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The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response

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The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. / Staudigl, Michael; Gersting, Søren W; Danecka, Marta K; Messing, Dunja D; Woidy, Mathias; Pinkas, Daniel; Kemter, Kristina F; Blau, Nenad; Muntau, Ania C.

In: HUM MOL GENET, Vol. 20, No. 13, 01.07.2011, p. 2628-41.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Staudigl, M, Gersting, SW, Danecka, MK, Messing, DD, Woidy, M, Pinkas, D, Kemter, KF, Blau, N & Muntau, AC 2011, 'The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response', HUM MOL GENET, vol. 20, no. 13, pp. 2628-41. https://doi.org/10.1093/hmg/ddr165

APA

Staudigl, M., Gersting, S. W., Danecka, M. K., Messing, D. D., Woidy, M., Pinkas, D., Kemter, K. F., Blau, N., & Muntau, A. C. (2011). The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. HUM MOL GENET, 20(13), 2628-41. https://doi.org/10.1093/hmg/ddr165

Vancouver

Staudigl M, Gersting SW, Danecka MK, Messing DD, Woidy M, Pinkas D et al. The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. HUM MOL GENET. 2011 Jul 1;20(13):2628-41. https://doi.org/10.1093/hmg/ddr165

Bibtex

@article{6f2ba9448d0c40e28a83141ccc9129ca,
title = "The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response",
abstract = "The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4)-responsive PAH deficiency.",
keywords = "Biopterin, Coenzymes, Enzyme Activation, Genotype, HEK293 Cells, Humans, Kinetics, Molecular Chaperones, Mutation, Phenylalanine, Phenylalanine Hydroxylase, Phenylketonurias",
author = "Michael Staudigl and Gersting, {S{\o}ren W} and Danecka, {Marta K} and Messing, {Dunja D} and Mathias Woidy and Daniel Pinkas and Kemter, {Kristina F} and Nenad Blau and Muntau, {Ania C}",
year = "2011",
month = jul,
day = "1",
doi = "10.1093/hmg/ddr165",
language = "English",
volume = "20",
pages = "2628--41",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "13",

}

RIS

TY - JOUR

T1 - The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response

AU - Staudigl, Michael

AU - Gersting, Søren W

AU - Danecka, Marta K

AU - Messing, Dunja D

AU - Woidy, Mathias

AU - Pinkas, Daniel

AU - Kemter, Kristina F

AU - Blau, Nenad

AU - Muntau, Ania C

PY - 2011/7/1

Y1 - 2011/7/1

N2 - The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4)-responsive PAH deficiency.

AB - The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4)-responsive PAH deficiency.

KW - Biopterin

KW - Coenzymes

KW - Enzyme Activation

KW - Genotype

KW - HEK293 Cells

KW - Humans

KW - Kinetics

KW - Molecular Chaperones

KW - Mutation

KW - Phenylalanine

KW - Phenylalanine Hydroxylase

KW - Phenylketonurias

U2 - 10.1093/hmg/ddr165

DO - 10.1093/hmg/ddr165

M3 - SCORING: Journal article

C2 - 21527427

VL - 20

SP - 2628

EP - 2641

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 13

ER -