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Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism

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Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism. / Eichinger, Anna; Danecka, Marta K; Möglich, Tamara; Borsch, Julia; Woidy, Mathias; Büttner, Lars; Muntau, Ania C; Gersting, Søren W.

In: HUM MOL GENET, Vol. 27, No. 10, 15.05.2018, p. 1732-1742.

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

Harvard

Eichinger, A, Danecka, MK, Möglich, T, Borsch, J, Woidy, M, Büttner, L, Muntau, AC & Gersting, SW 2018, 'Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism', HUM MOL GENET, vol. 27, no. 10, pp. 1732-1742. https://doi.org/10.1093/hmg/ddy079

APA

Eichinger, A., Danecka, M. K., Möglich, T., Borsch, J., Woidy, M., Büttner, L., Muntau, A. C., & Gersting, S. W. (2018). Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism. HUM MOL GENET, 27(10), 1732-1742. https://doi.org/10.1093/hmg/ddy079

Vancouver

Eichinger A, Danecka MK, Möglich T, Borsch J, Woidy M, Büttner L et al. Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism. HUM MOL GENET. 2018 May 15;27(10):1732-1742. https://doi.org/10.1093/hmg/ddy079

Bibtex

@article{6e2af200b0064e18a20c929746b8e601,
title = "Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism",
abstract = "Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH4). Physiologically, phenylalanine availability is governed by nutrient intake, whereas liver BH4 is kept at constant level. In phenylketonuria, PAH deficiency leads to elevated blood phenylalanine and is often caused by PAH protein misfolding with loss of function. Here, we report secondary hepatic BH4 deficiency in Pah-deficient mice. Alterations in de novo synthesis and turnover of BH4 were ruled out as molecular causes. We demonstrate that kinetically instable and aggregation-prone variant Pah proteins trap BH4, shifting the pool of free BH4 towards bound BH4. Interference of PAH protein misfolding with metabolite-based control of l-phenylalanine turnover suggests a mechanistic link between perturbation of protein homeostasis and disturbed regulation of metabolic pathways.",
keywords = "Journal Article",
author = "Anna Eichinger and Danecka, {Marta K} and Tamara M{\"o}glich and Julia Borsch and Mathias Woidy and Lars B{\"u}ttner and Muntau, {Ania C} and Gersting, {S{\o}ren W}",
year = "2018",
month = may,
day = "15",
doi = "10.1093/hmg/ddy079",
language = "English",
volume = "27",
pages = "1732--1742",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "10",

}

RIS

TY - JOUR

T1 - Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism

AU - Eichinger, Anna

AU - Danecka, Marta K

AU - Möglich, Tamara

AU - Borsch, Julia

AU - Woidy, Mathias

AU - Büttner, Lars

AU - Muntau, Ania C

AU - Gersting, Søren W

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH4). Physiologically, phenylalanine availability is governed by nutrient intake, whereas liver BH4 is kept at constant level. In phenylketonuria, PAH deficiency leads to elevated blood phenylalanine and is often caused by PAH protein misfolding with loss of function. Here, we report secondary hepatic BH4 deficiency in Pah-deficient mice. Alterations in de novo synthesis and turnover of BH4 were ruled out as molecular causes. We demonstrate that kinetically instable and aggregation-prone variant Pah proteins trap BH4, shifting the pool of free BH4 towards bound BH4. Interference of PAH protein misfolding with metabolite-based control of l-phenylalanine turnover suggests a mechanistic link between perturbation of protein homeostasis and disturbed regulation of metabolic pathways.

AB - Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH4). Physiologically, phenylalanine availability is governed by nutrient intake, whereas liver BH4 is kept at constant level. In phenylketonuria, PAH deficiency leads to elevated blood phenylalanine and is often caused by PAH protein misfolding with loss of function. Here, we report secondary hepatic BH4 deficiency in Pah-deficient mice. Alterations in de novo synthesis and turnover of BH4 were ruled out as molecular causes. We demonstrate that kinetically instable and aggregation-prone variant Pah proteins trap BH4, shifting the pool of free BH4 towards bound BH4. Interference of PAH protein misfolding with metabolite-based control of l-phenylalanine turnover suggests a mechanistic link between perturbation of protein homeostasis and disturbed regulation of metabolic pathways.

KW - Journal Article

U2 - 10.1093/hmg/ddy079

DO - 10.1093/hmg/ddy079

M3 - SCORING: Journal article

C2 - 29514280

VL - 27

SP - 1732

EP - 1742

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 10

ER -