ArticlePloS one2013
Structural features of the regulatory ACT domain of phenylalanine hydroxylase.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Synthetic closed-loop gene circuit for phenylalanine regulation.Nucleic acids research · 2025Article
- SNAT7 regulates mTORC1 via macropinocytosis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- A noncoding RNA modulator potentiates phenylalanine metabolism in mice.Science (New York, N.Y.) · 2021Article
- 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
- Conformational selection turns on phenylalanine hydroxylase.The Journal of biological chemistry · 2018Article
- 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
- Disruption of phenylalanine hydroxylase reduces adult lifespan and fecundity, and impairs embryonic development in parthenogenetic pea aphids.Scientific reports · 2016Article
- Article
- First Case Report of EX3del4765 Mutation in PAH Gene in Asian Population.Iranian Red Crescent medical journal · 2016Article
- Computational study of missense mutations in phenylalanine hydroxylase.Journal of molecular modeling · 2015Article
- A hydrophobic residue stabilizes dimers of regulatory ACT-like domains in plant basic helix-loop-helix transcription factors.The Journal of biological chemistryArticle
- Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies.International journal of health sciencesReview
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phenylalanine hydroxylase (PAH) catalyzes the conversion of L-Phe to L-Tyr. Defects in PAH activity, caused by mutations in the human gene, result in the autosomal recessively inherited disease hyperphenylalaninemia. PAH activity is regulated by multiple factors, including phosphorylation and ligand binding. In particular, PAH displays positive cooperativity for L-Phe, which is proposed to bind the enzyme on an allosteric site in the N-terminal regulatory domain (RD), also classified as an ACT domain. This domain is found in several proteins and is able to bind amino acids. We used molecular dynamics simulations to obtain dynamical and structural insights into the isolated RD of PAH. Here we show that the principal motions involve conformational changes leading from an initial open to a final closed domain structure. The global intrinsic motions of the RD are correlated with exposure to solvent of a hydrophobic surface, which corresponds to the ligand binding-site of the ACT domain. Our results strongly suggest a relationship between the Phe-binding function and the overall dynamic behaviour of the enzyme. This relationship may be affected by structure-disturbing mutations. To elucidate the functional implications of the mutations, we investigated the structural effects on the dynamics of the human RD PAH induced by six missense hyperphenylalaninemia-causing mutations, namely p.G46S, p.F39C, p.F39L, p.I65S, p.I65T and p.I65V. These studies showed that the alterations in RD hydrophobic interactions induced by missense mutations could affect the functionality of the whole enzyme.
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