Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo.
The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(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(4) responsiveness in Pah(enu1), 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(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(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(enu1) will be essential for pharmaceutical drug optimization and to design individually tailored therapies.
Gersting
Søren W
SW
Department of Molecular Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
Lagler
Florian B
FB
Eichinger
Anna
A
Kemter
Kristina F
KF
Danecka
Marta K
MK
Messing
Dunja D
DD
Staudigl
Michael
M
Domdey
Katharina A
KA
Zsifkovits
Clemens
C
Fingerhut
Ralph
R
Glossmann
Hartmut
H
Roscher
Adelbert A
AA
Muntau
Ania C
AC
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010649:Phenylalanine / Q000378:metabolism; D010651:Phenylalanine Hydroxylase / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020836:Protein Structure, Quaternary
D018832:Molecular Chaperones; D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin