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Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo

Standard

Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. / Gersting, Søren 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.

in: HUM MOL GENET, Jahrgang 19, Nr. 10, 15.05.2010, S. 2039-49.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Gersting, SW, Lagler, FB, Eichinger, A, Kemter, KF, Danecka, MK, Messing, DD, Staudigl, M, Domdey, KA, Zsifkovits, C, Fingerhut, R, Glossmann, H, Roscher, AA & Muntau, AC 2010, 'Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo', HUM MOL GENET, Jg. 19, Nr. 10, S. 2039-49. https://doi.org/10.1093/hmg/ddq085

APA

Gersting, S. W., Lagler, F. B., Eichinger, A., Kemter, K. F., Danecka, M. K., Messing, D. D., Staudigl, M., Domdey, K. A., Zsifkovits, C., Fingerhut, R., Glossmann, H., Roscher, A. A., & Muntau, A. C. (2010). Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. HUM MOL GENET, 19(10), 2039-49. https://doi.org/10.1093/hmg/ddq085

Vancouver

Gersting SW, Lagler FB, Eichinger A, Kemter KF, Danecka MK, Messing DD et al. Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. HUM MOL GENET. 2010 Mai 15;19(10):2039-49. https://doi.org/10.1093/hmg/ddq085

Bibtex

@article{aaf48fc76a92416bae77945c39470c5f,
title = "Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo",
abstract = "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.",
keywords = "Amino Acid Substitution, Animals, Biopterin, COS Cells, Cercopithecus aethiops, Disease Models, Animal, Humans, Hydroxylation, Kinetics, Mice, Molecular Chaperones, Mutation, Phenylalanine, Phenylalanine Hydroxylase, Protein Folding, Protein Processing, Post-Translational, Protein Structure, Quaternary",
author = "Gersting, {S{\o}ren W} and Lagler, {Florian B} and Anna Eichinger and Kemter, {Kristina F} and Danecka, {Marta K} and Messing, {Dunja D} and Michael Staudigl and Domdey, {Katharina A} and Clemens Zsifkovits and Ralph Fingerhut and Hartmut Glossmann and Roscher, {Adelbert A} and Muntau, {Ania C}",
year = "2010",
month = may,
day = "15",
doi = "10.1093/hmg/ddq085",
language = "English",
volume = "19",
pages = "2039--49",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "10",

}

RIS

TY - JOUR

T1 - Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo

AU - Gersting, Søren W

AU - Lagler, Florian B

AU - Eichinger, Anna

AU - Kemter, Kristina F

AU - Danecka, Marta K

AU - Messing, Dunja D

AU - Staudigl, Michael

AU - Domdey, Katharina A

AU - Zsifkovits, Clemens

AU - Fingerhut, Ralph

AU - Glossmann, Hartmut

AU - Roscher, Adelbert A

AU - Muntau, Ania C

PY - 2010/5/15

Y1 - 2010/5/15

N2 - 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.

AB - 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.

KW - Amino Acid Substitution

KW - Animals

KW - Biopterin

KW - COS Cells

KW - Cercopithecus aethiops

KW - Disease Models, Animal

KW - Humans

KW - Hydroxylation

KW - Kinetics

KW - Mice

KW - Molecular Chaperones

KW - Mutation

KW - Phenylalanine

KW - Phenylalanine Hydroxylase

KW - Protein Folding

KW - Protein Processing, Post-Translational

KW - Protein Structure, Quaternary

U2 - 10.1093/hmg/ddq085

DO - 10.1093/hmg/ddq085

M3 - SCORING: Journal article

C2 - 20179079

VL - 19

SP - 2039

EP - 2049

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 10

ER -