End product control of amino acid synthesis by cultured human cells.

In bacteria, the end product of a number of biosynthetic pathways has been found to act as a metabolic control to limit further synthesis, either by repressing enzyme formation (l-3) or by inhibiting enzyme activity (“negative feedback”) (4-6). Several examples of enzyme repression in cultured mammalian cells have been reported, including the synthesis of glutamine from glutamic acid (7), of arginine from citrulline (8), of purines from glycine (9, lo), of proline from glutamic acid (ll), and of carbamyl aspartate as the first step in pyrimidine synthesis (12). End product inhibition of pyrimidine synthesis has been reported in extracts of ascites tumor cells (13), and of purine synthesis in cultured mouse cells (9, 14). The data to be reported here show that the prior growth of human cells in the presence of serine and glycine similarly represses their following synthesis from glucose, and that the presence of preformed glycine and proline inhibits their continuing synthesis from glucose and glutamine, respectively. The addition of preformed amino acid in relatively high concentration to human cell cultures did not, however, reduce the synthesis de novo of serine or alanine from glucose, of glycine from serine, of proline from ornithine, or of ornithine from arginine. Similarly, preformed cystine, cystathionine, or homocystine did not inhibit their synthesis from methionine. Finally, except in the case of serine and glycine synthesis from glucose, prior growth of human cells for several generations in the presence or absence of preformed amino acids usually failed to affect the rate of their subsequent synthesis.