Regulation of rat liver carbamyl phosphate synthetase I. Inhibition by metal ions and activation by amino acids and other chelating agents.

Homogeneous rat liver carbamyl phosphate synthetase I is activated by ornithine and other amino acids. A strong correlation is observed between the ability of each amino acid to chelate heavy metal ions and to activate carbamyl phosphate synthetase I. The enzyme is also activated by the chelating agents ethylenediaminetetraacetic acid, 8-hydroxyquinoline, and o-phenanthroline. The thiols cysteine, dithiothreitol, and glutathione also activate the enzyme, apparently by chelating inhibitory metal ion(s). Experiments carried out under essentially metal ion-free conditions have established directly that micromolar concentrations Of Zn2+, Cu2+, and Cd2+ inhibit carbamyl phosphate synthetase I. Previous in vivo studies have shown that carbamyl phosphate synthetase I is rapidly activated by the addition of ornithine. The present in vitro findings, as well as the previous in vivo findings, suggest a regulatory scheme for carbamyl phosphate synthetase I in which (a) the enzyme is inhibited by physiological levels of heavy metal ions and (b) this inhibition can be relieved by the addition of ornithine or other amino acids.