{PDOC00316}
{PS00367; BH4_AAA_HYDROXYL_1}
{PS51410; BH4_AAA_HYDROXYL_2}
{BEGIN}
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* Tetrahydrobiopterin-dependent aromatic amino acid hydroxylase family signature and profile *
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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.

-Consensus pattern: P-D-x(2)-H-[DE]-[LIVF]-[LIVMFY]-G-H-[LIVMC]-[PA]
                    [The 2 H's are iron or copper ligands]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: February 2010 / Text revised; profile added.

[ 1] Grenett H.E., Ledley F.D., Reed L.L., Woo S.L.C.
     "Full-length cDNA for rabbit tryptophan hydroxylase: functional
     domains and evolution of aromatic amino acid hydroxylases."
     Proc. Natl. Acad. Sci. U.S.A. 84:5530-5534(1987).
     PubMed=3475690
[ 2] Fitzpatrick P.F.
     "Mechanism of aromatic amino acid hydroxylation."
     Biochemistry 42:14083-14091(2003).
     PubMed=14640675; DOI=10.1021/bi035656u
[ 3] Teigen K., Dao K.K., McKinney J.A., Gorren A.C., Mayer B.,
     Froystein N.A., Haavik J., Martinez A.
     "Tetrahydrobiopterin binding to aromatic amino acid hydroxylases.
     Ligand recognition and specificity."
     J. Med. Chem. 47:5962-5971(2004).
     PubMed=15537351; DOI=10.1021/jm0497646
[ 4] Andersen O.A., Flatmark T., Hough E.
     "High resolution crystal structures of the catalytic domain of human
     phenylalanine hydroxylase in its catalytically active Fe(II) form and
     binary complex with tetrahydrobiopterin."
     J. Mol. Biol. 314:279-291(2001).
     PubMed=11718561; DOI=10.1006/jmbi.2001.5061
[ 5] Hoang L., Byck S., Prevost L., Scriver C.R.
     "PAH Mutation Analysis Consortium Database: a database for
     disease-producing and other allelic variation at the human PAH
     locus."
     Nucleic Acids Res. 24:127-131(1996).
     PubMed=8594560
[ 6] Onishi A., Liotta L.J., Benkovic S.J.
     "Cloning and expression of Chromobacterium violaceum phenylalanine
     hydroxylase in Escherichia coli and comparison of amino acid sequence
     with mammalian aromatic amino acid hydroxylases."
     J. Biol. Chem. 266:18454-18459(1991).
     PubMed=1655752
[ 7] Zhao G.S., Xia T., Song J., Jensen R.A.
     "Pseudomonas aeruginosa possesses homologues of mammalian
     phenylalanine hydroxylase and 4 alpha-carbinolamine dehydratase/DCoH
     as part of a three-component gene cluster."
     Proc. Natl. Acad. Sci. U.S.A. 91:1366-1370(1994).
     PubMed=8108417

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