Abstract
Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. TPH belongs to the family of the aromatic amino acid hydroxylases, including phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict requirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases. Although structural information about TPH is not yet available, the high sequence homology between the three mammalian hydroxylases, notably at the catalytic domains, and the similarity of the reactions that they catalyze, indicate that they share a similar 3D-structure and a common catalytic mechanism. Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH. This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines. The interactions of these ligands with the enzyme are discussed focusing on the physiological and pharmacological regulation of serotonin biosynthesis, notably by tryptophan supplementation therapy and substitution therapy with tetrahydrobiopterin analogues (positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinsons disease patients (enzyme inhibition).
Keywords: Human Tryptophan Hydroxylase, Serotonin Biosynthesis, Tryptophan hydroxylase TPH, Hydroxylation, Tryptophan hydroxylase, Dihydroxyphenylalanine L-DOPA, Aromatic Amino Acid Hydroxylases, Pterins, Catecholamines
Current Medicinal Chemistry
Title: A Structural Approach into Human Tryptophan Hydroxylase and its Implications for the Regulation of Serotonin Biosynthesis
Volume: 8 Issue: 9
Author(s): Aurora Martinez, Per M. Knappskog and Jan Haavik
Affiliation:
Keywords: Human Tryptophan Hydroxylase, Serotonin Biosynthesis, Tryptophan hydroxylase TPH, Hydroxylation, Tryptophan hydroxylase, Dihydroxyphenylalanine L-DOPA, Aromatic Amino Acid Hydroxylases, Pterins, Catecholamines
Abstract: Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. TPH belongs to the family of the aromatic amino acid hydroxylases, including phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict requirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases. Although structural information about TPH is not yet available, the high sequence homology between the three mammalian hydroxylases, notably at the catalytic domains, and the similarity of the reactions that they catalyze, indicate that they share a similar 3D-structure and a common catalytic mechanism. Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH. This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines. The interactions of these ligands with the enzyme are discussed focusing on the physiological and pharmacological regulation of serotonin biosynthesis, notably by tryptophan supplementation therapy and substitution therapy with tetrahydrobiopterin analogues (positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinsons disease patients (enzyme inhibition).
Export Options
About this article
Cite this article as:
Martinez Aurora, Knappskog M. Per and Haavik Jan, A Structural Approach into Human Tryptophan Hydroxylase and its Implications for the Regulation of Serotonin Biosynthesis, Current Medicinal Chemistry 2001; 8 (9) . https://dx.doi.org/10.2174/0929867013372616
DOI https://dx.doi.org/10.2174/0929867013372616 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Obesity and Pregnancy
Current Women`s Health Reviews N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease
Current Alzheimer Research Can Untargeted Metabolomics Be Utilized in Drug Discovery/Development?
Current Topics in Medicinal Chemistry Acknowledgements to Reviewers
Current Neuropharmacology Consciousness, Functional Networks and Delirium Screening
Current Aging Science Resveratrol: A Multifunctional Cytoprotective Molecule
Current Pharmaceutical Biotechnology Therapeutic Potential of <i>Citrus sinensis</i> Peels Against Rotenone Induced Parkinsonism in Rats
Current Bioactive Compounds Pharmacokinetic and Toxicological Characteristics of Tripterigium Glycosides and Their Derivatives
Current Drug Metabolism Multi-Target Mining of Alzheimer Disease Proteome with Hansch’s QSBR-Perturbation Theory and Experimental-Theoretic Study of New Thiophene Isosters of Rasagiline
Current Drug Targets Medicinal Applications of Cannabinoids Extracted from Cannabis sativa (L.): A New Route in the Fight Against COVID-19?
Current Pharmaceutical Design Neuronal and Glial Responses to Polyamines in the Ischemic Brain
Current Neurovascular Research Alzheimer's Disease and Chinese Medicine as a Useful Alternative Intervention Tool: A Mini-Review
Current Alzheimer Research Social Network Analysis of Dementia Wards in Psychiatric Hospitals to Explore the Advancement of Personhood in Patients with Alzheimer’s Disease
Current Alzheimer Research Cholesterol and Apoe: A Target for Alzheimers Disease Therapeutics
Current Drug Targets - CNS & Neurological Disorders Formulation and Assessment of In Vivo Anti-Inflammatory Potential of Omega-3-Fatty Acid Loaded Self Emulsifying Nanoemulsion
Current Nanomedicine Blood-brain Barrier Disruption May Contribute to White Matter Lesions in the Setting of Internal Jugular Venous Stenosis
Current Neurovascular Research Cerebral Hypoperfusion During Carotid Artery Stenosis can Lead to Cognitive Deficits that may be Independent of White Matter Lesion Load
Current Neurovascular Research Translational Challenge Models in Support of Efficacy Studies: Effect of Cerebral Hypoxia on Cognitive Performances in Rodents
CNS & Neurological Disorders - Drug Targets Cytoprotection by Melatonin, Precursors and Metabolites in an In Vitro Model of Neurotoxicity Induced by Okadaic Acid
Letters in Drug Design & Discovery CYP2B6 and OPRM1 Receptor Polymorphisms at Methadone Clinics And Novel OPRM1 Haplotypes: A Cross-Sectional Study
Drug Metabolism Letters