Multifunctional protein CAD (CAD)

Multifunctional protein CAD is a large, highly conserved multi-domain enzyme responsible for catalyzing the first three rate-limiting steps in the de novo synthesis of pyrimidine nucleotides in animals[1][2][3][6][7]. The CAD polypeptide (~243 kDa, hexameric assembly) physically fuses four enzymatic activities: glutaminase (GATase), carbamoyl-phosphate synthetase II (CPS II), aspartate transcarbamoylase (ATCase), and dihydroorotase (DHOase), allowing efficient channeling of substrates and precise regulation of pyrimidine synthesis[1][2][3][7]. It initiates cytosolic pyrimidine nucleotide biosynthesis by producing carbamoyl phosphate, which is processed through sequential enzymatic reactions to ultimately form dihydroorotate, a precursor for uridine monophosphate (UMP)—an essential building block for DNA and RNA. CAD activity is tightly regulated by feedback from end-product nucleotides and by phosphorylation (including through mTOR and S6 kinase pathways)[1][2][3]. Mutations in CAD cause severe congenital metabolic syndromes (such as congenital disorder of glycosylation, Type Iz), while overexpression or dysregulation can promote tumorigenesis, making CAD a potential (early research stage) therapeutic target in cancer[1][2]. The CAD megaenzyme's unique architecture, regulation, and essential role in metabolism reflect its centrality to both normal biology and disease pathogenesis.

Other names

Carbamoyl-phosphate synthetase 2/aspartate transcarbamylase/dihydroorotaseCAD proteinCarbamoyl-phosphate synthetase 2 (CPS II)Aspartate transcarbamoylase (ATC/ATCase)Dihydroorotase (DHO/DHOase)

Inhibition of CAD leads to suppression of de novo pyrimidine synthesis, resulting in limitation of nucleotide availability, thus decreasing DNA/RNA synthesis in highly proliferative cells such as cancer cells[1][2]. Feedback inhibition by uridine triphosphate (UTP) and uridine monophosphate (UMP); activation by 5-phosphoribosyl-α-pyrophosphate (PRPP)[1][2][3].