STRUCTURE OF TETRAMERIC HUMAN PHENYLALANINE-HYDROXYLASE AND ITS IMPLICATIONS FOR PHENYLKETONURIA

Phenylalanine hydroxylase (PheOH) catalyzes the conversion of L-phenyl alanine to L-tyrosine, the rate-limiting step in the oxidative degrada tion of phenylalanine. Mutations in the human PheOH gene cause phenylk etonuria, a common autosomal recessive metabolic disorder that in untr eated patients often results in varying degrees of mental retardation. We have determined the crystal structure of human PheOH (residues 118 -452), The enzyme crystallizes as a tetramer with each monomer consist ing of a catalytic and a tetramerization domain. The tetramerization d omain is characterized by the presence of a domain swapping arm that i nteracts with the other monomers forming an antiparallel coiled-coil. The structure is the first report of a tetrameric PheOH and displays a n overall architecture similar to that of the functionally related tyr osine hydroxylase. In contrast to the tyrosine hydroxylase tetramer st ructure, a very pronounced asymmetry is observed in the phenylalanine hydroxylase, caused by the occurrence of two alternate conformations i n the hinge region that leads to the coiled-coil helix. Examination of the mutations causing PKU shows that some of the most frequent mutati ons are located at the interface of the catalytic and tetramerization domains. Their effects on the structural and cellular stability of the enzyme are discussed.