Enzymology of the Phenylalanine-Hydroxylating System

Abstract

The phenylalanine-hydroxylating system consists of 3 essential components, phenylalanine hydroxylase (PAH), dihydropteridine reductase (DHPR) and the coenzyme, tetrahydrobiopterin (BH(4)). DHPR and BH(4) are also essential components of the tyrosineand tryptophan-hydroxylating systems. During the hydroxylation reaction, BH(4) is converted to the quinonoid dihydrobiopterin. The reduction of this latter compound back to BH4 is catalyzed by the reductase in the presence of NADH. In addition to the classic form of phenylketonuria, which is caused by a lack of PAH, a form is caused by a lack of DHPR and another by a deficiency of BH(4) caused by the lack of an enzyme involved in its de novo biosynthesis. Besides hyperphenylalaninemia, these variant forms are characterized by neurological deterioration.

Genetics of Phenylketonuria: Then and Now

“…BH 4 acts as a cofactor for PAH in the hydroxylation of Phe to tyrosine, emerging from the reaction as 4a-hydroxy BH 4 and a recycling pathway involving two enzymes restores BH 4 via a qinonoid dihydrobiopterin intermediate [Kaufman, 1987;Blau et al, 2010;Werner, et al, 2011;Heintz et al, 2013]. BH 4 is also a cofactor for other amino acid hydroxylases, notably those present in the synthetic pathways of monoamine neurotransmitters [Werner et al, 2011].…”

Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency

“…BH 4 is the natural cofactor for phenylalanine (Phe), tyrosine, and tryptophan hydroxylase as well as for all three forms of nitric oxide synthase [29,34] (Fig. 1).…”

Sepiapterin Treatment in Atherosclerosis

“…The function of BH 4 in these aromatic amino acid hydroxylases involves redox-active donation of electrons and reductive enzyme activation and is associated with a tightly coupled system for regeneration of BH 4 from the oxidized dihydrobiopterin. 8,10 See page 1655In addition to its role in the biosynthesis of monoamine neurotransmitters, BH 4 serves as an essential cofactor in all isoforms of nitric oxide synthases (NOS), with the Km for BH 4 for NOS several orders of magnitude lower than for the aromatic amino acid hydroxylases: NOS, Ϸ0.3 mol/L vs Ϸ3 mol/L for phenylalanine hydroxylase, Ϸ30 mol/L for tyrosine hydroxylase and tryptophan hydroxylase, suggesting tight coupling of the cofactor with enzyme. 8 However, the precise function(s) of BH 4 in NOS enzymatic activity is not as well defined as in the aromatic amino acid hydroxylase enzymes and may vary according to enzyme isoform.…”

“…The function of BH 4 in these aromatic amino acid hydroxylases involves redox-active donation of electrons and reductive enzyme activation and is associated with a tightly coupled system for regeneration of BH 4 from the oxidized dihydrobiopterin. 8,10 See page 1655…”