Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria.

Mutations in the gene encoding for phenylalanine hydroxylase (PAH) result in phenylketonuria (PKU) or hyperphenylalaninemia (HPA). Several 3-dimensional structures of truncated forms of PAH have been determined in our laboratory and by others, using x-ray crystallographic techniques. These structures have allowed for a detailed mapping of the >250 missense mutations known to cause PKU or HPA found throughout the 3 domains of PAH. This structural information has helped formulate rules that might aid in predicting the likely effects of unclassified or newly discovered PAH mutations. Also, with the aid of recent crystal structure determinations of co-factor and substrate analogs bound at the PAH active site, the recently discovered tetrahydrobiopterin-responsive PKU/HPA genotypes can be mapped onto the PAH structure, providing a molecular basis for this tetrahydrobiopterin response.

[1]  B. Ames.  A role for supplements in optimizing health: the metabolic tune-up. , 2004, Archives of biochemistry and biophysics.

[2]  N. Blau,et al.  Tetrahydrobiopterin Responsiveness in Phenylketonuria. Two New Cases and a Review of Molecular Genetic Findings , 2002, Journal of Inherited Metabolic Disease.

[3]  R. Stevens,et al.  A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninaemia and phenylketonuria , 2001, Journal of Inherited Metabolic Disease.

[4]  T. Flatmark,et al.  The PKU mutation S349P causes complete loss of catalytic activity in the recombinant phenylalanine hydroxylase enzyme , 1995, Human Genetics.

[5]  U. Lichter-Konecki,et al.  Geographical distribution of the P281L mutation at the phenylalanine hydroxylase locus: possible origin in southeastern Europe , 1994, Journal of Inherited Metabolic Disease.

[6]  T. Flatmark,et al.  Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis and substrate activation. , 2002, Journal of molecular biology.

[7]  A. Boneh,et al.  How practical are recommendations for dietary control in phenylketonuria? , 2002, The Lancet.

[8]  B. Ames,et al.  High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. , 2002, The American journal of clinical nutrition.

[9]  N. Blau,et al.  Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency: possible regulation of gene expression in a patient with the homozygous L48S mutation. , 2002, Molecular genetics and metabolism.

[10]  R. Levine,et al.  Chemistry and Biology of Pteridines and Folates , 2002, Springer US.

[11]  J. Haavik,et al.  Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity. , 2001, Biochemistry.

[12]  T. Flatmark,et al.  High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. , 2001, Journal of molecular biology.

[13]  M. Ugarte,et al.  Expression Analysis of Phenylketonuria Mutations , 2000, The Journal of Biological Chemistry.

[14]  R. Stevens,et al.  Crystal structure and site-specific mutagenesis of pterin-bound human phenylalanine hydroxylase. , 2000, Biochemistry.

[15]  R. Stevens,et al.  The structural basis of phenylketonuria. , 1999, Molecular genetics and metabolism.

[16]  S. Kure,et al.  Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. , 1999, The Journal of pediatrics.

[17]  R. Stevens,et al.  Structural Insight into the Aromatic Amino Acid Hydroxylases and Their Disease-Related Mutant Forms. , 1999, Chemical reviews.

[18]  R. Stevens,et al.  Structural basis of autoregulation of phenylalanine hydroxylase , 1999, Nature Structural Biology.

[19]  T. Chang,et al.  A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  H. Levy.  Phenylketonuria: old disease, new approach to treatment. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R C Stevens,et al.  Partial characterization and three-dimensional-structural localization of eight mutations in exon 7 of the human phenylalanine hydroxylase gene associated with phenylketonuria. , 1998, European journal of biochemistry.

[22]  R. Stevens,et al.  Structure of Tetrameric Human Phenylalanine Hydroxylase and Its Implications for Phenylketonuria* , 1998, The Journal of Biological Chemistry.

[23]  M. Ugarte,et al.  Molecular basis of phenylketonuria in Venezuela: Presence of two novel null mutations , 1998, Human mutation.

[24]  P. Waters,et al.  Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene (PAH) , 1998, Human mutation.

[25]  X. Estivill,et al.  Two novel mutations in exon 11 of the PAH gene (V1163 del TG and P362T) associated with classic phenylketonuria and mild phenylketonuria , 1998, Human mutation.

[26]  P. Waters,et al.  Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. , 1997, American journal of human genetics.

[27]  R. Stevens,et al.  Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria , 1997, Nature Structural Biology.

[28]  Raymond C. Stevens,et al.  Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases , 1997, Nature Structural Biology.

[29]  J. M. Aarden,et al.  Structure/function relationships in human phenylalanine hydroxylase. Effect of terminal deletions on the oligomerization, activation and cooperativity of substrate binding to the enzyme. , 1996, European journal of biochemistry.

[30]  T. J. Kappock,et al.  Pterin-Dependent Amino Acid Hydroxylases. , 1996, Chemical reviews.

[31]  R. Matalon,et al.  Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study. , 1996, American journal of human genetics.

[32]  T. Flatmark,et al.  PKU mutation (D143G) associated with an apparent high residual enzyme activity: Expression of a kinetic variant form of phenylalanine hydroxylase in three different systems , 1996, Human mutation.

[33]  P. Knappskog,et al.  Relative Frequency, Heterogeneity and Geographic Clustering of PKU Mutations in Norway , 1996, European journal of human genetics : EJHG.

[34]  R. Cotton,et al.  Structure and function of the aromatic amino acid hydroxylases. , 1995, The Biochemical journal.

[35]  T. Flatmark,et al.  Expression of recombinant human phenylalanine hydroxylase as fusion protein in Escherichia coli circumvents proteolytic degradation by host cell proteases. Isolation and characterization of the wild-type enzyme. , 1995, The Biochemical journal.

[36]  A. Masamune,et al.  Ectopic transcription: an application to the analysis of splicing errors in phenylalanine hydroxylase mRNA , 1994, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[37]  M. Ugarte,et al.  Spectrum and origin of phenylketonuria mutations in Spain , 1994, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[38]  D. W. Gray,et al.  Regulation of rat liver phenylalanine hydroxylase. III. Control of catalysis by (6R)-tetrahydrobiopterin and phenylalanine. , 1994, The Journal of biological chemistry.

[39]  P. Bénit,et al.  Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria , 1994, Human mutation.

[40]  P. Bosco,et al.  Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. , 1993, Human molecular genetics.

[41]  P. Guldberg,et al.  Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis. , 1993, Genomics.

[42]  S. Benkovic,et al.  Expression of rat liver phenylalanine hydroxylase in insect cells and site-directed mutagenesis of putative non-heme iron-binding sites. , 1993, The Journal of biological chemistry.

[43]  T. Flatmark,et al.  Expression of wild type and mutant forms of human phenylalanine hydroxylase in E. coli. , 1993, Advances in experimental medicine and biology.

[44]  B. Dworniczak,et al.  Two missense mutations causing mild hyperphenylalaninemia associated with DNA haplotype 12 , 1992, Human mutation.

[45]  C R Scriver,et al.  In vitro and in vivo correlations for I65T and M1V mutations at the phenylalanine hydroxylase locus , 1992, Human mutation.

[46]  R. Cotton,et al.  Localization of cofactor binding sites with monoclonal anti-idiotype antibodies: phenylalanine hydroxylase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[47]  T. Flatmark,et al.  EPR and 1H-NMR spectroscopic studies on the paramagnetic iron at the active site of phenylalanine hydroxylase and its interaction with substrates and inhibitors. , 1991, European journal of biochemistry.

[48]  W. H. Lo,et al.  Missense mutations prevalent in Orientals with phenylketonuria: molecular characterization and clinical implications. , 1991, Genomics.

[49]  F. Güttler,et al.  Molecular basis of phenotypic heterogeneity in phenylketonuria. , 1991, The New England journal of medicine.

[50]  B. Dworniczak,et al.  Phenylalanine hydroxylase gene: novel missense mutation in exon 7 causing severe phenylketonuria. , 1991, Genomics.

[51]  C. Romano,et al.  Phenylketonuria missense mutations in the Mediterranean. , 1991, Genomics.

[52]  R. Gitzelmann,et al.  Missense mutations associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene. , 1990, American journal of human genetics.

[53]  A. Dilella,et al.  An ammo-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2 , 1987, Nature.

[54]  A. Dilella,et al.  The human phenylalanine hydroxylase gene. , 1985, Progress in clinical and biological research.

[55]  T. Flatmark,et al.  The effect of ligands of phenylalanine 4-monooxygenase on the cAMP-dependent phosphorylation of the enzyme. , 1984, The Journal of biological chemistry.

[56]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.