Regulation of the activity of hepatic phenylalanine hydroxylase

Abstract

Rat liver phenylalanine hydroxylase catalyzes the tetrahydropterin-dependent oxidation of phenylalanine to tyrosine, according to equation 1. In addition to the naturally-occurring coenzyme, tetrahydrobiopterin (BH4), certain synthetic analogs of BH4 such as 6-methyltetrahydropterin (6MPH4) have high cofactor activity. (formula; see text) The hydroxylase can be activated by a variety of reversible and irreversible modifications, including those caused by partial proteolysis, by interaction with phospholipids such as lysolecithin, by alkylation of a single sulfhydryl group, by phosphorylation catalyzed by cAMP-dependent protein kinase, and by preincubation with its substrate, phenylalanine. All of these modes of activation greatly increase the hydroxylase activity in the presence of BH4, whereas the activity in the presence of 6MPH4 is increased only slightly. The ratio of hydroxylase activity in the presence of BH4 compared to the activity in the presence of 6MPH4, therefore, is a useful index of the state of activation of the enzyme. Of the various activation mechanisms listed above, only phosphorylation of the enzyme and phenylalanine-activation appear to operate in vivo. The evidence indicates that these two regulatory mechanisms act synergistically. Thus, phosphorylation of the enzyme by cAMP-dependent protein kinase is stimulated by phenylalanine, especially in the presence of BH4, (which by itself inhibits), whereas phosphorylation sensitizes the enzyme to activation by phenylalanine. One of the consequences of these interlocking control mechanisms is to enhance the responsiveness of the activity of the hydroxylase to alterations in tissue levels of phenylalanine. As a result, elevated concentrations of phenylalanine can be rapidly metabolized, thereby protecting the fetal and neonatal brain from possible damage by excess phenylalanine.