SULM – Schweizerische Union für Labormedizin | Union Suisse de Médecine de Laboratoire | Swiss Union of Laboratory Medicine

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B. Thöny1 , N. Blau1 , A. Martinez2

1Division of Clinical Chemistry, Department of Pediatrics, University of Zürich, Switzerland, 2Department of Biomedicine, University of Bergen, Norway

Tetrahydrobiopterin (BH4) is an essential oxygen-activating cofactor for nitric oxide synthase (NOS) and aromatic amino acid hydroxylases, and is necessary for NO-, monoamine neurotransmitter, as well as for phenylalanine catabolism. BH4-responsive phenylalanine hydroxylase (PAH) deficiency is a variant of hyperphenylalaninemia or phenylketonuria (PKU) caused by mutations in the human PAH gene that respond to oral BH4 loading by lowering serum phenylalanine. Moreover, about two-thirds of all mild PKU patients are BH4-responsive and thus can be potentially treated with BH4 instead of a low-phenylalanine diet. Although there has been an increase in the amount of information relating to the diagnosis and treatment of this new variant of PKU, very little is known about the mechanism of BH4-responsiveness. Here, we investigated the response of wild-type PAH activity to BH4 in transgenic mice with a complete or partial deficiency in the endogenous cofactor biosynthesis. In this in vivo situation, the rate of hepatic PAH enzyme activity increased with BH4 content without affecting gene expression or Pah-mRNA stability. We also show in a coupled transcription-translation in-vitro assay that the presence of BH4 enhanced wild-type PAH enzyme activity. Our results indicate that BH4 has a chaperon-like effect on PAH synthesis and is a protecting cofactor against enzyme auto-inactivation and degradation. These findings thus contribute to the understanding of the regulation of PAH by BH4 and provide a molecular explanation for cofactor-responsive PKU.

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