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A Phenylalanine Fiasco: The Structure of Phenylalanine Hydroxylase and its Impact on Phenylketonuria
Author(s) -
Kahn Jenna,
Koh Ally,
Luckcuck Rachel,
McNeice Jules,
Walter Ellie,
Yao Wendy,
Baxley Ann,
Link Tina
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.665.8
Subject(s) - phenylalanine hydroxylase , tetrahydrobiopterin , hyperphenylalaninemia , phenylalanine , tyrosine , chemistry , tyrosine hydroxylase , phenylketonurias , mutation , tetramer , amino acid , biochemistry , enzyme , medicine , gene , cofactor
Phenylketonuria (PKU) is a devastating metabolic disease that is unfortunately common: it affects between 1 in 10,000 and 1 in 15,000 newborns in the United States. This disorder is caused by mutation in the gene for phenylalanine hydroxylase (PheOH), a biopterin‐dependent aromatic amino acid hydroxylase which catalyzes the breakdown of phenylalanine (Phe) into tyrosine (Tyr). Structurally, it comprises a catalytic domain, a regulatory domain in the N‐terminus, and a C‐terminal domain responsible for tetramerization of the monomers. It catalyzes the hydroxylation of Phe to Tyr, which is the rate‐limiting step in the breakdown of phenylalanine. There are over 500 documented mutations on the PheOH gene, but the most common ones disrupt tetramer assembly, increase sensitivity to proteolytic cleavage and aggregation, or remove essential structures such as the C‐terminus. These mutations can cause a buildup of blood Phe, leading to hyperphenylalaninemia (HPA) and PKU. PKU, the most severe form of HPA, is an autosomal recessive disorder characterized by the total or near‐total absence of PheOH. Untreated, PKU causes a buildup of Phe at the blood‐brain barrier, which leads to severe intellectual disabilities in affected individuals. If detected early and treated carefully, people with PKU can lead fairly normal lives; however, any neurological damage already incurred is irreversible. Using x‐ray crystallography, researchers have created models of the structure of PheOH. Understanding the structure of PheOH is essential to developing new therapies to treat PKU. We created a model of PheOH using 3D modeling and printing technology that highlights several of the most common PKU‐causing mutations, located at the juncture between the catalytic and tetramerization domains. Support or Funding Information Walton High School SMART (Students Modeling a Research Topic) Team is sponsored by Milwaukee School of Engineering.