Pyrimidine synthesis enzyme (CAD)

Pyrimidine synthesis enzymes are a group of proteins involved in the de novo biosynthesis of pyrimidine nucleotides (such as UMP, UDP, UTP, and CTP). In mammals, the first three steps are catalyzed by a single trifunctional, cytoplasmic enzyme known as CAD, which includes carbamoyl phosphate synthetase II, aspartate transcarbamoylase, and dihydroorotase. Subsequent reactions are catalyzed by dihydroorotate dehydrogenase (DHODH; mitochondrial) and uridine monophosphate synthase (UMPS; cytoplasmic). These enzymes are tightly regulated by feedback inhibition of end-products such as UTP and UDP, and their activity is critical for cell proliferation and protein synthesis. Dysregulation or inhibition of these enzymes is associated with cancer, autoimmune disorders, and rare inborn errors of metabolism. Drugs targeting DHODH are approved for rheumatoid arthritis and multiple sclerosis, and are in development for oncology indications. In summary, the term “Pyrimidine synthesis enzyme” is not sufficiently specific for canonical use—CAD, DHODH, or UMPS are more accurate depending on the context. These enzymes are validated therapeutic targets with significant biological and clinical roles.

Other names

Pyrimidine biosynthetic enzymeCAD (Carbamoyl-phosphate synthetase II/aspartate transcarbamoylase/dihydroorotase)Carbamoyl-phosphate synthetase IIDihydroorotate dehydrogenase (DHODH)Uridine monophosphate synthase (UMPS)

Inhibition of pyrimidine biosynthesis, reducing cellular nucleotide pools and impairing DNA/RNA synthesis, which limits cell proliferation (especially immune or tumor cells)