ReviewMolecular genetics and metabolism2017
New protein structures provide an updated understanding of phenylketonuria.
Review in Molecular genetics and metabolism, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 28 citations in OpenAlex.
- Sepiapterin: A Distinct, Dual Mechanism of Action that Leads to Potential Treatment Benefits Across the Spectrum of Phenylketonuria Disease Severities.Advances in therapy · 2026Article
- Deubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity.Cell biology and toxicology · 2023Article
- 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
- Development of an mRNA replacement therapy for phenylketonuria.Molecular therapy. Nucleic acids · 2022Article
- A noncoding RNA modulator potentiates phenylalanine metabolism in mice.Science (New York, N.Y.) · 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
- Protein Degradation and the Pathologic Basis of Phenylketonuria and Hereditary Tyrosinemia.International journal of molecular sciences · 2020Review
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 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
- Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding.The Journal of biological chemistry · 2018Article
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Authors and funding
1 author at 1 institution in 1 country.
Funding
Abstract
Phenylketonuria (PKU) and less severe hyperphenylalaninemia (HPA) constitute the most common inborn error of amino acid metabolism, and is most often caused by defects in phenylalanine hydroxylase (PAH) function resulting in accumulation of Phe to neurotoxic levels. Despite the success of dietary intervention in preventing permanent neurological damage, individuals living with PKU clamor for additional non-dietary therapies. The bulk of disease-associated mutations are PAH missense variants, which occur throughout the entire 452 amino acid human PAH protein. While some disease-associated mutations affect protein structure (e.g. truncations) and others encode catalytically dead variants, most have been viewed as defective in protein folding/stability. Here we refine this view to address how PKU-associated missense variants can perturb the equilibrium among alternate native PAH structures (resting-state PAH and activated PAH), thus shifting the tipping point of this equilibrium to a neurotoxic Phe concentration. This refined view of PKU introduces opportunities for the design or discovery of therapeutic pharmacological chaperones that can help restore the tipping point to healthy Phe levels and how such a therapeutic might work with or without the inhibitory pharmacological chaperone BH
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