Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD protein)

Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD protein) is a large, multifunctional enzyme that catalyzes the first three committed steps of de novo pyrimidine biosynthesis, producing precursors of uridine monophosphate (UMP)[1][3][6][8]. CAD assembles as a hexamer comprised of a 243 kDa polypeptide subdivided into four major functional domains: glutaminase, carbamoyl-phosphate synthetase II (CPS II), aspartate transcarbamylase (ATC), and dihydroorotase (DHO)[1][2][3]. It plays an essential role in nucleotide metabolism, cell growth, and proliferation, and is regulated by both metabolic feedback (UTP) and growth-factor signaling networks[6]. Pathological mutations in CAD can cause severe developmental and neurological disorders[3], and the enzyme is a validated therapeutic target for certain cancer types due to its requirement for cell proliferation[2][4]. The most studied CAD-targeting drug is PALA, though clinical use is limited; further investigation into pyrimidine biosynthesis inhibitors is ongoing for oncology and rare metabolic indications.

Other names

Carbamoyl phosphate synthetase 2-aspartate transcarbamylase-dihydroorotaseMultifunctional protein CADPYR1_HUMAN (UniProtKB Entry Name)CAD

Inhibitors block pyrimidine nucleotide synthesis, arresting cell growth and proliferation (e.g., PALA acts as a transition-state analog for ATCase activity within CAD)[2][4]. Feedback inhibitors such as uridine triphosphate (UTP) regulate CAD enzymatic activity in cells[1].