title: Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells.
abstract: Tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency is a recently recognized variant of phenylketonuria, with a probable multifactorial molecular basis. In this study we have investigated the effect of BH4 on PAH gene expression in human hepatoma. Our results show that increased BH4 levels result in an enhancement of PAH activity and PAH protein, due to longer turnover rates, while PAH mRNA levels remain unchanged. This was confirmed for mutant PAH proteins (A309V, V388M and Y414C) associated to in vivo BH4 responsiveness, validating previous studies. We can conclude that there is no effect of the cofactor on PAH gene transcription, probably being the chemical chaperone effect of BH4 stabilizing mutant PAH proteins the major underlying mechanism of the response.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguado
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Lourdes R
authors.initials: LR
authors.lastname: Desviat
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020125:Mutation, Missense; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000235:genetics*; D010661:Phenylketonurias; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D001708:Biopterins; D010651:Phenylalanine Hydroxylase; C003402:sapropterin