ArticleAmerican journal of human genetics2001
Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine.
Article in American journal of human genetics, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 41 citations in OpenAlex.
- Metabolic phenotypes of phenylketonuria. Kinetic and molecular evaluation of the Blaskovics protein loading test.Journal of inherited metabolic disease · 2009Trial
- 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
- Phenylalanine 4-Hydroxylase Contributes to Endophytic BacteriumFrontiers in genetics · 2021Article
- Structure of full-length wild-type human phenylalanine hydroxylase by small angle X-ray scattering reveals substrate-induced conformational stability.Scientific reports · 2019Article
- The phenylketonuria-associated substitution R68S converts phenylalanine hydroxylase to a constitutively active enzyme but reduces its stability.The Journal of biological chemistry · 2019Article
- 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
- X-ray Scattering Studies of Protein Structural Dynamics.Chemical reviews · 2017Review
- 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
- An additional substrate binding site in a bacterial phenylalanine hydroxylase.European biophysics journal : EBJ · 2013Article
- Role of the phenylalanine-hydroxylating system in aromatic substance degradation and lipid metabolism in the oleaginous fungus Mortierella alpina.Applied and environmental microbiology · 2013Article
- Article
- Allosteric regulation of phenylalanine hydroxylase.Archives of biochemistry and biophysics · 2012Review
- Direct evidence for a phenylalanine site in the regulatory domain of phenylalanine hydroxylase.Archives of biochemistry and biophysics · 2011Article
- Connecting mutant phenylalanine hydroxylase with phenylketonuria.Journal of clinical monitoring and computing · 2008Article
- Mutation of a rice gene encoding a phenylalanine biosynthetic enzyme results in accumulation of phenylalanine and tryptophan.The Plant cell · 2008Article
- Substrate-induced conformational transition in human phenylalanine hydroxylase as studied by surface plasmon resonance analyses: the effect of terminal deletions, substrate analogues and phosphorylation.The Biochemical journal · 2003Article
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperphenylalaninemia due to a deficiency of phenylalanine hydroxylase (PAH) is an autosomal recessive disorder caused by >400 mutations in the PAH gene. Recent work has suggested that the majority of PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation. In this study, we describe an alternative mechanism by which some PAH mutations may render PAH defective. Database searches were used to identify regions in the N-terminal domain of PAH with homology to the regulatory domain of prephenate dehydratase (PDH), the rate-limiting enzyme in the bacterial phenylalanine biosynthesis pathway. Naturally occurring N-terminal PAH mutations are distributed in a nonrandom pattern and cluster within residues 46-48 (GAL) and 65-69 (IESRP), two motifs highly conserved in PDH. To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wild-type and five mutant (G46S, A47V, T63P/H64N, I65T, and R68S) forms of the N-terminal domain (residues 2-120) of human PAH were expressed as fusion proteins in Escherichia coli. Binding studies showed that the wild-type form of this domain specifically binds phenylalanine, whereas all mutations abolished or significantly reduced this phenylalanine-binding capacity. Our data suggest that impairment of phenylalanine-mediated activation of PAH may be an important disease-causing mechanism of some N-terminal PAH mutations, which may explain some well-documented genotype-phenotype discrepancies in PAH deficiency.
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