Biopterin-dependent aromatic amino acid hydroxylase

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PDB 1mmt EBI.jpg
crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase (Fe(II)) complexed with tetrahydrobiopterin and norleucine
Symbol Biopterin_H
Pfam PF00351
InterPro IPR019774
SCOP 1toh
CDD cd00361

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

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[edit]

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.


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.


  1. ^ Grenett HE, Ledley FD, Reed LL, Woo SL (August 1987). "Full-length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases". Proc. Natl. Acad. Sci. U.S.A. 84 (16): 5530–4. PMC 298896Freely accessible. PMID 3475690. doi:10.1073/pnas.84.16.5530. 
  2. ^ Erlandsen H, Fusetti F, Martinez A, Hough E, Flatmark T, Stevens RC (December 1997). "Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria". Nat. Struct. Biol. 4 (12): 995–1000. PMID 9406548. doi:10.1038/nsb1297-995. 
  3. ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. PMID 19948186. doi:10.1016/j.pharmthera.2009.11.005. 
  4. ^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. PMID 15860375. doi:10.1016/ 
  5. ^ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. PMID 24374199. doi:10.1016/j.ejphar.2013.12.025. The highest level of brain CYP2D activity was found in the substantia nigra ... The in vitro and in vivo studies have shown the contribution of the alternative CYP2D-mediated dopamine synthesis to the concentration of this neurotransmitter although the classic biosynthetic route to dopamine from tyrosine is active. ... Tyramine levels are especially high in the basal ganglia and limbic system, which are thought to be related to individual behavior and emotion (Yu et al., 2003c). ... Rat CYP2D isoforms (2D2/2D4/2D18) are less efficient than human CYP2D6 for the generation of dopamine from p-tyramine. The Km values of the CYP2D isoforms are as follows: CYP2D6 (87–121 μm) ≈ CYP2D2 ≈ CYP2D18 > CYP2D4 (256 μm) for m-tyramine and CYP2D4 (433 μm) > CYP2D2 ≈ CYP2D6 > CYP2D18 (688 μm) for p-tyramine 

This article incorporates text from the public domain Pfam and InterPro IPR019774