Increased synthesis of carbamoyl-phosphate synthase II (EC 6.3.5.5) in hepatoma 3924A

Carbamoyl-phosphate synthase II (glutamine-hydrolyzing) (EC 6.3.5.5) (synthase II) is the first and rate-limiting enzyme in the de novo UTP biosynthetic pathway. Leucine pulse-labeling in the rat demonstrated that in the rapidly proliferating hepatoma 3924A the ratio of radioactivity of synthase II to that of total cytosolic protein was 168.2 +/- 11.0 (SE) X 10(-3). This synthetic rate for the tumor enzyme was 9.7-fold higher than that for the liver synthase II, 17.4 +/- 4.0 X 10(-3). Since the degradation rate for hepatoma 3924A enzyme (t1/2 = 65.5 h) was similar to the rate for liver synthase II (t1/2 = 69.3 h), the increase in tumor synthase II activity and amount was due primarily to an elevation in enzyme synthesis in the presence of an unaltered catabolic rate. The results indicate that the reprogramming of gene expression in the hepatoma entails an increased production rate of the rate-limiting enzyme of UTP synthesis. This increase in the activity, concentration, and synthesis of tumor synthase II should provide a heightened capacity for the de novo pyrimidine biosynthetic pathway, thus conferring a selective advantage to the cancer cells.