This chapter describes the aromatic L‐amino acids tryptophan and tyrosine and the effects on tyrosine metabolism of phenylalanine. Tryptophan and phenylalanine are essential amino acids and must ultimately be derived from dietary proteins; tyrosine is obtained both from dietary proteins and from the hydroxylation of phenylalanine by phenylalanine hydroxylase (PAH). The proportions of dietary tr...

Phosphorylation of phenylalanine hydroxylase (PAH) at Ser by cyclic AMP-dependent protein kinase is a post-translational modification that increases its basal activity and facilitates its activation by the substrate L-Phe. So far there is no structural information on the flexible N-terminal tail (residues 1–18), including the phosphorylation site. To get further insight into the molecular basis...

Phenylketonuria (PKU) is an autosomal recessive genetic disorder in which mutations in the phenylalanine-4-hydroxylase (PAH) gene result in an inactive enzyme (PAH, EC 1.14.16.1). The effect is an inability to metabolize phenylalanine (Phe), translating into elevated levels of Phe in the bloodstream (hyperphenylalaninemia). If therapy is not implemented at birth, mental retardation can occur. P...

Use of tetrahydrobiopterin for treatment of patients with phenylketonuria (PKU) is a ‘‘hot topic” among patients and doctors taking care of them. An increasing number of publications are describing decreases in blood phenylalanine (Phe) concentrations in persons receiving tetrahydrobiopterin. From the practical point of view, however, data on the extent of tetrahydrobiopterin responsiveness are...

Liver phenylalanine hydroxylase is allosterically activated by phenylalanine. The structural changes that accompany activation have not been identified, but recent studies of the effects of phenylalanine on the isolated regulatory domain of the enzyme support a model in which phenylalanine binding promotes regulatory domain dimerization. Such a model predicts that compounds that stabilize the r...

A method was developed to study the unsupplemented phenylalanine hydroxylase system in rat liver slices. All of the components of the system--tetrahydrobiopterin, dihydropteridine reductase, and the hydroxylase itself--are present under conditions which should be representative of the actual physiological state of the animal. The properties of the system in liver slices have been compared to th...

Four members spanning three generations of one family have phenylketonuria of varying degrees of severity. Two first cousins were screened in the neonatal period and have had dietary phenylalanine restriction since diagnosis, the older patient having been classified as having more severe PKU and the younger one as having mild PKU. Their mutual grandfather and his older brother also have a signi...

Reversible phosphorylation is the major mechanism underlying the short-term hormonal control of phenylalanine hydroxylase activity in the liver. We report here, for the first time, the impact of a range of hormonal effectors on both the phosphorylation state and enzymic activity of phenylalanine hydroxylase present in isolated rat proximal kidney tubules. The most potent stimulator of enzyme ph...

A monoclonal antibody directed against monkey liver phenylalanine hydroxylase was produced by using a rat-myeloma--rat-spleen-cell-fusion system. This antibody showed the interesting property of increasing mammalian phenylalanine hydroxylase activity more than 2-fold. Perhaps monoclonal antibodies with this effect on other enzyme or proteins could be developed.