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), Parkinsons 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.
Keywords: Aromatic amino acid hydroxylases, Tetrahydrobiopterin, Molecular interaction field analysis, Selectivity, Computational structural biology
Current Medicinal Chemistry
Title: Selectivity and Affinity Determinants for Ligand Binding to the Aromatic Amino Acid Hydroxylases
Volume: 14 Issue: 4
Author(s): Knut Teigen, Jeffrey Alan McKinney, Jan Haavik and Aurora Martinez
Affiliation:
Keywords: Aromatic amino acid hydroxylases, Tetrahydrobiopterin, Molecular interaction field analysis, Selectivity, Computational structural biology
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), Parkinsons 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.
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Cite this article as:
Teigen Knut, Alan McKinney Jeffrey, Haavik Jan and Martinez Aurora, Selectivity and Affinity Determinants for Ligand Binding to the Aromatic Amino Acid Hydroxylases, Current Medicinal Chemistry 2007; 14 (4) . https://dx.doi.org/10.2174/092986707779941023
DOI https://dx.doi.org/10.2174/092986707779941023 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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