Tyrosine hydroxylase
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| Location (UCSC) | Chr 11: 2.16 – 2.17 Mb | Chr 7: 142.45 – 142.48 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Tyrosine hydroxylase or tyrosine 3-monooxygenase is the
Reaction
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ExPASy NiceZyme view | | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Tyrosine hydroxylase catalyzes the reaction in which 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 the cofactor. Like the other aromatic amino acid hydroxylases (AAAHs), tyrosine hydroxylase use the cofactor tetrahydrobiopterin (BH4) under normal conditions, although other similar molecules may also work as a cofactor for tyrosine hydroxylase.[7]
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.[8][9] Then, the NAD(P)H dependent enzyme dihydropteridine reductase (DHPR) converts q-BH2 back to BH4.[8] 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. If the iron is oxidized to Fe(III), the enzyme is inactivated.[10]
The product of the enzymatic reaction, L-DOPA, can be transformed to dopamine by the enzyme
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 hydroxylase, however it can hydroxylate L-phenylalanine to form L-tyrosine and small amounts of 3-hydroxyphenylalanine.[7][12][13] 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.[7][14]
Structure
Tyrosine hydroxylase is a
Regulation
Tyrosine hydroxylase activity is increased in the short term by
Tyrosine hydroxylase is mainly present in the cytosol, although it also is found in some extent in the plasma membrane.[33] The membrane association may be related to catecholamine packing in vesicles and export through the synaptic membrane.[33] The binding of tyrosine hydroxylase to membranes involves the N-terminal region of the enzyme, and may be regulated by a three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes.[34]
Tyrosine hydroxylase can also be regulated by inhibition. Phosphorylation at Ser40 relieves feedback inhibition by the catecholamines dopamine, epinephrine, and norepinephrine.[35][36] The catecholamines trap the active-site iron in the Fe(III) state, inhibiting the enzyme.[7]
It has been shown that the expression of tyrosine hydroxylase can be affected by the expression of
Long term regulation of tyrosine hydroxylase can also be mediated by phosphorylation mechanisms.
Clinical significance
Furthermore, alterations in the tyrosine hydroxylase enzyme activity may be involved in disorders such as
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
Tyrosine hydroxylase can be inhibited by the drug α-methyl-para-tyrosine (
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000180176 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000214 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8638482.
- ^ PMID 8822146.
- ^ S2CID 35753000.
- ^ PMID 17305546.
- PMID 10727395.
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- ^ PMID 14216443.
- ^ PMID 10872454.
- .
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- S2CID 46042840.
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- PMID 2902075.
- ^ S2CID 930361.
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- ^ S2CID 20007900.
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- PMID 3475690.
- PMID 1973163.
- S2CID 14759673.
- PMID 16644734.
- ^ S2CID 24324381.
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- ^ S2CID 5950778.
- ^ PMID 19801645.
- PMID 1352289.
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- ^ S2CID 20406829.
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- ^ "Patient registry".
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- S2CID 37490585.
- PMID 10623641.
- PMID 5545929.
- PMID 5726288.
Further reading
- Masserano JM, Weiner N (1983). "Tyrosine hydroxylase regulation in the central nervous system". Molecular and Cellular Biochemistry. 53–54 (1–2): 129–52. S2CID 19361815.
- 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". Molecular Neurobiology. 26 (2–3): 389–403. S2CID 8814324.
- Joh TH, Park DH, Reis DJ (Oct 1978). "Direct phosphorylation of brain tyrosine hydroxylase by cyclic AMP-dependent protein kinase: mechanism of enzyme activation". Proceedings of the National Academy of Sciences of the United States of America. 75 (10): 4744–8. PMID 33381.
- Haycock JW, Ahn NG, Cobb MH, Krebs EG (Mar 1992). "ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ". Proceedings of the National Academy of Sciences of the United States of America. 89 (6): 2365–9. PMID 1347949.
- Haycock JW (Jul 1990). "Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40". The Journal of Biological Chemistry. 265 (20): 11682–91. PMID 1973163.
- Craig SP, Buckle VJ, Lamouroux A, Mallet J, Craig I (1986). "Localization of the human tyrosine hydroxylase gene to 11p15: gene duplication and evolution of metabolic pathways". Cytogenetics and Cell Genetics. 42 (1–2): 29–32. PMID 2872999.
- Grima B, Lamouroux A, Boni C, Julien JF, Javoy-Agid F, Mallet J (1987). "A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics". Nature. 326 (6114): 707–11. S2CID 4314044.
- Kaneda N, Kobayashi K, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T (Aug 1987). "Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene". Biochemical and Biophysical Research Communications. 146 (3): 971–5. PMID 2887169.
- Kobayashi K, Kaneda N, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T (Aug 1987). "Isolation of a full-length cDNA clone encoding human tyrosine hydroxylase type 3". Nucleic Acids Research. 15 (16): 6733. PMID 2888085.
- O'Malley KL, Anhalt MJ, Martin BM, Kelsoe JR, Winfield SL, Ginns EI (Nov 1987). "Isolation and characterization of the human tyrosine hydroxylase gene: identification of 5' alternative splice sites responsible for multiple mRNAs". Biochemistry. 26 (22): 6910–4. PMID 2892528.
- Le Bourdellès B, Boularand S, Boni C, Horellou P, Dumas S, Grima B, Mallet J (Mar 1988). "Analysis of the 5' region of the human tyrosine hydroxylase gene: combinatorial patterns of exon splicing generate multiple regulated tyrosine hydroxylase isoforms". Journal of Neurochemistry. 50 (3): 988–91. S2CID 44602622.
- Ginns EI, Rehavi M, Martin BM, Weller M, O'Malley KL, LaMarca ME, McAllister CG, Paul SM (May 1988). "Expression of human tyrosine hydroxylase cDNA in invertebrate cells using a baculovirus vector". The Journal of Biological Chemistry. 263 (15): 7406–10. PMID 2896667.
- Kobayashi K, Kaneda N, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T (Jun 1988). "Structure of the human tyrosine hydroxylase gene: alternative splicing from a single gene accounts for generation of four mRNA types". Journal of Biochemistry. 103 (6): 907–12. PMID 2902075.
- Coker GT, Vinnedge L, O'Malley KL (Dec 1988). "Characterization of rat and human tyrosine hydroxylase genes: functional expression of both promoters in neuronal and non-neuronal cell types". Biochemical and Biophysical Research Communications. 157 (3): 1341–7. PMID 2905129.
- Vulliet PR, Woodgett JR, Cohen P (Nov 1984). "Phosphorylation of tyrosine hydroxylase by calmodulin-dependent multiprotein kinase". The Journal of Biological Chemistry. 259 (22): 13680–3. PMID 6150037.
- Zhou QY, Quaife CJ, Palmiter RD (Apr 1995). "Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development". Nature. 374 (6523): 640–3. S2CID 4259663.
- Lüdecke B, Bartholomé K (Jun 1995). "Frequent sequence variant in the human tyrosine hydroxylase gene". Human Genetics. 95 (6): 716. S2CID 1057532.
- Lüdecke B, Dworniczak B, Bartholomé K (Jan 1995). "A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome". Human Genetics. 95 (1): 123–5. S2CID 26870241.
- Knappskog PM, Flatmark T, Mallet J, Lüdecke B, Bartholomé K (Jul 1995). "Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene". Human Molecular Genetics. 4 (7): 1209–12. PMID 8528210.
External links
- GeneReviews/NIH/NCBI/UW entry on Tyrosine Hydroxylase Deficiency including Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia or Segawa Syndrome and Autosomal Recessive Infantile Parkinsonism
- Tyrosine+hydroxylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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