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J Biol Chem, Vol. 273, Issue 27, 16962-16967, July 3, 1998
From the Phenylalanine hydroxylase (PheOH) catalyzes the
conversion of L-phenylalanine to
L-tyrosine, the rate-limiting step in the oxidative
degradation of phenylalanine. Mutations in the human PheOH gene cause
phenylketonuria, a common autosomal recessive metabolic disorder that
in untreated 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 consisting of a catalytic and a tetramerization domain. The
tetramerization domain is characterized by the presence of a domain
swapping arm that interacts with the other monomers forming an
antiparallel coiled-coil. The structure is the first report of a
tetrameric PheOH and displays an overall architecture similar to that
of the functionally related tyrosine hydroxylase. In contrast to the
tyrosine hydroxylase tetramer structure, a very pronounced asymmetry is
observed in the phenylalanine hydroxylase, caused by the occurrence
of two alternate conformations in the hinge region that leads to the
coiled-coil helix. Examination of the mutations causing PKU shows that
some of the most frequent mutations are located at the interface of the
catalytic and tetramerization domains. Their effects on the structural
and cellular stability of the enzyme are discussed.
Structure of Tetrameric Human Phenylalanine Hydroxylase and Its
Implications for Phenylketonuria
,
, and
Department of Chemistry, University of
California and Physical Biosciences Division, Lawrence Berkeley
National Laboratory, Berkeley, California 94720, ¶ Protein
Crystallography Group, Chemistry Department, University of Tromsø,
N-9037 Tromsø, Norway, and Department of Biochemistry and
Molecular Biology, University of Bergen, Årstadveien 19, N-5009
Bergen, Norway
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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