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Recombinant human (liver) phenylalanine hydroxylase (PheOH, phenylalanine 4-monooxygenase, EC is reported to exist in solution as a pH-dependent equilibrium between homotetramers and homodimers (Martinez et al,34). The molecular weight of one subunit is approximately 50 kDa (between 50 and 53 kDa). It has an absolute requirement for ferrous iron to be active, and uses the cofactors BH4 and O2 to perform the hydroxylation reaction. PheOH, like the two other aromatic amino acid hydroxylases tyrosine hydroxylase (TyrOH, tyrosine 3-monooxygenase, EC and tryptophan hydroxylase (TrpOH, tryptophan 5-monooxygenase, EC, consists of three domains: the regulatory domain (residues 1-142), the catalytic domain (residues 143-410), and a short tetramerization domain (residues 411-452).

Due to problems in crystallizing the full-length version of human PheOH, no structure of an intact tetramer (full-length PheOH) exists. However, based on the crystal structures of several truncated forms of PheOH, including the regulatory/catalytic domains (Kobe et al,37) and catalytic/tetramerization domains (Fusetti et al,19), a full-length composite model can be constructed by superimposing the respective catalytic domains.(Figs. 100-1 and 100-2; Table 1).

Fig. 100-1

Bar graph showing the truncations made in PheOH in order to form crystals. The figure contains information about the oligomeric state of the protein along with the resolution of the crystal structures.

Fig. 100-2

Animation of the composite model of phenylalanine hydroxylase. The regulatory domain (residues 19-142) is colored orange, the catalytic domain (residues 143-410) is colored gray, and the tetramerization domain is colored blue. The active site iron is shown as a yellow sphere.

Table 1:Crystal Structures of Phenylalanine Hydroxylase Solved to Date


Truncated dimeric rat PheOH (ΔCOOH 429) in both phosphorylated and dephosphorylated forms was expressed in insect cells and crystallized; the structure was refined to 2.2 Â and 2.6 ...

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