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Review
. 2015 Dec:35:1-6.
doi: 10.1016/j.sbi.2015.07.004. Epub 2015 Jul 31.

Structural insights into the regulation of aromatic amino acid hydroxylation

Paul F Fitzpatrick  1
Affiliations
Review

Structural insights into the regulation of aromatic amino acid hydroxylation

Paul F Fitzpatrick. Curr Opin Struct Biol. 2015 Dec.

Abstract

The aromatic amino acid hydroxylases phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase are homotetramers, with each subunit containing a homologous catalytic domain and a divergent regulatory domain. The solution structure of the regulatory domain of tyrosine hydroxylase establishes that it contains a core ACT domain similar to that in phenylalanine hydroxylase. The isolated regulatory domain of tyrosine hydroxylase forms a stable dimer, while that of phenylalanine hydroxylase undergoes a monomer-dimer equilibrium, with phenylalanine stabilizing the dimer. These solution properties are consistent with the regulatory mechanisms of the two enzymes, in that phenylalanine hydroxylase is activated by phenylalanine binding to an allosteric site, while tyrosine hydroxylase is regulated by binding of catecholamines in the active site.

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Figures

Figure 1
Figure 1
The reactions catalyzed by the aromatic amino acid hydroxylases phenylalanine hydroxylase (PheH), tyrosine hydroxylase (TyrH), and tryptophan hydroxylase (TrpH).
Figure 2
Figure 2
A, sequence alignments of the regulatory domains of human PheH, TyrH, and TrpH. The alignment of PheH and TyrH is based on the structures while the alignments of TrpH1 and TrpH2 are sequence-based. Residues conserved in all are in blue and residues conserved only in PheH, TrpH1, and TrpH2 are in red; B, overlay of the structures of the catalytic domains of human PheH (PDB file 1pah, red), TyrH (PDB file 2xsn, green) and TrpH1 (PDB file 1mlw, blue); C, overlay of the structures of the regulatory domains of rat PheH (blue, PDB file 2phm, residues 32-117) and rat TyrH (orange, PDB file 2mda, residues 75-159); D, overlay of the structures of the regulatory domain dimer of rat TyrH (blue, PDB file 2mda) and the ACT regulatory domain dimer of E. coli glyceraldehyde-3-phosphate dehydrogenase (green, PDB file 1psd).
Figure 2
Figure 2
A, sequence alignments of the regulatory domains of human PheH, TyrH, and TrpH. The alignment of PheH and TyrH is based on the structures while the alignments of TrpH1 and TrpH2 are sequence-based. Residues conserved in all are in blue and residues conserved only in PheH, TrpH1, and TrpH2 are in red; B, overlay of the structures of the catalytic domains of human PheH (PDB file 1pah, red), TyrH (PDB file 2xsn, green) and TrpH1 (PDB file 1mlw, blue); C, overlay of the structures of the regulatory domains of rat PheH (blue, PDB file 2phm, residues 32-117) and rat TyrH (orange, PDB file 2mda, residues 75-159); D, overlay of the structures of the regulatory domain dimer of rat TyrH (blue, PDB file 2mda) and the ACT regulatory domain dimer of E. coli glyceraldehyde-3-phosphate dehydrogenase (green, PDB file 1psd).
Figure 2
Figure 2
A, sequence alignments of the regulatory domains of human PheH, TyrH, and TrpH. The alignment of PheH and TyrH is based on the structures while the alignments of TrpH1 and TrpH2 are sequence-based. Residues conserved in all are in blue and residues conserved only in PheH, TrpH1, and TrpH2 are in red; B, overlay of the structures of the catalytic domains of human PheH (PDB file 1pah, red), TyrH (PDB file 2xsn, green) and TrpH1 (PDB file 1mlw, blue); C, overlay of the structures of the regulatory domains of rat PheH (blue, PDB file 2phm, residues 32-117) and rat TyrH (orange, PDB file 2mda, residues 75-159); D, overlay of the structures of the regulatory domain dimer of rat TyrH (blue, PDB file 2mda) and the ACT regulatory domain dimer of E. coli glyceraldehyde-3-phosphate dehydrogenase (green, PDB file 1psd).
Figure 2
Figure 2
A, sequence alignments of the regulatory domains of human PheH, TyrH, and TrpH. The alignment of PheH and TyrH is based on the structures while the alignments of TrpH1 and TrpH2 are sequence-based. Residues conserved in all are in blue and residues conserved only in PheH, TrpH1, and TrpH2 are in red; B, overlay of the structures of the catalytic domains of human PheH (PDB file 1pah, red), TyrH (PDB file 2xsn, green) and TrpH1 (PDB file 1mlw, blue); C, overlay of the structures of the regulatory domains of rat PheH (blue, PDB file 2phm, residues 32-117) and rat TyrH (orange, PDB file 2mda, residues 75-159); D, overlay of the structures of the regulatory domain dimer of rat TyrH (blue, PDB file 2mda) and the ACT regulatory domain dimer of E. coli glyceraldehyde-3-phosphate dehydrogenase (green, PDB file 1psd).
Figure 3
Figure 3
A, structure of the combined regulatory (red) and catalytic (cyan) domains of rat PheH (PDB file 2phm); B, model of the intact PheH tetramer, constructed from PDB files 2phm and 2pah; C, model of the structure of intact rat TyrH constructed from the separate structures of the catalytic and regulatory domains (PDB files 1toh and 2mda). In each, the regulatory domains are in red, the catalytic domains in cyan, and the tetramerization domains in blue.
Figure 3
Figure 3
A, structure of the combined regulatory (red) and catalytic (cyan) domains of rat PheH (PDB file 2phm); B, model of the intact PheH tetramer, constructed from PDB files 2phm and 2pah; C, model of the structure of intact rat TyrH constructed from the separate structures of the catalytic and regulatory domains (PDB files 1toh and 2mda). In each, the regulatory domains are in red, the catalytic domains in cyan, and the tetramerization domains in blue.
Figure 3
Figure 3
A, structure of the combined regulatory (red) and catalytic (cyan) domains of rat PheH (PDB file 2phm); B, model of the intact PheH tetramer, constructed from PDB files 2phm and 2pah; C, model of the structure of intact rat TyrH constructed from the separate structures of the catalytic and regulatory domains (PDB files 1toh and 2mda). In each, the regulatory domains are in red, the catalytic domains in cyan, and the tetramerization domains in blue.
Figure 4
Figure 4
The regulatory mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase. For both mechanisms Ea is active enzyme and Ei is inactive enzyme.
See this image and copyright information in PMC

References

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