Hydroxylase

Function

Hydroxylases are enzymes which add an hydroxyl group to organic compounds. This addition is the first step of aerobic oxidative degradation.

Aromatic amino acid hydroxylases consists of phenylalanine hydroxylase, tyrosine hydroxylase and tryptophan hydroxylase. These enzymes all contain iron and use BH₄ as a co-substrate in the hydroxylation of their respective aromatic amino acids. Additionally all mammalian AAAH form homotetramers and each monomer consists of three domains. These domains are the N-terminal regulatory domain (100-150 residues), the catalytic domain (approximately 315 residues) and the C-terminal tetramerization domain (approximately 30-40 residues)^[1].

Phenylalanine hydroxylase (PAH) is found in the liver where it catalyses the hydroxylation of phenylalanine to tyrosine. This is the first step in the oxidative degradation of phenylalanine^[2]. Mutations in PAH leading to a decrease in enzyme activity result in the disease phenylketonuria, where phenylalanine is converted to phenylpyruvate. Phenylpyruvate is toxic and leads to mental retardation. PAH is also found in some bacteria, but only PAH from the bacteria Chromobacterium violaceum^[3] and Colwellia psychrerythraea^[4] have been characterized. The bacterial PAHs are monomeric and do not contain a regulatory domain. All the aromatic amino acid hydroxylases are believed to have evolved from common ancestor containing only the catalytic domain^[5].

Tyrosine hydroxylase (TH) is found in the brain and in the adrenal gland where it catalyses the conversion of tyrosine to 3,4-dihydroxyphenylalanine (DOPA)^[6]. This is the first and rate limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine and epinephrine (see scheme).

Tryptophan hydroxylase (TPH) (tryptophan 5-monooxygenase, EC 1.14.16.4) catalyses the reaction between tryptophan, 5,6,7,8-tetrahydrobiopterin (BH₄) and O₂ to give 5-hydroxytryptophan and 4a-hydroxy-tetrahydrobiopterin^[7][8].

This reaction is the first and rate limiting step in the biosynthesis of serotonin (See scheme).

Together with phenylalanine hydroxylase (EC 1.14.16.1) and tyrosine hydroxylase (EC 1.14.16.2), TPH form the small enzyme family of aromatic amino acid hydroxylases (AAAH). These enzymes all contain iron and use BH₄ as a co-substrate in the hydroxylation of their respective aromatic amino acids. Additionally all mammalian AAAH form homotetramers and each monomer consists of three domains. These domains are the N-terminal regulatory domain (100-150 residues), the catalytic domain (approximately 315 residues) and the C-terminal tetramerization domain (approximately 30-40 residues). For more details see Tryptophan hydroxylase 1 with bound tryptophan. TPH exists in two isoforms called TPH isoform 1 (TPH1) and TPH isoform 2 (TPH2)^[9]. The existence of two isoforms was observed when TPH was purified and characterised from different tissues. The gene encoding for rabbit TPH1 was identified in 1987 by Grenett et al.^[10] and a few years later the human gene for TPH1 was identified on chromosome 11 ^[11]. The gene for isoform 2 was identified in 2003 by Walther et al. and the human gene is located on chromosome 12 ^[12]. The two isoforms are expressed in different tissues. TPH2 is mainly expressed in serotonergic neurons of the brain and gut ^[13]. TPH1 is expressed in other parts of the body such as the pineal gland ^[13], skin cells ^[14], mast cells^[7], intestinal mucosa and enterochromafin cells ^[15] and in cancer cells ^[16]. The main difference between the two isoforms is that the N-terminal is extended by 46 residues in TPH2^[9].

Disease

Phenylalanine hydroxylase mutations result in intolerance to the dietary intake of phenylalanine and produces phenylketonuria disorders^[17].

Deficiency in tyrosine hydroxylase has been observed in dopa responsive dystonia and juvenile parkinsonism. A reduced 3,4-dihydroxyphenylalanine production is also observed in Parkinson’s disease^[18].