Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells

被引：32

作者：

Aguado, C ^{[1
]}

Pérez, B ^{[1
]}

Ugarte, M ^{[1
]}

Desviat, LR ^{[1
]}

机构：

[1] Univ Autonoma Madrid, CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain

来源：

FEBS LETTERS | 2006年 / 580卷 / 07期

关键词：

tetrahydrobiopterin; phenylketonuria; PAH gene expression; BH4-responsiveness; PKU mutations; chemical chaperon;

D O I：

10.1016/j.febslet.2006.02.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

引用

页码：1697 / 1701

页数：5

共 30 条

[1] Spanish BH4-responsive phenylalanine hydroxylase-deficient patients:: Evolution of seven patients on long-term treatment with tetrahydrobiopterin [J].

Bélanger-Quintana, A ;

García, MJ ;

Castro, M ;

Desviat, LR ;

Pérez, B ;

Mejía, B ;

Ugarte, M ;

Martínez-Pardo, M .

MOLECULAR GENETICS AND METABOLISM, 2005, 86 :S61-S66

[2] Role of pyridoxal 5′-phosphate in the structural stabilization of O-acetylserine sulfhydrylase [J].

Bettati, S ;

Benci, S ;

Campanini, B ;

Raboni, S ;

Chirico, G ;

Beretta, S ;

Schnackerz, KD ;

Hazlett, TL ;

Gratton, E ;

Mozzarelli, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (51) :40244-40251

[3] The metabolic and molecular bases of tetrahydroblopterin-responsive phenylalanine hydroxylase deficiency [J].

Blau, N ;

Erlandsen, H .

MOLECULAR GENETICS AND METABOLISM, 2004, 82 (02) :101-111

[4]

Blau N, 2001, METABOLIC MOL BASES, P1725

[5] Tetrahydrobiopterin responsiveness:: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype [J].

Desviat, LR ;

Pérez, B ;

Bélanger-Quintana, A ;

Castro, M ;

Aguado, C ;

Sánchez, A ;

García, MJ ;

Martínez-Pardo, M ;

Ugarte, M .

MOLECULAR GENETICS AND METABOLISM, 2004, 83 (1-2) :157-162

[6] STRATEGY FOR THE SCREENING OF TETRAHYDROBIOPTERIN DEFICIENCY AMONG HYPERPHENYLALANINAEMIC PATIENTS - 15-YEARS EXPERIENCE [J].

DHONDT, JL .

JOURNAL OF INHERITED METABOLIC DISEASE, 1991, 14 (02) :117-127

[7] The covalent FAD of monoamine oxidase: Structural and functional role and mechanism of the flavinylation reaction [J].

Edmondson, DE ;

Newton-Vinson, P .

ANTIOXIDANTS & REDOX SIGNALING, 2001, 3 (05) :789-806

[8] Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations [J].

Erlandsen, H ;

Pey, AL ;

Gámez, A ;

Pérez, B ;

Desviat, LR ;

Aguado, C ;

Koch, R ;

Surendran, S ;

Tyring, S ;

Matalon, R ;

Scriver, CR ;

Ugarte, M ;

Martínez, A ;

Stevens, RC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (48) :16903-16908

[9] Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria [J].

Hennermann, JB ;

Bührer, C ;

Blau, N ;

Vetter, B ;

Mönch, E .

MOLECULAR GENETICS AND METABOLISM, 2005, 86 :S86-S90

[10]

Hyland K, 1996, J NEUROCHEM, V67, P752

← 1 2 3 →