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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 [Haavik and Toska]. 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 [Teigen 2007, thony]. Then, the NAD(P)H dependent enzyme dihydropteridine reductase (DHPR) converts q-BH2 back to BH4 [Teigen 2007]. 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 [Haavik and Toska]. 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 [nagatsu]. 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 [Nagatsu].

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 [Fitzpatrick1999, Haavik og Flatmark 1987] [3]. 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 [Haavik and Flatmark 1987, Haavik and Toska].

The enzyme, an oxygenase, is found in the cytosol of all cells containing catecholamines. This initial reaction is the rate limiting step in the production of catecholamines.

The enzyme is highly specific, not accepting indole derivatives - which is unusual as many other enzymes involved in the production of catecholamines do. It can, however, hydroxylate phenylalanine to form tyrosine.[3]

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.[4] 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.[5] 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.[6] The amino terminal ~150 amino acids make up a regulatory domain, thought to control access of substrates to the active site.[7] 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[8], 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.[9][10] 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.[11][12]

Regulation

Tyrosine hydroxylase activity is regulated chronically (days) by protein synthesis.[13]

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.[14][5] Serine 40 is phosphorylated by the cAMP-dependent protein kinase.[15] Serine 19 (and serine 40 to a lesser extent) is phosphorylated by the calcium-calmodulin-dependent protein kinase;[16] MAPKAPK-2 (mitogen-activated-protein kinase-activating protein kinase also phosphorylates the same serines but has a preference for serine40.[17] Serine 31 is phosphorylated by ERK1 and ERK 2 (extracellular regulated kinases 1&2).[18] Phosphorylation at serine 40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine.[19][20] Phosphorylation at serine 19 causes a two-fold increase of activity, through an unknown mechanism that requires the 14-3-3 proteins.[21] 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.[22]

Increase in tyrosine hydroxylase activity due to phosphorylation can be sustained by nicotine for up to 48 hours.[13]

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.[23]

Older examples of inhibitors mentioned in the literature include oudenone[24] and aquayamycin.[25]

References

  1. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8638482, please use {{cite journal}} with |pmid=8638482 instead.
  2. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8822146, please use {{cite journal}} with |pmid=8822146 instead.
  3. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/ja00082a046, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/ja00082a046 instead.
  4. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 7964718, please use {{cite journal}} with |pmid=7964718 instead.
  5. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 10872454, please use {{cite journal}} with |pmid=10872454 instead.
  6. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8535244, please use {{cite journal}} with |pmid=8535244 instead.
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  13. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17064352, please use {{cite journal}} with |pmid=17064352 instead.
  14. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1973163, please use {{cite journal}} with |pmid=1973163 instead.
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  18. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1347949, please use {{cite journal}} with |pmid=1347949 instead.
  19. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1352289, please use {{cite journal}} with |pmid=1352289 instead.
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  24. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 5545929, please use {{cite journal}} with |pmid=5545929 instead.
  25. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 5726288, please use {{cite journal}} with |pmid=5726288 instead.

Further reading

  • Masserano JM, Weiner N (1983). "Tyrosine hydroxylase regulation in the central nervous system". Mol. Cell. Biochem. 53–54 (1–2): 129–52. doi:10.1007/BF00225250. PMID 6137760.
  • Meloni R, Biguet NF, Mallet J (2002). "Post-genomic era and gene discovery for psychiatric diseases: there is a new art of the trade? The example of the HUMTH01 microsatellite in the Tyrosine Hydroxylase gene". Mol. Neurobiol. 26 (2–3): 389–403. doi:10.1385/MN:26:2-3:389. PMID 12428766.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Joh TH, Park DH, Reis DJ (1979). "Direct phosphorylation of brain tyrosine hydroxylase by cyclic AMP-dependent protein kinase: mechanism of enzyme activation". Proc. Natl. Acad. Sci. U.S.A. 75 (10): 4744–8. doi:10.1073/pnas.75.10.4744. PMC 336196. PMID 33381.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Haycock JW, Ahn NG, Cobb MH, Krebs EG (1992). "ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ". Proc. Natl. Acad. Sci. U.S.A. 89 (6): 2365–9. doi:10.1073/pnas.89.6.2365. PMC 48658. PMID 1347949.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Haycock JW (1990). "Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40". J. Biol. Chem. 265 (20): 11682–91. PMID 1973163.
  • Craig SP; Buckle VJ; Lamouroux A; et al. (1986). "Localization of the human tyrosine hydroxylase gene to 11p15: gene duplication and evolution of metabolic pathways". Cytogenet. Cell Genet. 42 (1–2): 29–32. doi:10.1159/000132246. PMID 2872999. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Grima B; Lamouroux A; Boni C; et al. (1987). "A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics". Nature. 326 (6114): 707–11. doi:10.1038/326707a0. PMID 2882428. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Kaneda N; Kobayashi K; Ichinose H; et al. (1987). "Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene". Biochem. Biophys. Res. Commun. 146 (3): 971–5. doi:10.1016/0006-291X(87)90742-X. PMID 2887169. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Kobayashi K; Kaneda N; Ichinose H; et al. (1987). "Isolation of a full-length cDNA clone encoding human tyrosine hydroxylase type 3". Nucleic Acids Res. 15 (16): 6733. doi:10.1093/nar/15.16.6733. PMC 306135. PMID 2888085. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • O'Malley KL; Anhalt MJ; Martin BM; et al. (1988). "Isolation and characterization of the human tyrosine hydroxylase gene: identification of 5' alternative splice sites responsible for multiple mRNAs". Biochemistry. 26 (22): 6910–4. doi:10.1021/bi00396a007. PMID 2892528. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Le Bourdellès B; Boularand S; Boni C; et al. (1988). "Analysis of the 5' region of the human tyrosine hydroxylase gene: combinatorial patterns of exon splicing generate multiple regulated tyrosine hydroxylase isoforms". J. Neurochem. 50 (3): 988–91. doi:10.1111/j.1471-4159.1988.tb03009.x. PMID 2892893. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Ginns EI; Rehavi M; Martin BM; et al. (1988). "Expression of human tyrosine hydroxylase cDNA in invertebrate cells using a baculovirus vector". J. Biol. Chem. 263 (15): 7406–10. PMID 2896667. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Kobayashi K; Kaneda N; Ichinose H; et al. (1988). "Structure of the human tyrosine hydroxylase gene: alternative splicing from a single gene accounts for generation of four mRNA types". J. Biochem. 103 (6): 907–12. PMID 2902075. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  • Coker GT, Vinnedge L, O'Malley KL (1989). "Characterization of rat and human tyrosine hydroxylase genes: functional expression of both promoters in neuronal and non-neuronal cell types". Biochem. Biophys. Res. Commun. 157 (3): 1341–7. doi:10.1016/S0006-291X(88)81022-2. PMID 2905129.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Vulliet PR, Woodgett JR, Cohen P (1984). "Phosphorylation of tyrosine hydroxylase by calmodulin-dependent multiprotein kinase". J. Biol. Chem. 259 (22): 13680–3. PMID 6150037.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Zhou QY, Quaife CJ, Palmiter RD (1995). "Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development". Nature. 374 (6523): 640–3. doi:10.1038/374640a0. PMID 7715703.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Lüdecke B, Bartholomé K (1995). "Frequent sequence variant in the human tyrosine hydroxylase gene". Hum. Genet. 95 (6): 716. doi:10.1007/BF00209496. PMID 7789962.
  • Lüdecke B, Dworniczak B, Bartholomé K (1995). "A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome". Hum. Genet. 95 (1): 123–5. doi:10.1007/BF00225091. PMID 7814018.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Knappskog PM; Flatmark T; Mallet J; et al. (1996). "Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene". Hum. Mol. Genet. 4 (7): 1209–12. doi:10.1093/hmg/4.7.1209. PMID 8528210. {{cite journal}}: Unknown parameter |author-separator= ignored (help)

PMID:2902075 - mRNA splicing = 4 proteins
PMID:9228951 - crystal structure
PMID:9753429 - crystal structure with bound fake cofactor and iron

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