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
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
收藏
页码:1697 / 1701
页数:5
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