Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine

American Journal of Human Genetics
T GjettingF Güttler

Abstract

Hyperphenylalaninemia due to a deficiency of phenylalanine hydroxylase (PAH) is an autosomal recessive disorder caused by >400 mutations in the PAH gene. Recent work has suggested that the majority of PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation. In this study, we describe an alternative mechanism by which some PAH mutations may render PAH defective. Database searches were used to identify regions in the N-terminal domain of PAH with homology to the regulatory domain of prephenate dehydratase (PDH), the rate-limiting enzyme in the bacterial phenylalanine biosynthesis pathway. Naturally occurring N-terminal PAH mutations are distributed in a nonrandom pattern and cluster within residues 46-48 (GAL) and 65-69 (IESRP), two motifs highly conserved in PDH. To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wild-type and five mutant (G46S, A47V, T63P/H64N, I65T, and R68S) forms of the N-terminal domain (residues 2-120) of human PAH were expressed as fusion proteins in Escherichia coli. Binding studies showed that the wild-type form of this domain specifically binds phenylalanine, whereas all mutations abolished...Continue Reading

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Citations

Jul 19, 2013·European Biophysics Journal : EBJ·Judith A RonauChittaranjan Das
Mar 28, 2008·Amino Acids·Jessica Siltberg-Liberles, Aurora Martinez
Jul 18, 2009·Journal of Inherited Metabolic Disease·U LangenbeckUNKNOWN German Collaborative Study on Phenylketonuria (PKU) / Hyperphenylalaninemia (HPA)
Nov 19, 2013·PloS One·Carla CarluccioAdriana Zagari
Nov 8, 2006·Journal of Nutritional Science and Vitaminology·Keiko Tazuya-MurayamaKazuko Yamada
Sep 6, 2008·Journal of Clinical Monitoring and Computing·Shaomin Yan, Guang Wu
Mar 5, 2013·IUBMB Life·Marte I Flydal, Aurora Martinez
Oct 20, 2015·Journal of Biomolecular Structure & Dynamics·Carla CarluccioAdriana Zagari
Jun 25, 2017·Molecular Genetics and Metabolism·Eileen K Jaffe
Mar 26, 2003·Human Mutation·Charles R ScriverChristineh Sarkissian
Jan 30, 2016·The Journal of Biological Chemistry·Shengnan Zhang, Paul F Fitzpatrick
Mar 26, 2003·Biochemistry·Matthías ThórólfssonAurora Martínez
May 11, 2021·Journal of Biomolecular Structure & Dynamics·Tolga AslanNecla Birgul Iyison
May 31, 2017·Chemical Reviews·Steve P MeisburgerNozomi Ando
Oct 19, 2010·Archives of Biochemistry and Biophysics·Jun LiPaul F Fitzpatrick

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