title: Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease.
abstract: The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets.
authors.affiliation: a Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders , University of Bergen , Bergen , Norway.
authors.forename: Kai
authors.initials: K
authors.lastname: Waløen
authors.affiliation: b Computational Biology Unit, Department of Informatics , University of Bergen , Bergen , Norway.
authors.forename: Rune
authors.initials: R
authors.lastname: Kleppe
authors.affiliation: a Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders , University of Bergen , Bergen , Norway.
authors.forename: Aurora
authors.initials: A
authors.lastname: Martinez
authors.affiliation: a Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders , University of Bergen , Bergen , Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D018832:Molecular Chaperones; D014446:Tyrosine 3-Monooxygenase; C497467:TPH1 protein, human; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase
keywords: 14-3-3; ADHD; Tyrosine hydroxylase; aromatic amino acid hydroxylase; dopamine; human disease; mental disorder; osteoporosis; serotonin; tryptophan hydroxylase