title: Selectivity and affinity determinants for ligand binding to the aromatic amino acid hydroxylases.
abstract: Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes, i.e. the aromatic amino acid hydroxylases (AAHs). The reactions catalyzed by these enzymes are important for biomedicine and their mutant forms in humans are associated with phenylketonuria (phenylalanine hydroxylase), Parkinson's disease and DOPA-responsive dystonia (tyrosine hydroxylase), and possibly neuropsychiatric and gastrointestinal disorders (tryptophan hydroxylase 1 and 2). We attempt to rationalize current knowledge about substrate and inhibitor specificity based on the three-dimensional structures of the enzymes and their complexes with substrates, cofactors and inhibitors. In addition, further insights on the selectivity and affinity determinants for ligand binding in the AAHs were obtained from molecular interaction field (MIF) analysis. We applied this computational structural approach to a rational analysis of structural differences at the active sites of the enzymes, a strategy that can help in the design of novel selective ligands for each AAH.
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
authors.forename: Knut
authors.initials: K
authors.lastname: Teigen
authors.forename: Jeffrey Alan
authors.initials: JA
authors.lastname: McKinney
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.forename: Aurora
authors.initials: A
authors.lastname: Martínez
mesh_terms: D015195:Drug Design; D006801:Humans; D008024:Ligands; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D010651:Phenylalanine Hydroxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D006899:Mixed Function Oxygenases; D010651:Phenylalanine Hydroxylase; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase