Aguado Cristina, Pérez Belén, Ugarte Magdalena, Desviat Lourdes R
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
FEBS Lett. 2006 Mar 20;580(7):1697-701. doi: 10.1016/j.febslet.2006.02.005. Epub 2006 Feb 17.
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.
四氢生物蝶呤（BH4）反应性苯丙氨酸羟化酶（PAH）缺乏症是苯丙酮尿症最近被认识到的一种变体，可能具有多因素分子基础。在本研究中，我们研究了BH4对人肝癌中PAH基因表达的影响。我们的结果表明，由于周转率延长，BH4水平升高导致PAH活性和PAH蛋白增强，而PAH mRNA水平保持不变。这在与体内BH4反应性相关的突变PAH蛋白（A309V、V388M和Y414C）中得到证实，验证了先前的研究。我们可以得出结论，辅因子对PAH基因转录没有影响，BH4稳定突变PAH蛋白的化学伴侣效应可能是反应的主要潜在机制。
