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.