ArticleArchives of biochemistry and biophysics2013
A new model for allosteric regulation of phenylalanine hydroxylase: implications for disease and therapeutics.
Article in Archives of biochemistry and biophysics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 58 citations in OpenAlex.
- Blood phenylalanine lowering partially reverses white matter changes in a mouse model of phenylketonuria.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Time-Dependent Kinetic Complexities in Enzyme Assays: A Review.Biomolecules · 2025Review
- Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis.Biochemistry · 2025Article
- Hyperphenylalaninemias genotyping: Results of over 60 years of history in Lombardy, Italy.Endocrinology, diabetes & metabolism · 2023Article
- Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants.Scientific reports · 2022Article
- Impact of Fluorinated Ionic Liquids on Human Phenylalanine Hydroxylase-A Potential Drug Delivery System.Nanomaterials (Basel, Switzerland) · 2022Article
- Systemic tryptophan homeostasis.Frontiers in molecular biosciences · 2022Review
- Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria.Scientific reports · 2021Article
- Mechanisms of OBiochemistry · 2021Article
- Unravelling the Complex Denaturant and Thermal-Induced Unfolding Equilibria of Human Phenylalanine Hydroxylase.International journal of molecular sciences · 2021Article
- Manipulation of a cation-π sandwich reveals conformational flexibility in phenylalanine hydroxylase.Biochimie · 2021Article
- Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives.Biomolecules · 2021Article
- ProtCID: a data resource for structural information on protein interactions.Nature communications · 2020Article
- Porphobilinogen synthase: An equilibrium of different assemblies in human health.Progress in molecular biology and translational science · 2020Review
- Wrangling Shape-Shifting Morpheeins to Tackle Disease and Approach Drug Discovery.Frontiers in molecular biosciences · 2020Review
- Structure of full-length wild-type human phenylalanine hydroxylase by small angle X-ray scattering reveals substrate-induced conformational stability.Scientific reports · 2019Article
- Biophysical characterization of full-length human phenylalanine hydroxylase provides a deeper understanding of its quaternary structure equilibrium.The Journal of biological chemistry · 2019Article
- Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding.The Journal of biological chemistry · 2018Article
- New protein structures provide an updated understanding of phenylketonuria.Molecular genetics and metabolism · 2017Review
- X-ray Scattering Studies of Protein Structural Dynamics.Chemical reviews · 2017Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The structural basis for allosteric regulation of phenylalanine hydroxylase (PAH), whose dysfunction causes phenylketonuria (PKU), is poorly understood. A new morpheein model for PAH allostery is proposed to consist of a dissociative equilibrium between two architecturally different tetramers whose interconversion requires a ∼90° rotation between the PAH catalytic and regulatory domains, the latter of which contains an ACT domain. This unprecedented model is supported by in vitro data on purified full length rat and human PAH. The conformational change is both predicted to and shown to render the tetramers chromatographically separable using ion exchange methods. One novel aspect of the activated tetramer model is an allosteric phenylalanine binding site at the intersubunit interface of ACT domains. Amino acid ligand-stabilized ACT domain dimerization follows the multimerization and ligand binding behavior of ACT domains present in other proteins in the PDB. Spectroscopic, chromatographic, and electrophoretic methods demonstrate a PAH equilibrium consisting of two architecturally distinct tetramers as well as dimers. We postulate that PKU-associated mutations may shift the PAH quaternary structure equilibrium in favor of the low activity assemblies. Pharmacological chaperones that stabilize the ACT:ACT interface can potentially provide PKU patients with a novel small molecule therapeutic.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.