Human Phenylalanine Hydroxylase

1
Human Phenylalanine Hydroxylase

• Shannon Phan
• BCMB8010

2
History

• Asbjørn Folling ,1934 Siblings with severe
  mental disabilities excrete phenylpyruvic acid in
  their urine
• Disorder termed phenylpyruvic oligophrenia, but
  later changed to phenylketonuria by Lionel
  Penrose
• George Jervis, 1953 Patients with
  phenylketonuria (PKU) have decreased hepatic
  phenylalanine hydroxylase (PheOH) activity and
  elevated L-phenylalanine levels in the blood
• Seymour Kaufman, 1963 PheOH requires BH4 as a
  cofactor
• Savio L.C. Woo, 1983 Isolated and cloned cDNA of
  human phenylalanine hydroxylase from chromosome
  12

3
Function

• PheOH is one of three pterin-dependent amino acid
  hydroxylases. (Tyrosine hydroxylase and
  tryptophan hydroxylase are the two others.)
• Catalyzes the conversion of L-phenylalanine to
  L-tyrosine via hydroxylation of the aromatic ring
• Expressed in both the liver and the kidney
• Found in a wide range of organisms, from
  Chromobacterium violaceum to humans.

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Reaction Catalyzed by PheOH
5
Structure
6
Structure
Dimeric Form
Tetrameric Form PDB ID 2PAH
PDB ID 2PAH
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Catalytic Site
Top-down view of PheOH complexed with BH4 and
3-(2-Thienyl)-L-alanine (THA) PDB ID 1KW0
Interactions between active site residues and THA
PDB ID 1KW0
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Biological Aspects

• PheOH functional deficiency leads to
  hyperphenylalaninemia (HPA)
• PKU Severe, impaired neural development
• Non-PKU HPA Mild symptoms
• Most cases caused by mutations in the PAH gene
• 2 of cases caused by mutations in genes
  associated with BH4 synthesis
• Accumulation of L-phenylalanine and its
  metabolites in the blood leads to neurotoxicity
  and impaired cognitive development
• Abnormal branching of dendritic spines and neuron
  myelination
• Treatment Dietary restriction, BH4
  supplementation (some cases)

9
References

• Chemical Stuctures were created using ChemBioDraw
  Ultra 12. All images were created with Pymol and
  Microsoft PowerPoint using PDB ID 2PAH (Fusetti
  et al., 1998), 1PHZ (Kobe et al., 1999), and 1KW0
  (Anderson et al., 2002)
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