title: Kinetic and stability analysis of PKU mutations identified in BH4-responsive patients.
abstract: From all the different molecular mechanisms put forward to explain the basis of BH4 responsiveness in PKU patients, a clear picture is now emerging based on the results from expression studies performed with a number of missense mutations identified in patients with a positive response in BH4 loading tests. Two of the proposed mechanisms, namely decreased binding affinity of the mutant proteins for the natural cofactor and stabilization effect of BH4, have been confirmed for several PKU mutations and the results are reviewed here. The actual view supports a multifactorial basis of the response, highlighting the necessity of detailed in vitro characterization of each mutant PAH protein. Several of the confirmed molecular mechanisms may be operating simultaneously, as exemplified in the data presented, and this may result in different degrees of BH4 responsiveness.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.forename: Lourdes R
authors.initials: LR
authors.lastname: Desviat
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.forename: Aurora
authors.initials: A
authors.lastname: Martínez
authors.forename: Rymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D003067:Coenzymes / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D015870:Gene Expression; D006207:Half-Life; D006801:Humans; D020125:Mutation, Missense; D010651:Phenylalanine Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010661:Phenylketonurias / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D003067:Coenzymes; D011993:Recombinant Fusion Proteins; D001708:Biopterins; D010651:Phenylalanine Hydroxylase; C003402:sapropterin