F. Fusetti et al., STRUCTURE OF TETRAMERIC HUMAN PHENYLALANINE-HYDROXYLASE AND ITS IMPLICATIONS FOR PHENYLKETONURIA, The Journal of biological chemistry, 273(27), 1998, pp. 16962-16967
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.