Biopterin-dependent aromatic amino acid hydroxylase

Biopterin-dependent aromatic amino acid hydroxylases (AAAH) are a family of aromatic amino acid hydroxylase enzymes which includes phenylalanine 4-hydroxylase (EC 1.14.16.1), tyrosine 3-hydroxylase (EC 1.14.16.2), and tryptophan 5-hydroxylase (EC 1.14.16.4). These enzymes primarily hydroxylate the amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, respectively.

Biopterin_H
crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase (Fe(II)) complexed with tetrahydrobiopterin and norleucine
Identifiers
Symbol	Biopterin_H
Pfam	PF00351
InterPro	IPR019774
PROSITE	PDOC00316
SCOP2	1toh / SCOPe / SUPFAM
CDD	cd00361
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

The AAAH enzymes are functionally and structurally related proteins which act as rate-limiting catalysts for important metabolic pathways.^[1] Each AAAH enzyme contains iron and catalyzes the ring hydroxylation of aromatic amino acids using tetrahydrobiopterin (BH4) as a substrate. The AAAH enzymes are regulated by phosphorylation at serines in their N-termini.

Role in metabolism

In humans, phenylalanine hydroxylase deficiency can cause phenylketonuria, the most common inborn error of amino acid metabolism.^[2] Phenylalanine hydroxylase catalyzes the conversion of L-phenylalanine to L-tyrosine. Tyrosine hydroxylase catalyzes the rate-limiting step in catecholamine biosynthesis: the conversion of L-tyrosine to L-DOPA. Similarly, tryptophan hydroxylase catalyzes the rate-limiting step in serotonin biosynthesis: the conversion of L-tryptophan to 5-hydroxy-L-tryptophan.

Biosynthetic pathways for catecholamines and trace amines in the human brain[3][4][5] L-Phenylalanine L-Tyrosine L-DOPA Epinephrine Phenethylamine p-Tyramine Dopamine Norepinephrine N-Methylphenethylamine N-Methyltyramine p-Octopamine Synephrine 3-Methoxytyramine AADC AADC AADC primary pathway PNMT PNMT PNMT PNMT AAAH AAAH brain CYP2D6 minor pathway COMT DBH DBH In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.

Structure

It has been suggested that the AAAH enzymes each contain a conserved C-terminal catalytic (C) domain and an unrelated N-terminal regulatory (R) domain. It is possible that the R protein domains arose from genes that were recruited from different sources to combine with the common gene for the catalytic core. Thus, by combining with the same C domain, the proteins acquired the unique regulatory properties of the separate R domains.