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Tyrosine hydroxylase activity is regulated chronically (days) by protein synthesis.<ref name="pmid17064352">{{cite pmid|17064352|noedit}}</ref>
Tyrosine hydroxylase activity is regulated chronically (days) by protein synthesis.<ref name="pmid17064352">{{cite pmid|17064352|noedit}}</ref>


Tyrosine hydroxylase activity is increased in the short term by phosphorylation. The regulatory domain of tyrosine hydroxylase contains at least three serine residues that are phosphorylated by multiple protein kinases.<ref name="pmid1973163">{{cite pmid|1973163|noedit}}</ref><ref name="pmid10872454" /> Serine 40 is phosphorylated by the cAMP-dependent protein kinase.<ref name="pmid2878973">{{cite pmid|2878973|noedit}}</ref> Serine 19 (and serine 40 to a lesser extent) is phosphorylated by the calcium-calmodulin-dependent protein kinase;<ref name="pmid16644734">{{cite pmid|16644734|noedit}}</ref> MAPKAPK-2 (mitogen-activated-protein kinase-activating protein kinase also phosphorylates the same serines but has a preference for serine40.<ref name="pmid7901013">{{cite pmid|7901013|noedit}}</ref> Serine 31 is phosphorylated by ERK1 and ERK 2 (extracellular regulated kinases 1&2).<ref name="pmid1347949">{{cite pmid|1347949|noedit}}</ref> Phosphorylation at serine 40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine.<ref name="pmid1352289">{{cite pmid|1352289|noedit}}</ref><ref name="pmid9636040">{{cite pmid|9636040|noedit}}</ref> Phosphorylation at serine 19 causes a two-fold increase of activity, through an unknown mechanism that requires the 14-3-3 proteins.<ref name="pmid2902623">{{cite pmid|2902623|noedit}}</ref> Phosphorylation at serine 31 causes a slight increase of activity, and again the mechanism is unknown. Tyrosine hydroxylase is somewhat stabilized to heat inactivation when the regulatory serines are phosphorylated.<ref name="pmid15639226">{{cite pmid|15639226|noedit}}</ref>
Tyrosine hydroxylase activity is increased in the short term by [[phosphorylation]]. The regulatory domain of tyrosine hydroxylase contains at least three serine residues that are phosphorylated by multiple protein kinases.<ref name="pmid1973163">{{cite pmid|1973163|noedit}}</ref><ref name="pmid10872454" /> Serine 40 is phosphorylated by the cAMP-dependent protein kinase.<ref name="pmid2878973">{{cite pmid|2878973|noedit}}</ref> Serine 19 (and serine 40 to a lesser extent) is phosphorylated by the calcium-calmodulin-dependent protein kinase;<ref name="pmid16644734">{{cite pmid|16644734|noedit}}</ref> MAPKAPK-2 (mitogen-activated-protein kinase-activating protein kinase also phosphorylates the same serines but has a preference for serine40.<ref name="pmid7901013">{{cite pmid|7901013|noedit}}</ref> Serine 31 is phosphorylated by ERK1 and ERK 2 (extracellular regulated kinases 1&2).<ref name="pmid1347949">{{cite pmid|1347949|noedit}}</ref> Phosphorylation at serine 40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine.<ref name="pmid1352289">{{cite pmid|1352289|noedit}}</ref><ref name="pmid9636040">{{cite pmid|9636040|noedit}}</ref> Phosphorylation at serine 19 causes a two-fold increase of activity, through an unknown mechanism that requires the 14-3-3 proteins.<ref name="pmid2902623">{{cite pmid|2902623|noedit}}</ref> Phosphorylation at serine 31 causes a slight increase of activity, and again the mechanism is unknown. Tyrosine hydroxylase is somewhat stabilized to heat inactivation when the regulatory serines are phosphorylated.<ref name="pmid15639226">{{cite pmid|15639226|noedit}}</ref>


Increase in tyrosine hydroxylase activity due to phosphorylation can be sustained by nicotine for up to 48 hours.<ref name="pmid17064352"/>
Increase in tyrosine hydroxylase activity due to phosphorylation can be sustained by nicotine for up to 48 hours.<ref name="pmid17064352"/>

Revision as of 17:51, 11 April 2012

Template:PBB

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).[1][2] It does so using tetrahydrobiopterin as a coenzyme. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine (noradrenaline) and epinephrine (adrenaline). In humans, tyrosine hydroxylase is encoded by the TH gene.[2]

Reaction

Tyrosine hydroxylase catalyzes conversion of tyrosine to L-3,4-dihydroxyphenylalanine

Tyrosine hydroxylase is catalyzing the reaction where L-Tyrosine is hydroxylated in the meta position to obtain L-3,4-dihydroxyphenylalanine (L-DOPA). The enzyme is an oxygenase which means it uses molecular oxygen to hydroxylate its substrates. One of the oxygen atoms in O2 is used to hydroxylate the tyrosine molecule to obtain L-DOPA and the other one is used to hydroxylate its cofactor. Like the other amino acid hydroxylases (AAHs), tyrosine hydroxylase use the cofactor tetrahydrobiopterin (BH4) under normal conditions, although other similar molecules may also work as a cofactor for tyrosine hydroxylase[3].

The AAHs 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[4][5]. Then, the NAD(P)H dependent enzyme dihydropteridine reductase (DHPR) converts q-BH2 back to BH4[4]. Each of the four subunits in tyrosine hydroxylase is coordinated with an iron(II) atom presented in the active site. The oxidation state of this iron atom is important for the catalytic turnover in the enzymatic reaction[3]. If the iron is oxidized to Fe(III), the enzyme is inactivated.

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[6]. 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[6].

The enzyme is highly specific, not accepting indole derivatives - which is unusual as many other enzymes involved in the production of catecholamines do. Tryptophan is a poor substrate for tyrosine hydroxylate, however it can hydroxylate L-phenylalanine to form L-tyrosine and small amounts of 3-hydroxyphenylalanine[3][7][8]. 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 DOPA to form 5-s-cysteinyl DOPA or other DOPA derivatives[3][9]

Structure

Tyrosine hydroxylase from rat showing two of its domains, the tetramerization domain (pink) and the catalytic domain (blue). The regulatory domain (not shown) would sit somewhere on the right hand side of the image where also the enzyme's substrate would enter from.

Tyrosine hydroxylase is a tetramer of four identical subunits. Each subunit consists of three domains. At the carboxy terminal end of the peptide chain there's a short alpha helix domain that allows tetramerization.[10] 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.[7] The iron is held in place by two histidine residues and one glutamate residue, making it a non-heme, non-iron-sulfur iron-containing enzyme.[11] The amino terminal ~150 amino acids make up a regulatory domain, thought to control access of substrates to the active site.[12] 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[13], though none of their structures have yet been properly determined. As for the tetramerization and catalytic domains their structure was found with rat tyrosine hydroxylase using X-ray crystallography.[14][15] 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.[16][17]

Regulation

Tyrosine hydroxylase activity is regulated chronically (days) by protein synthesis.[18]

Tyrosine hydroxylase activity is increased in the short term by phosphorylation. The regulatory domain of tyrosine hydroxylase contains at least three serine residues that are phosphorylated by multiple protein kinases.[19][7] Serine 40 is phosphorylated by the cAMP-dependent protein kinase.[20] Serine 19 (and serine 40 to a lesser extent) is phosphorylated by the calcium-calmodulin-dependent protein kinase;[21] MAPKAPK-2 (mitogen-activated-protein kinase-activating protein kinase also phosphorylates the same serines but has a preference for serine40.[22] Serine 31 is phosphorylated by ERK1 and ERK 2 (extracellular regulated kinases 1&2).[23] Phosphorylation at serine 40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine.[24][25] Phosphorylation at serine 19 causes a two-fold increase of activity, through an unknown mechanism that requires the 14-3-3 proteins.[26] Phosphorylation at serine 31 causes a slight increase of activity, and again the mechanism is unknown. Tyrosine hydroxylase is somewhat stabilized to heat inactivation when the regulatory serines are phosphorylated.[27]

Increase in tyrosine hydroxylase activity due to phosphorylation can be sustained by nicotine for up to 48 hours.[18]

Clinical significance

Dopamine

Tyrosine hydroxylase can be inhibited by the drug α-methyl-para-tyrosine (Metirosine). This inhibition can lead to a depletion of dopamine and norepinepherine in the brain due to the lack of the precursor L-Dopa (L-3,4-dyhydroxyphenylalanine) which is synthesized by tyrosine hydroxylase. This drug is rarely used and can cause depression, but it is useful in treating pheochromocytoma and also resistant hypertension.

Tyrosine hydroxylase is an autoantigen in Autoimmune Polyendocrine Syndrome (APS) type I.[28]

Older examples of inhibitors mentioned in the literature include oudenone[29] and aquayamycin.[30]

References

  1. ^ Kaufman S (1995). "Tyrosine hydroxylase". Adv. Enzymol. Relat. Areas Mol. Biol. Advances in Enzymology - and Related Areas of Molecular Biology. 70: 103–220. doi:10.1002/9780470123164.ch3. ISBN 9780470123164. PMID 8638482.
  2. ^ a b Nagatsu T (1995). "Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology". Essays Biochem. 30: 15–35. PMID 8822146.
  3. ^ a b c d Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 9626667, please use {{cite journal}} with |pmid=9626667 instead.
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Further reading

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