Tyrosine Hydroxylase and Regulation of Dopamine Synthesis

Overview

Journal Arch Biochem Biophys

Publisher Elsevier

Specialties Biochemistry
Biophysics

Date 2010 Dec 24

PMID 21176768

Citations 392

Authors

S Colette Daubner

Tiffany Le

Shanzhi Wang

Affiliations

Soon will be listed here.

Abstract

Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine biosynthesis; it uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to DOPA. Its amino terminal 150 amino acids comprise a domain whose structure is involved in regulating the enzyme's activity. Modes of regulation include phosphorylation by multiple kinases at four different serine residues, and dephosphorylation by two phosphatases. The enzyme is inhibited in feedback fashion by the catecholamine neurotransmitters. Dopamine binds to TyrH competitively with tetrahydrobiopterin, and interacts with the R domain. TyrH activity is modulated by protein-protein interactions with enzymes in the same pathway or the tetrahydrobiopterin pathway, structural proteins considered to be chaperones that mediate the neuron's oxidative state, and the protein that transfers dopamine into secretory vesicles. TyrH is modified in the presence of NO, resulting in nitration of tyrosine residues and the glutathionylation of cysteine residues.

Citing Articles

Auricular acupuncture plays a neuroprotective role in 6-hydroxydopamine-induced Parkinson's disease in rats.

Nguyen H, Lee D, Hsieh C J Tradit Complement Med. 2025; 15(2):128-139.

PMID: 40060148 PMC: 11883624. DOI: 10.1016/j.jtcme.2024.05.008.

Evidence of COMT dysfunction in the olfactory bulb in Parkinson's disease.

Beauchamp L, Ellett L, Juan S, Liu X, Hunt C, Parish C Acta Neuropathol. 2025; 149(1):21.

PMID: 40024917 PMC: 11872990. DOI: 10.1007/s00401-025-02861-y.

Exploring Potential Medications for Alzheimer's Disease with Psychosis by Integrating Drug Target Information into Deep Learning Models: A Data-Driven Approach.

Miranda O, Jiang C, Qi X, Kofler J, Sweet R, Wang L Int J Mol Sci. 2025; 26(4).

PMID: 40004081 PMC: 11855865. DOI: 10.3390/ijms26041617.

Overexpression in Suprachiasmatic Nucleus Protects from Retinal Neurovascular Deficits in Diabetes.

Mahajan N, Luo Q, Lukkes J, Abhyankar S, Bhatwadekar A bioRxiv. 2025; .

PMID: 39975095 PMC: 11838600. DOI: 10.1101/2025.02.05.636648.

Plastic sex-trait modulation by differential gene expression according to social environment in male red deer.

Broggini C, Abril N, Membrillo A, de la Pena E, Carranza J BMC Genomics. 2025; 26(1):160.

PMID: 39966742 PMC: 11837354. DOI: 10.1186/s12864-025-11326-1.

References

Halskau Jr O, Ying M, Baumann A, Kleppe R, Rodriguez-Larrea D, Almas B . Three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes. J Biol Chem. 2009; 284(47):32758-69. PMC: 2781693. DOI: 10.1074/jbc.M109.027706. View

Sura G, Daubner S, Fitzpatrick P . Effects of phosphorylation by protein kinase A on binding of catecholamines to the human tyrosine hydroxylase isoforms. J Neurochem. 2004; 90(4):970-8. PMC: 1839072. DOI: 10.1111/j.1471-4159.2004.02566.x. View

FITZPATRICK P . The pH dependence of binding of inhibitors to bovine adrenal tyrosine hydroxylase. J Biol Chem. 1988; 263(31):16058-62. View

Andersen O, Flatmark T, Hough E . Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis and substrate activation. J Mol Biol. 2002; 320(5):1095-108. DOI: 10.1016/s0022-2836(02)00560-0. View

Koob G, Volkow N . Neurocircuitry of addiction. Neuropsychopharmacology. 2009; 35(1):217-38. PMC: 2805560. DOI: 10.1038/npp.2009.110. View

Wang S, Sura G, Dangott L, Fitzpatrick P . Identification by hydrogen/deuterium exchange of structural changes in tyrosine hydroxylase associated with regulation. Biochemistry. 2009; 48(22):4972-9. PMC: 2730116. DOI: 10.1021/bi9004254. View

Ara J, Przedborski S, Naini A, Jackson-Lewis V, Trifiletti R, Horwitz J . Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci U S A. 1998; 95(13):7659-63. PMC: 22714. DOI: 10.1073/pnas.95.13.7659. View

FITZPATRICK P . The aromatic amino acid hydroxylases. Adv Enzymol Relat Areas Mol Biol. 2000; 74:235-94. DOI: 10.1002/9780470123201.ch6. View

Borges C, Geddes T, Throck Watson J, Kuhn D . Dopamine biosynthesis is regulated by S-glutathionylation. Potential mechanism of tyrosine hydroxylast inhibition during oxidative stress. J Biol Chem. 2002; 277(50):48295-302. DOI: 10.1074/jbc.M209042200. View

10.

Ramsey A, FITZPATRICK P . Effects of phosphorylation on binding of catecholamines to tyrosine hydroxylase: specificity and thermodynamics. Biochemistry. 2000; 39(4):773-8. DOI: 10.1021/bi991901r. View

11.

Ichimura T, Isobe T, Okuyama T, Yamauchi T, Fujisawa H . Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+,calmodulin-dependent protein kinase II. FEBS Lett. 1987; 219(1):79-82. DOI: 10.1016/0014-5793(87)81194-8. View

12.

Molinoff P, Axelrod J . Biochemistry of catecholamines. Annu Rev Biochem. 1971; 40:465-500. DOI: 10.1146/annurev.bi.40.070171.002341. View

13.

Souza J, Friel T, Jiang G, Vrana K, Sharov V, Barron L . Nitration and inactivation of tyrosine hydroxylase by peroxynitrite. J Biol Chem. 2001; 276(49):46017-23. DOI: 10.1074/jbc.M105564200. View

14.

Toska K, Kleppe R, Armstrong C, Morrice N, Cohen P, Haavik J . Regulation of tyrosine hydroxylase by stress-activated protein kinases. J Neurochem. 2002; 83(4):775-83. DOI: 10.1046/j.1471-4159.2002.01172.x. View

15.

Kuhn D, Geddes T . Tetrahydrobiopterin prevents nitration of tyrosine hydroxylase by peroxynitrite and nitrogen dioxide. Mol Pharmacol. 2003; 64(4):946-53. DOI: 10.1124/mol.64.4.946. View

16.

Kleppe R, Toska K, Haavik J . Interaction of phosphorylated tyrosine hydroxylase with 14-3-3 proteins: evidence for a phosphoserine 40-dependent association. J Neurochem. 2001; 77(4):1097-107. DOI: 10.1046/j.1471-4159.2001.00318.x. View

17.

Williams J, Northrop D . Substrate specificity and structure-activity relationships of gentamicin acetyltransferase I. The dependence of antibiotic resistance upon substrate Vmax/Km values. J Biol Chem. 1978; 253(17):5908-14. View

18.

Arnsten A . Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997; 11(2):151-62. DOI: 10.1177/026988119701100208. View

19.

Bobrovskaya L, Dunkley P, Dickson P . Phosphorylation of Ser19 increases both Ser40 phosphorylation and enzyme activity of tyrosine hydroxylase in intact cells. J Neurochem. 2004; 90(4):857-64. DOI: 10.1111/j.1471-4159.2004.02550.x. View

20.

Royo M, Fitzpatrick P, Daubner S . Mutation of regulatory serines of rat tyrosine hydroxylase to glutamate: effects on enzyme stability and activity. Arch Biochem Biophys. 2005; 434(2):266-74. DOI: 10.1016/j.abb.2004.11.007. View