title: Tyrosine hydroxylase phosphorylation: regulation and consequences.
abstract: The rate-limiting enzyme in catecholamine synthesis is tyrosine hydroxylase. It is phosphorylated at serine (Ser) residues Ser8, Ser19, Ser31 and Ser40 in vitro, in situ and in vivo. A range of protein kinases and protein phosphatases are able to phosphorylate or dephosphorylate these sites in vitro. Some of these enzymes are able to regulate tyrosine hydroxylase phosphorylation in situ and in vivo but the identity of the kinases and phosphatases is incomplete, especially for physiologically relevant stimuli. The stoichiometry of tyrosine hydroxylase phosphorylation in situ and in vivo is low. The phosphorylation of tyrosine hydroxylase at Ser40 increases the enzyme's activity in vitro, in situ and in vivo. Phosphorylation at Ser31 also increases the activity but to a much lesser extent than for Ser40 phosphorylation. The phosphorylation of tyrosine hydroxylase at Ser19 or Ser8 has no direct effect on tyrosine hydroxylase activity. Hierarchical phosphorylation of tyrosine hydroxylase occurs both in vitro and in situ, whereby the phosphorylation at Ser19 increases the rate of Ser40 phosphorylation leading to an increase in enzyme activity. Hierarchical phosphorylation depends on the state of the substrate providing a novel form of control of tyrosine hydroxylase activation.
authors.affiliation: School of Biomedical Sciences, The University of Newcastle, Callaghan, New South Wales, Australia. Peter.Dunkley@newcastle.edu.au
authors.forename: Peter R
authors.initials: PR
authors.lastname: Dunkley
authors.forename: Larisa
authors.initials: L
authors.lastname: Bobrovskaya
authors.forename: Mark E
authors.initials: ME
authors.lastname: Graham
authors.forename: Ellak I
authors.initials: EI
authors.lastname: von Nagy-Felsobuki
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Dickson
mesh_terms: D000818:Animals; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases