Regulatory properties of phenylalanine, tyrosine and tryptophan hydroxylases.

I have previously discussed the idea that the three pterindependent enzymes, phenylalanine (EC 1.14.16. I ) , tyrosine (EC 1.14.16.2) and tryptophan hydroxylase (EC 1.14.16.4), constitute a family of enzymes whose individual members share many properties, both physical and catalytic (Kaufman, 1974). This notion has predictive value since there have been many instances where the discovery of a regulatory property for one of the enzymes, often first with phenylalanine hydroxylase, has led to the expectation that this property will be shared by the others, an expectation that frequently has been realized. The general Characteristics of this group of enzymes were first established from studies carried out with hepatic phenylalanine hydroxylase. The feature which distinguishes them from other enzymes, of course, is that they all require a naturally occurring unconjugated pterin. After showing that the hydroxylating system is complex, consisting of at least two essential enzymes and a non-protein cofactor, we isolated the cofactor from rat liver extracts on the basis of its ability to stimulate the conversion of phenylalanine to tyrosine in the presence of the two enzymes (Kaufman, 1958; Kaufman & Levenberg, 1959), and proved that it is the reduced form of the unconjugated pterin, 2-amino4hydroxy -6-[ 1,2-dihydroxypropyI(L-erythro)pteridine] (Kaufman, 1963), whose trivial name is biopterin ('pterin'is the name for a 2-amino-4-hydroxypteridine). The structure for tetrahydrobiopterin (BH,), the active form of the coenzyme, is shown in Fig. I . Although biopterin had been isolated previously from human urine (Patterson et al., 1956), its function, if any, in mammals was obscure. The demonstration that BH, is an essential component of the phenylalanine-hydroxylating system established the first metabolic role for any unconjugated pterin and the first coenzyme role for BH,. In addition to the naturally occurring coenzyme, several synthetic tetrahydropterins, such as 6-methyltetrahydropterin (6-MPH,) and 6,7-dimethyltetrahydropterin (DMPH,), were shown to be active with the phenylalaninehydroxylating system (Kaufman, 1959; Kaufman & Levenberg, 1959), both of these synthetic compounds being considerably more active with unactivated rat liver phenylalanine hydroxylase (Kaufman & Levenberg, 1959; Kaufman, 1970) and human liver phenylalanine hydroxylase (Kaufman, 1969; Friedman et al., 1973) than is BH,. The other essential components of the phenylalanine-