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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Eichinger A,Danecka MK,Möglich T,Borsch J,Woidy M,Büttner L,Muntau AC,Gersting SWdoi
10.1093/hmg/ddy079subject
Has Abstractpub_date
2018-05-15 00:00:00pages
1732-1742issue
10eissn
0964-6906issn
1460-2083pii
4921283journal_volume
27pub_type
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