SUPPLEMENT ARTICLE |
Structural Studies on Phenylalanine Hydroxylase and Implications Toward Understanding and Treating Phenylketonuria
From the Department of Molecular Biology, Scripps Research Institute, La Jolla, California
Mutations in the gene encoding for phenylalanine hydroxylase (PAH) result in phenylketonuria (PKU) or hyperphenylalaninemia (HPA). Several 3-dimensional structures of truncated forms of PAH have been determined in our laboratory and by others, using x-ray crystallographic techniques. These structures have allowed for a detailed mapping of the >250 missense mutations known to cause PKU or HPA found throughout the 3 domains of PAH. This structural information has helped formulate rules that might aid in predicting the likely effects of unclassified or newly discovered PAH mutations. Also, with the aid of recent crystal structure determinations of co-factor and substrate analogs bound at the PAH active site, the recently discovered tetrahydrobiopterin-responsive PKU/HPA genotypes can be mapped onto the PAH structure, providing a molecular basis for this tetrahydrobiopterin response.
Key Words: phenylalanine hydroxylase • 3-dimensional structure • structural basis • phenylketonuria • BH4-responsive hyperphenylalaninemia • co-factor therapy
Abbreviations: PAH, phenylalanine hydroxylase • 
-Phe, -phenylalanine • BH4, tetrahydrobiopterin • PKU, phenylketonuria • HPA, hyperphenylalaninemia • ARS, autoregulatory sequence • CBR, co-factor-binding region
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