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PROSITE documentation PDOC00316

Tetrahydrobiopterin-dependent aromatic amino acid hydroxylase family signature and profile





Description

Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes: the aromatic amino acid hydroxylase [1]. These enzymes are structurally and functionally similar. The eukaryotic forms include a regulatory N-terminal domain, a catalytic domain and a C-terminal oligomerization motif. The eukaryotic enzymes are all homotetramers [2,3].

Three-dimensional structures have been determined for the three types of enzymes (see for example <PDB:1J8U>). The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function [4].

Enzymes that belong to the aromatic amino acid hydroxylase family are listed below:

  • Phenylalanine-4-hydroxylase (EC 1.14.16.1) (PAH). Catalyzes the conversion of phenylalanine to tyrosine. In humans, deficiencies [5] of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum [6], PAH is copper- dependent; it is iron-dependent in Pseudomonas aeruginosa [7].
  • Tyrosine 3-hydroxylase (EC 1.14.16.2) (TYH). Catalyzes the rate limiting step in catecholamine biosynthesis: the conversion of tyrosine to 3,4- dihydroxy-L-phenylalanine.
  • Tryptophan 5-hydroxylase (EC 1.14.16.4) (TRH). Catalyzes the rate-limiting step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy- anthranilate.

As a signature pattern for this family, we selected a conserved region in the central part of these enzymes, which contains two conserved histidines that are involved in the binding to iron. The profile we developed contains the catalytic domain and the coiled-coil C-terminal oligomerization motif.

PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html --------------------------------------------------------------------------------.

Last update:

February 2010 / Text revised; profile added.

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Technical section

PROSITE methods (with tools and information) covered by this documentation:

BH4_AAA_HYDROXYL_2, PS51410; Biopterin-dependent aromatic amino acid hydroxylase family profile  (MATRIX)

BH4_AAA_HYDROXYL_1, PS00367; Biopterin-dependent aromatic amino acid hydroxylases signature  (PATTERN)


References

1AuthorsGrenett H.E. Ledley F.D. Reed L.L. Woo S.L.C.
TitleFull-length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases.
SourceProc. Natl. Acad. Sci. U.S.A. 84:5530-5534(1987).
PubMed ID3475690

2AuthorsFitzpatrick P.F.
TitleMechanism of aromatic amino acid hydroxylation.
SourceBiochemistry 42:14083-14091(2003).
PubMed ID14640675
DOI10.1021/bi035656u

3AuthorsTeigen K. Dao K.K. McKinney J.A. Gorren A.C. Mayer B. Froystein N.A. Haavik J. Martinez A.
TitleTetrahydrobiopterin binding to aromatic amino acid hydroxylases. Ligand recognition and specificity.
SourceJ. Med. Chem. 47:5962-5971(2004).
PubMed ID15537351
DOI10.1021/jm0497646

4AuthorsAndersen O.A. Flatmark T. Hough E.
TitleHigh resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin.
SourceJ. Mol. Biol. 314:279-291(2001).
PubMed ID11718561
DOI10.1006/jmbi.2001.5061

5AuthorsHoang L. Byck S. Prevost L. Scriver C.R.
TitlePAH Mutation Analysis Consortium Database: a database for disease-producing and other allelic variation at the human PAH locus.
SourceNucleic Acids Res. 24:127-131(1996).
PubMed ID8594560

6AuthorsOnishi A. Liotta L.J. Benkovic S.J.
TitleCloning and expression of Chromobacterium violaceum phenylalanine hydroxylase in Escherichia coli and comparison of amino acid sequence with mammalian aromatic amino acid hydroxylases.
SourceJ. Biol. Chem. 266:18454-18459(1991).
PubMed ID1655752

7AuthorsZhao G.S. Xia T. Song J. Jensen R.A.
TitlePseudomonas aeruginosa possesses homologues of mammalian phenylalanine hydroxylase and 4 alpha-carbinolamine dehydratase/DCoH as part of a three-component gene cluster.
SourceProc. Natl. Acad. Sci. U.S.A. 91:1366-1370(1994).
PubMed ID8108417



PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see prosite_license.html.

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