ArticleBiochemistry2014
Activation of phenylalanine hydroxylase by phenylalanine does not require binding in the active site.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Time-Dependent Kinetic Complexities in Enzyme Assays: A Review.Biomolecules · 2025Review
- Neurotransmitter metabolites in milk ferments ofHeliyon · 2024Article
- Whole-exome sequencing reveals genetic variants that may play a role in neurocytomas.Journal of neuro-oncology · 2024Article
- Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia.Biomolecules · 2023Article
- Nutrient sensors and their crosstalk.Experimental & molecular medicine · 2023Review
- Coupling a droplet generator with conventional ESI-MS for quantitative analysis of small-volume samples.Analytical and bioanalytical chemistry · 2022Article
- The phenylketonuria-associated substitution R68S converts phenylalanine hydroxylase to a constitutively active enzyme but reduces its stability.The Journal of biological chemistry · 2019Article
- Phosphorylation of Phenylalanine Hydroxylase Increases the Rate Constant for Formation of the Activated Conformation of the Enzyme.Biochemistry · 2018Article
- Substituting TyrFEBS open bio · 2017Article
- PKU mutation p.G46S prevents the stereospecific binding of l-phenylalanine to the dimer of human phenylalanine hydroxylase regulatory domain.FEBS open bio · 2017Article
- Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat.Nature chemical biology · 2016Article
- The regulatory domain of human tryptophan hydroxylase 1 forms a stable dimer.Biochemical and biophysical research communications · 2016Article
- Domain Movements upon Activation of Phenylalanine Hydroxylase Characterized by Crystallography and Chromatography-Coupled Small-Angle X-ray Scattering.Journal of the American Chemical Society · 2016Article
- Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain.Scientific reports · 2016Article
- Identification of the Allosteric Site for Phenylalanine in Rat Phenylalanine Hydroxylase.The Journal of biological chemistry · 2016Article
- First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Structural insights into the regulation of aromatic amino acid hydroxylation.Current opinion in structural biology · 2015Review
- The Amino Acid Specificity for Activation of Phenylalanine Hydroxylase Matches the Specificity for Stabilization of Regulatory Domain Dimers.Biochemistry · 2015Article
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4 authors.
Funding
Abstract
Phenylalanine hydroxylase (PheH), a liver enzyme that catalyzes the hydroxylation of excess phenylalanine in the diet to tyrosine, is activated by phenylalanine. The lack of activity at low levels of phenylalanine has been attributed to the N-terminus of the protein's regulatory domain acting as an inhibitory peptide by blocking substrate access to the active site. The location of the site at which phenylalanine binds to activate the enzyme is unknown, and both the active site in the catalytic domain and a separate site in the N-terminal regulatory domain have been proposed. Binding of catecholamines to the active-site iron was used to probe the accessibility of the active site. Removal of the regulatory domain increases the rate constants for association of several catecholamines with the wild-type enzyme by ∼2-fold. Binding of phenylalanine in the active site is effectively abolished by mutating the active-site residue Arg270 to lysine. The k(cat)/K(phe) value is down 10⁴ for the mutant enzyme, and the K(m) value for phenylalanine for the mutant enzyme is >0.5 M. Incubation of the R270K enzyme with phenylalanine also results in a 2-fold increase in the rate constants for catecholamine binding. The change in the tryptophan fluorescence emission spectrum seen in the wild-type enzyme upon activation by phenylalanine is also seen with the R270K mutant enzyme in the presence of phenylalanine. Both results establish that activation of PheH by phenylalanine does not require binding of the amino acid in the active site. This is consistent with a separate allosteric site, likely in the regulatory domain.
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