Iphenylalanine Metabolism and Folic Acid

Amethopterin and related folic antagonists inhibit the reduction of folic acid to tetrahydro folic acid (2). The clinical effects of these drugs are thought to be related in turn to the role of tetrahydro folic acid in single-carbon transfer reactions during nucleic acid synthesis (3). Recently, pteridines such as folic acid have been implicated in another area of metabolism, the conversion of phenylalanine to tyrosine. In this conversion the pteridine is thought to act as a cofactor which is reduced in a separate enzymatic reaction, then takes part in the actual hydroxylation of phenylalanine. The reaction sequence as it is currently deduced from studies in vitro is presented in Figure 1. Enzymatic activities corresponding to phenylalanine hydroxylase ("rat enzyme") and the cofactor-reducing enzyme ("sheep enzyme"), as well as the cofactor itself, have been observed in normal human liver (4). It has been shown that folic acid antagonists such as amethopterin inhibit tyrosine synthesis in a partially purified enzyme system, and in vivo in the rat (5). The site of inhibition is believed to be the enzymatic reduction of the pteridine cofactor. The work reported here is an investigation of the effects of amethopterin on phenylalanine metabolism in man, and the possible relevance of this effect to the clinical properties of folic antagonists. Experiments were also performed on rodents to explore the possible interrelationship of folic acid metabolism, phenylalanine metabolism, and cancer chemotherapy.