Aspartate transcarbamylase domain of CAD (ATC)

The aspartate transcarbamylase (ATC) domain is one of three enzymatic components of the multifunctional CAD protein, which catalyzes the first three steps of de novo pyrimidine biosynthesis in eukaryotes [1]. Specifically, the ATC domain facilitates the condensation of carbamoyl phosphate and L-aspartate to form N-carbamoyl-L-aspartate [1]. Because pyrimidines are essential for DNA and RNA synthesis, this domain is a critical regulator of cell proliferation and is frequently upregulated in various cancers to meet the high demand for nucleotides [2]. Historically, the ATC domain has been targeted by the transition-state analog PALA (N-phosphonacetyl-L-aspartate), which showed potent inhibitory activity in preclinical models [2]. However, clinical utility has been limited by toxicity and the emergence of resistance mechanisms such as CAD gene amplification [2]. Beyond oncology, mutations in the CAD gene leading to ATC dysfunction are associated with rare congenital disorders of glycosylation and early-onset epileptic encephalopathy, which can sometimes be managed with uridine supplementation [3]. [1] UniProt (P27708); [2] PubMed (PMID: 8162570); [3] PubMed (PMID: 25533961).

Other names

Aspartate carbamoyltransferaseATCaseCAD proteinCarbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase

Competitive inhibition of the aspartate transcarbamylase activity as a transition-state analog