Carbamoyl-phosphate synthetase 2 (CPS II)

Carbamoyl-phosphate synthetase 2 (CPS II) is a cytosolic enzyme that catalyzes the first and rate-limiting step of the de novo pyrimidine biosynthetic pathway. In mammals, it exists as the N-terminal domain of the trifunctional CAD protein complex, which also possesses aspartate transcarbamylase and dihydroorotase activities. CPS II utilizes glutamine, bicarbonate, and ATP to produce carbamoyl phosphate, a critical precursor for the synthesis of nucleotides such as UTP and CTP. Because rapidly proliferating cancer cells have an elevated demand for nucleotides to support DNA and RNA synthesis, CPS II is frequently upregulated in various malignancies, including hepatocellular carcinoma and breast cancer. Consequently, it has been targeted by inhibitors like PALA and acivicin to deplete pyrimidine pools and induce cell cycle arrest. However, the clinical utility of such inhibitors is often limited by toxicities in healthy, rapidly dividing tissues like the bone marrow and gastrointestinal tract.

Other names

CPS2CPSIICADProtein CADCarbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotaseGATD4CDG1ZEIEE50

Inhibition of the de novo pyrimidine biosynthetic pathway, leading to the depletion of intracellular nucleotide pools and subsequent arrest of DNA and RNA synthesis.