrosine hydroxylase activity is increased in the short term by phosphorylation. The regulatory domain of tyrosine hydroxylase contains multiple serine (Ser) residues, including Ser8, Ser19, Ser31 and Ser40, that are phosphorylated by a variety of protein kinases. Ser40 is phosphorylated by the cAMP dependent protein kinase. Ser19 (and Ser40 to a lesser extent) is phosphorylated by the calcium calmodulin dependent protein kinase. MAPKAPK2 (mitogen activated protein kinase activating protein kinase) has a preference for Ser40, but also phosphorylates Ser19 about half the rate of Ser40. Ser31 is phosphorylated by ERK1 and ERK2 (extracellular regulated kinases 1&2), and increases the enzyme activity to a lesser extent than for Ser40 phosphorylation. Phosphorylation at Ser31 causes a slight increase of activity, and here the mechanism is unknown. Tyrosine hydroxylase is somewhat stabilized to heat inactivation when the regulatory serines are phosphorylated. Tyrosine hydroxylase is mainly present in the cytosol, although it also is found in some extent in the plasma membrane. The membrane association may be related to catecholamine packing in vesicles and export through the synaptic membrane. Tyrosine hydroxylase can also be regulated by inhibition. Phosphorylation at Ser40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine. The catecholamines trap the active site iron in the Fe(III) state, inhibiting the enzyme. Long term regulation of tyrosine hydroxylase can also be mediated by phosphorylation mechanisms. Hormones (e. g. glucocorticoids), drugs (e. g. cocaine), or second messengers such as cAMP increase tyrosine hydroxylase transcription. Increase in tyrosine hydroxylase activity due to phosphorylation can be sustained by nicotine for up to 48 hours.

Tyrosine hydroxylase deficiency leads to impaired synthesis of dopamine as well as epinephrine and norepinephrine. It is represented by a progressive encephalopathy and poor prognosis. Clinical features include dystonia that is minimally or nonresponsive to levodopa, extrapyramidal symptoms, ptosis, miosis, and postural hypotension. This is a progressive and often lethal disorder, which can be improved but not cured by levodopa. Due to the low number of patients and overlapping symptoms with other disorders, early diagnosis and treatment remain challenging. Response to treatment is variable and the long term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies, a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). Furthermore, alterations in the tyrosine hydroxylase enzyme activity may be involved in disorders such as Segawa's dystonia, Parkinson's disease and schizophrenia. Tyrosine hydroxylase is activated by phosphorylation dependent binding to 14 3 3 proteins. The activity of tyrosine hydroxylase in the brains of patients with Alzheimer's disease has been shown to be significantly reduced compared to healthy individuals. Tyrosine hydroxylase is also an autoantigen in autoimmune polyendocrine syndrome (APS) type I. A consistent abnormality in Parkinson's disease is degeneration of dopaminergic neurons in the substantia nigra, leading to a reduction of striatal dopamine levels. As tyrosine hydroxylase catalyzes the formation of L DOPA, the rate limiting step in the biosynthesis of dopamine, tyrosine hydroxylase deficiency does not cause Parkinson's disease, but typically gives rise to infantile parkinsonism, although the spectrum extends to a condition resembling dopamine responsive dystonia. A direct pathogenetic role of tyrosine hydroxylase has also been suggested, as the enzyme is a source of H2O2 and other reactive oxygen species (ROS), and a target for radical mediated injury. It has been demonstrated that L DOPA is effectively oxidized by mammalian tyrosine hydroxylase, possibly contributing to the cytotoxic effects of L DOPA. and aquayamycin.