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:
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.,Norway
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.
Export Options
About this article
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 |

- Author Guidelines
- Editorial Policies
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Allegations from Whistleblowers
- Publishing Ethics and Rectitude
- Increase Visibility Of Your Article
- Archiving Policies
- Reviewer Guidelines
- Guest Editor Guidelines
- Board Recruitment Workflow
- Short Guide
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Announcements
- Forthcoming Thematic Issues
Related Articles
-
Novel Therapeutic Targets in Neuropsychiatric Disorders: The Neuroepigenome
Current Pharmaceutical Design Endocannabinoid Blockade and the Cardiovascular System
Current Drug Therapy Recent Advances in Pegylated Interferon Antiviral Therapy of Chronic Hepatitis C
Anti-Infective Agents in Medicinal Chemistry Influence of Aging on the Dopaminergic Neurons in the Substantia Nigra Pars Compacta of Rats
Current Aging Science Cannabis Use in Patients at Clinical High Risk of Psychosis: Impact on Prodromal Symptoms and Transition to Psychosis
Current Pharmaceutical Design The Need for Physiologically Relevant Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ) Ligands
Endocrine, Metabolic & Immune Disorders - Drug Targets The Influence of Marijuana Use on Neurocognitive Functioning in Adolescents
Current Drug Abuse Reviews Doxorubicin vs. ladirubicin: methods for improving osteosarcoma treatment
Mini-Reviews in Medicinal Chemistry Curcumin and Immunity
Current Bioactive Compounds N-Acetylserotonin vs Melatonin: In-Vitro Controlled Release from Hydrophilic Matrix Tablets
Letters in Drug Design & Discovery CYP2B6 and OPRM1 Receptor Polymorphisms at Methadone Clinics And Novel OPRM1 Haplotypes: A Cross-Sectional Study
Drug Metabolism Letters Recent Structural and Computational Insights into Conformational Diseases
Current Medicinal Chemistry Sulfation in Dog
Current Drug Metabolism Transition States and Inhibitors of the Purine Nucleoside Phosphorylase Family
Current Topics in Medicinal Chemistry The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind
Current Neuropharmacology New Developments of Clinical Trial in Immunotherapy for Alzheimer's Disease
Current Pharmaceutical Biotechnology Effect of Myricetin on the Loss of Dopaminergic Neurons in the Transgenic Drosophila Model of Parkinson’s Disease
Current Drug Therapy Aging, Mitochondria and Male Reproductive Function
Current Aging Science The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications
Current Medicinal Chemistry Coagulopathy as a Therapeutic Target for TRALI: Rationale and Possible Sites of Action
Current Pharmaceutical Design