ArticleProceedings of the National Academy of Sciences of the United States of America2016
First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 52 citations in OpenAlex.
- DNAJC12 Stabilizes Phenylalanine Hydroxylase and Facilitates Its Substrate-Dependent Activation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Deubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity.Cell biology and toxicology · 2023Article
- The A328 V/E (rs2887147) polymorphisms in human tryptophan hydroxylase 2 compromise enzyme activity.Biochemistry and biophysics reports · 2023Article
- Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation.Nature communications · 2022Article
- Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.Frontiers in pharmacology · 2022Article
- Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency.Journal of personalized medicine · 2021Review
- The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase.Nature communications · 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
- In Silico and In Vitro Tailoring of a Chitosan Nanoformulation of a Human Metabolic Enzyme.Pharmaceutics · 2021Article
- Markov State Models to Elucidate Ligand Binding Mechanism.Methods in molecular biology (Clifton, N.J.) · 2021Review
- E3 Ubiquitin Ligase APC/CInternational journal of molecular sciences · 2020Article
- 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
- 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
- Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase.Genes · 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
- The phenylketonuria-associated substitution R68S converts phenylalanine hydroxylase to a constitutively active enzyme but reduces its stability.The Journal of biological chemistry · 2019Article
- The quaternary structure of human tyrosine hydroxylase: effects of dystonia-associated missense variants on oligomeric state and enzyme activity.Journal of neurochemistry · 2019Article
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8 authors at 5 institutions in 2 countries.
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Abstract
Improved understanding of the relationship among structure, dynamics, and function for the enzyme phenylalanine hydroxylase (PAH) can lead to needed new therapies for phenylketonuria, the most common inborn error of amino acid metabolism. PAH is a multidomain homo-multimeric protein whose conformation and multimerization properties respond to allosteric activation by the substrate phenylalanine (Phe); the allosteric regulation is necessary to maintain Phe below neurotoxic levels. A recently introduced model for allosteric regulation of PAH involves major domain motions and architecturally distinct PAH tetramers [Jaffe EK, Stith L, Lawrence SH, Andrake M, Dunbrack RL, Jr (2013) Arch Biochem Biophys 530(2):73-82]. Herein, we present, to our knowledge, the first X-ray crystal structure for a full-length mammalian (rat) PAH in an autoinhibited conformation. Chromatographic isolation of a monodisperse tetrameric PAH, in the absence of Phe, facilitated determination of the 2.9 Å crystal structure. The structure of full-length PAH supersedes a composite homology model that had been used extensively to rationalize phenylketonuria genotype-phenotype relationships. Small-angle X-ray scattering (SAXS) confirms that this tetramer, which dominates in the absence of Phe, is different from a Phe-stabilized allosterically activated PAH tetramer. The lack of structural detail for activated PAH remains a barrier to complete understanding of phenylketonuria genotype-phenotype relationships. Nevertheless, the use of SAXS and X-ray crystallography together to inspect PAH structure provides, to our knowledge, the first complete view of the enzyme in a tetrameric form that was not possible with prior partial crystal structures, and facilitates interpretation of a wealth of biochemical and structural data that was hitherto impossible to evaluate.
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