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Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells
Author(s) -
Aguado Cristina,
Pérez Belén,
Ugarte Magdalena,
Desviat Lourdes R.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.02.005
Subject(s) - tetrahydrobiopterin , phenylalanine hydroxylase , mutant , chemistry , gene expression , gene , biochemistry , in vivo , transcription factor , microbiology and biotechnology , cofactor , phenylalanine , enzyme , biology , genetics , amino acid
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.