title: Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria.
abstract: 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.
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Erlandsen
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Patch
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gamez
authors.forename: Mary
authors.initials: M
authors.lastname: Straub
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D005838:Genotype; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010651:Phenylalanine Hydroxylase / Q000737:chemistry* / Q000235:genetics*; D010661:Phenylketonurias / Q000178:diet therapy / Q000188:drug therapy / Q000235:genetics*; D017354:Point Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D001708:Biopterins; D010651:Phenylalanine Hydroxylase; C003402:sapropterin