Conformational analysis of the N-terminal sequence Met1–Val60 of the tyrosine hydroxylase

Alieva, I. N.; Mustafayeva, Narmina; Gojayev, N.M.

doi:10.1016/j.molstruc.2005.09.026

Cited by 9 publications

(3 citation statements)

References 13 publications

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“…This is not consistent with a previous prediction from computational analyses that the first 60 residues contain two helices (residues 16-29 and residues 41-60) connected by a β turn. 44 The previous mass spectrometric analyses and the NMR T 2 values of these residues suggests that any helix formed by residues 46-56 is very dynamic. Residues 40-49 are heavily conserved across multiple species of TyrH from fish to human, while residues 50-59 form an unusual poly-alanine tract of variable length in different species.…”

Section: Discussionmentioning

confidence: 92%

The Solution Structure of the Regulatory Domain of Tyrosine Hydroxylase

Zhang

Huang

Ilangovan

et al. 2014

Journal of Molecular Biology

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Tyrosine hydroxylase (TyrH) catalyzes the hydroxylation of tyrosine to form 3,4-dihydroxyphenylalanine in the biosynthesis of the catecholamine neurotransmitters. The activity of the enzyme is regulated by phosphorylation of serine residues in a regulatory domain and by binding of catecholamines to the active site. Available structures of TyrH lack the regulatory domain, limiting the understanding of the effect of regulation on structure. We report the use of NMR spectroscopy to analyze the solution structure of the isolated regulatory domain of rat TyrH. The protein is composed of a largely unstructured N-terminal region (residues 1-71) and a well-folded C-terminal portion (residues 72-159). The structure of a truncated version of the regulatory domain containing residues 65-159 has been determined and establishes that it is an ACT domain. The isolated domain is a homodimer in solution, with the structure of each monomer very similar to that of the core of the regulatory domain of phenylalanine hydroxylase. Two TyrH regulatory domain monomers form an ACT domain dimer composed of a sheet of eight strands with four α-helices on one side of the sheet. Backbone dynamic analyses were carried out to characterize the conformational flexibility of TyrH65-159. The results provide molecular details critical for understanding the regulatory mechanism of TyrH.

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Section: Discussionmentioning

confidence: 92%

The Solution Structure of the Regulatory Domain of Tyrosine Hydroxylase

Zhang

Huang

Ilangovan

et al. 2014

Journal of Molecular Biology

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“…Perhaps arg37 and arg38 are important for the tertiary structure of the R domain. Supporting this idea, the molecular mechanics and dynamics work of Alieva et al (49) proposed that arg37 is necessary for an important β-turn in the R domain. A carboxylate residue could bind the catecholamine amino group, but alanine and glutamine substitution for the negatively-charged residues between position 32 and 68 (TyrHglu43, -asp44, -glu48, and glu-50) did not identify any carboxylate in the region important for dopamine binding.…”

Section: Effects That Results From Changes In the Regulatory Domainmentioning

confidence: 98%

Tyrosine hydroxylase and regulation of dopamine synthesis

Daubner

Wang

2011

Archives of Biochemistry and Biophysics

806

558

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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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“…Tyrosines 398 and 435 in MAO B (Tyr407 and Tyr444 in MAO A) are located on opposite sides of covalently bound inhibitors and substrates in all of the MAOs, forming an aromatic “sandwich”, and mutation of these residues alters activity (23–25). These tyrosines have been proposed to orient the substrate for oxidation or to activate the amine by enhancing its nucleophilicity (26). The substrate-binding site of human MAO A consists of a cavity approximately 400 Å 3 in size (27, 28), while in MAO B a smaller hydrophobic cavity, termed the “entrance cavity”, is positioned between the main substrate-binding site and the protein surface; rotation of an isoleucine residue (Ile199) allows the two cavities to be fused into one larger 700 Å 3 site (22).…”

Section: Monoamine Oxidases a And Bmentioning

confidence: 99%

Structures and mechanism of the monoamine oxidase family

Gaweska

Fitzpatrick

2011

BioMolecular Concepts

191

160

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Members of the monoamine oxidase family of flavoproteins catalyze the oxidation of primary and secondary amines, polyamines, amino acids, and methylated lysine side chains in proteins. The enzymes have similar overall structures, with conserved FAD-binding domains and varied substrate-binding sites. Multiple mechanisms have been proposed for the catalytic reactions of these enzymes. The present review compares the structures of different members of the family and the various mechanistic proposals.

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Conformational analysis of the N-terminal sequence Met1–Val60 of the tyrosine hydroxylase

Cited by 9 publications

References 13 publications

The Solution Structure of the Regulatory Domain of Tyrosine Hydroxylase

The Solution Structure of the Regulatory Domain of Tyrosine Hydroxylase

Tyrosine hydroxylase and regulation of dopamine synthesis

Structures and mechanism of the monoamine oxidase family

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