Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene

Sang Wun Kim, Jongsun Jung, Hyun Jeong Oh, Jihong Kim, Kwang Soo Lee, Dong Hwan Lee, Chan Park, Kuchan Kimm, Soo Kyung Koo, Sung Chul Jung

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Background: Phenylketonuria (PKU) is an inborn error of metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). We demonstrated PAH mutational spectrum from patients with PKU, including 10 novel and 3 tetrahydrobiopterin (BH4)-responsive mutations. In this study, 11 PAH missense mutations, including 6 novel mutations (P69S, G103S, L293M, G332V, S391I, A447P) found in our previous study, 2 mutations common in east Asian patients with PKU (R243Q, R413P), and 3 tetrahydrobiopterin (BH 4)-responsive mutations (R53H, R241C, R408Q) have been functionally and structurally analyzed. Methods: A transient protein overexpression system and an in vitro BH4-responsiveness study were used. The effects of PAH missense mutations on the PAH protein structure were also analyzed. To determine the conservation of 12 mutated residues, PAH was aligned using BLAST against full genomic sequences of 221 different species. Model structures of PAH protein and the composite tetramer were constructed using the software program, SHEBA. Results: No PAH activity was detected for some mutants. However, the residual activities associated with other mutants ranged over a wide spectrum. The missense mutations responsive to BH4 were not highly conserved throughout the 43 species in the multiple sequence alignment that encode PAH. The composite model structure of PAH revealed that dimer stability was reduced in the BH4-responsive mutants, whereas tetramer stability remained normal. Conclusion: This expression study analyzed PAH mutations and model structures of mutant PAH proteins are proposed. Correlation between the proposed mutant PAH structures and functions are suggested.

Original languageEnglish
Pages (from-to)279-287
Number of pages9
JournalClinica Chimica Acta
Issue number1-2
StatePublished - Mar 2006

Bibliographical note

Funding Information:
We thank the members of the Korean PKU family support group for their contribution and cooperation in this research. This study was supported by an intramural research grant from the National Institute of Health, Korea.


  • BH
  • Expression
  • Hyperphenylalaninemia
  • Modeling
  • Mutation
  • PAH
  • PKU
  • Phenylalanine hydroxylase
  • Phenylketonuria
  • Structure
  • Tetrahydrobiopterin


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