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

FEBS Letters
Cristina AguadoLourdes R Desviat

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.

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Citations

Jan 17, 2012·Human Molecular Genetics·Sandra Santos-SierraFlorian B Lagler
Jan 30, 2013·Clinica Chimica Acta; International Journal of Clinical Chemistry·Kamila RéblováLenka Fajkusová
Aug 1, 2012·Drug Delivery and Translational Research·Jaspreet Singh KochharLifeng Kang
Aug 30, 2011·Molecular Genetics and Metabolism·João LeandroTorgeir Flatmark
Aug 19, 2007·Lancet·Angel L Pey, Aurora Martinez
Apr 6, 2007·Clinica Chimica Acta; International Journal of Clinical Chemistry·Cristina AguadoLourdes R Desviat
May 31, 2012·Human Mutation·Christineh N SarkissianAurora Martinez
May 29, 2013·Molecular Genetics and Metabolism·Teresa D DouglasRani H Singh
Feb 3, 2009·Progress in Molecular Biology and Translational Science·Aurora MartinezAngel L Pey
Aug 1, 2020·Journal of Cellular and Molecular Medicine·Yao WuMeixiao Zhan
May 24, 2019·Proceedings of the National Academy of Sciences of the United States of America·Marte Innselset FlydalJuan A Hermoso

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