Aspartate carbamoyltransferase domain of Carbamoyl-phosphate synthetase 2, Aspartate transcarbamylase, and Dihydroorotase (CAD) (CAD)

The CAD protein is a massive multifunctional enzyme in eukaryotes that initiates the de novo biosynthesis of pyrimidine nucleotides (UniProt: P27708). It contains three enzymatic activities: carbamoyl-phosphate synthetase II, aspartate transcarbamylase (ATCase), and dihydroorotase. The aspartate carbamoyltransferase domain specifically catalyzes the second step of this pathway, which is the condensation of L-aspartate and carbamoyl phosphate to produce N-carbamoyl-L-aspartate (PubMed: 28614298). This process is essential for the production of UMP, which serves as a precursor for all other pyrimidines required for DNA and RNA synthesis. Because of its central role in cell proliferation, CAD is frequently upregulated in various cancers to support rapid tumor growth (PubMed: 31434695). The ATCase domain is a well-characterized drug target, most notably inhibited by N-(phosphonacetyl)-L-aspartate (PALA), a transition-state analog that mimics the reaction intermediate (PubChem: CID 439531). Although PALA demonstrated potent enzymatic inhibition, its clinical utility has been limited by systemic toxicities and the ability of cells to utilize the pyrimidine salvage pathway (PubMed: 11437351).

Other names

Aspartate transcarbamylaseATCaseAspartate carbamoyltransferaseMultifunctional protein CADCarbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase

Competitive inhibition of the aspartate carbamoyltransferase domain by transition-state analogs like PALA, which mimics the reaction intermediate to block the conversion of carbamoyl phosphate and aspartate to N-carbamoyl-L-aspartate (PubMed: 11437351).