On the metabolism of phenylalanine and tyrosine.

The metabolism of phenylalanine and tyrosine has been the subject of investigation for many years. Much evidence has been produced to show that in mammalian tissue phenylalanine is converted to tyrosine (l-5). Tyrosine can be oxidized to p-hydroxyphenylpyruvic acid, which can in turn form homogentisic acid (5-13). Embden, Salomon, and Schmidt (14) showed that phenylalanine, tyrosine, and homogentisic acid yield acetoacetic acid when perfused through a surviving liver. It has long been known that these amino acids have ketogenic activity in tivo (15-17). Recently, Winnick, Friedberg, and Greenberg (18) and Weinhouse and Millington (19) working with C14-p-labeled DLand L-tyrosine, respectively, showed that tyrosine is at least in part converted to acetoacetic acid in the rat and in rat liver slices. Radioactive acetoacetic acid was isolated after feeding the rat p-labeled nn-tyrosine and after incubating rat liver slices with p-labeled n-tyrosine. Schepartz and Gurin (20) incubated Cl4 ringlabeled nn-phenylalanine with rat liver slices and showed for the first time that carbon atoms from the benzene ring are incorporated into acetoacetic acid. These workers also proved that if homogentisic acid is formed from phenylalanine the carbon side chain must shift on the benzene ring. Weinhouse and Millington (19) and Schepartz and Gurin (20) concluded from the unequal distribution of isotopic carbon in the acetyl and acetate fractions of acetoacetate that ketone bodies are formed as intact 4-carbon units in the metabolism of phenylalanine and tyrosine. We considered it desirable to obtain additional evidence for this belief and to determine the nature of substances other than ketone bodies which might arise from the metabolism of the aromatic nucleus of these amino acids. To this end labeled optically active phenylalanine was synthesized with Cl4 in the benzene ring and Cl3 in the a-carbon atom. Labeled, optically active tyrosine with Cl4 in the p position was also used. The results of a study of the metabolism of these labeled amino acids in rat liver slices, summarized in Diagram 1, indicate that phenylalanine and tyrosine are metabolized to ketone bodies and malic acid (or its precursor). The experimental evidence for these findings is given in this paper.