Tyrosine hydroxylase and regulation of dopamine synthesis

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 4 different serine residues, and dephosphorylation by 2 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. KeywordsTyrosine hydroxylase; dopamine biosynthesis; protein kinases; protein nitration; protein glutathionylation; protein-protein interactions; 14-3-3 protein; α-synuclein Tyrosine hydroxylase (TyrH) is the rate-limiting enzyme of catecholamine synthesis. It catalyzes the hydroxylation of tyrosine to L-DOPA (1). The catecholamines dopamine, epinephrine and norepinephrine are the products of the pathway, important as hormones and neurotransmitters in both the central and peripheral nervous systems. In the latter, they are synthesized in the adrenal medulla (1,2). The biosynthetic pathway is illustrated in Figure 1. These catechol monoamines play roles in many brain functions, such as attention (3), memory (4), cognition (5), and emotion (6,7). As the hormone of the fight-or-flight response, epinephrine produced in the adrenal gland affects many tissues throughout the body (8). Therefore deficits and surfeits in the levels of the catecholamines have many repercussions, perhaps including high blood pressure, bipolar disorder, addiction, and dystonias (9-11). Because of this, the activity of TyrH as the slowest enzyme in the pathway is of great interest in many fields of biomedical research.Given the importance of the activity of TyrH, the complexity of its regulation is not surprising. Control of its expression by transcriptional mechanisms is a very active field of research, as is the relatively new field of its degradation in the proteosome after † To whom inquiries should be addressed: Dept of Biological Sciences, St Mary's University, One Camino Santa Maria, San Antonio TX 78228, sdaubner@stmarytx.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could a...

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