ArticleProceedings of the National Academy of Sciences of the United States of America2004
Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 2 of them syntheses that pooled it.
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Who cites it
61 citing papers in PubMed, 2 syntheses or guidelines pooled it, 169 citations in OpenAlex.
- Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis.Nutrients · 2021Pooled it
- Sapropterin dihydrochloride for phenylketonuria.The Cochrane database of systematic reviews · 2015Pooled it
- Using change in plasma phenylalanine concentrations and ability to liberalize diet to classify responsiveness to tetrahydrobiopterin therapy in patients with phenylketonuria.Molecular genetics and metabolism · 2011Trial
- Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine.Journal of inherited metabolic disease · 2007Trial
- DNAJC12 Stabilizes Phenylalanine Hydroxylase and Facilitates Its Substrate-Dependent Activation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Mapping the Severity of Phenylalanine Hydroxylase Deficiency.Journal of inherited metabolic disease · 2026Review
- Sepiapterin: A Distinct, Dual Mechanism of Action that Leads to Potential Treatment Benefits Across the Spectrum of Phenylketonuria Disease Severities.Advances in therapy · 2026Article
- Natively entangled proteins are linked to human disease and pathogenic mutations likely due to a greater misfolding propensity.bioRxiv : the preprint server for biology · 2026Article
- Deubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity.Cell biology and toxicology · 2023Article
- Thermodynamics of iron, tetrahydrobiopterin, and phenylalanine binding to phenylalanine hydroxylase from Chromobacterium violaceum.Archives of biochemistry and biophysics · 2022Article
- Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants.Scientific reports · 2022Article
- Unravelling the Complex Denaturant and Thermal-Induced Unfolding Equilibria of Human Phenylalanine Hydroxylase.International journal of molecular sciences · 2021Article
- 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
- Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein.Journal of personalized medicine · 2020Article
- 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
- 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
- Tetrahydrobiopterin treatment reduces brain L-Phe but only partially improves serotonin in hyperphenylalaninemic ENU1/2 mice.Journal of inherited metabolic disease · 2018Article
- Identification of a hot-spot to enhanceRSC advances · 2018Article
1 more citing papers are in PubMed but not listed here.
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14 authors at 5 institutions in 3 countries.
Funding
Abstract
Phenylketonuria patients harboring a subset of phenylalanine hydroxylase (PAH) mutations have recently shown normalization of blood phenylalanine levels upon oral administration of the PAH cofactor tetrahydrobiopterin [(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)]. Several hypotheses have been put forward to explain BH4 responsiveness, but the molecular basis for the corrective effect(s) of BH4 has not been understood. We have investigated the biochemical, kinetic, and structural changes associated with BH4-responsive mutations (F39L, I65T, R68S, H170D, E178G, V190A, R261Q, A300S, L308F, A313T, A373T, V388M, E390G, P407S, and Y414C). The biochemical and kinetic characterization of the 15 mutants studied points toward a multifactorial basis for the BH4 responsiveness; the mutants show residual activity (>30% of WT) and display various kinetic defects, including increased Km (BH4) and reduced cooperativity of substrate binding, but no decoupling of cofactor (BH4) oxidation. For some, BH4 seems to function through stabilization and protection of the enzyme from inactivation and proteolytic degradation. In the crystal structures of a phenylketonuria mutant, A313T, minor changes were seen when compared with the WT PAH structures, consistent with the mild effects the mutant has upon activity of the enzyme both in vitro and in vivo. Truncations made in the A313T mutant PAH form revealed that the N and C termini of the enzyme influence active site binding. Of fundamental importance is the observation that BH4 appears to increase Phe catabolism if at least one of the two heterozygous mutations has any residual activity remaining.
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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.