Abstract
CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications.
Highlights
The route of formation of carbamoyl phosphate (CAP) was first discovered in microorganisms in 1955 [1]
We provide an overview of the current understanding of CAD and its critical roles in metabolism, physiological regulation, as well as disease progression
Human CAD involves the concerted action of four domains: glutamine amidotransferase (GATase), carbamylphosphatesynthetase II (CPSIIase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase)
Summary
The route of formation of carbamoyl phosphate (CAP) was first discovered in microorganisms in 1955 [1]. Genetic studies revealed the role of enzymatic synthesis of CAP in the pyrimidine pathway in Neurospora [2,3]. Aspartate transcarbamoylase (ATC) and dihydroorotase (DHO) were subsequently co-purified with CPS-2. These three enzymes form a single multi-enzymatic protein named CAD to participate in the de novo pyrimidine pathway in mammals [7,8]. Over the past two decades, studies from dozens of labs have revealed that CAD takes part in the de novo pyrimidine nucleotide synthesis, and plays a leading role in cellular and organismal physiology in various forms of life [9,10,11,12,13].
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