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, Jahrgang 27, Nr. 10, 15.05.2018, S. 1732-1742.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -