Pah super(e)nu1is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo

• Published in: Human molecular genetics Vol. 19; no. 10; pp. 2039 - 2049
• Main Authors: Gersting, Soeren W, Lagler, Florian B, Eichinger, Anna, Kemter, Kristina F, Danecka, Marta K, Messing, Dunja D, Staudigl, Michael, Domdey, Katharina A, Zsifkovits, Clemens, Fingerhut, Ralph, Glossmann, Hartmut, Roscher, Adelbert A, Muntau, Ania C
• Format: Journal Article
• Language: English
• Published: 15-05-2010
• Subjects: Animal models; Chaperones; Data processing; Drug development; Drugs; Enzymes; Molecular modelling; Pharmaceuticals; Phenylalanine 4-monooxygenase; Phenylketonuria; Protein folding; Protein structure; sapropterin
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq085

The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH sub(4)), for the treatment of phenylketonuria (PKU) as the first pharmacological chaperone drug initiated a paradigm change in the treatment of monogenetic diseases. Symptomatic treatment is now replaced by a causal pharmacological therapy correcting misfolding of the defective phenylalanine hydroxylase (PAH) in numerous patients. Here, we disclose BH sub(4) responsiveness in Pah super(e)nu1 a mouse model for PAH deficiency. Loss of function resulted from loss of PAH, a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. BH sub(4) attenuated this triad by conformational stabilization augmenting the effective PAH concentration. This led to the rescue of the biochemical phenotype and enzyme function in vivo. Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH sub(4) confined to the pathological metabolic state. Our data provide new molecular-level insights into the mechanisms underlying protein misfolding with loss of function and support a general model of pharmacological chaperone-induced stabilization of protein conformation to correct this intracellular phenotype. Pah super(e)nu1will be essential for pharmaceutical drug optimization and to design individually tailored therapies.