The early steps of pyrimidine biosynthesis are catalyzed by the enzymes carbamoyl phosphate synthetase (CPSase), aspartate transcarbamoylase (ATCase), and dihydroorotase (DHOase), which are commonly expressed separately and either function independently or associate into multifunctional complexes (Figure 1). In mammals, the enzymes are expressed as a single polypeptide chain (CAD) in the order CPS-DHO-ATC and associate into a hexamer [1,2]. The three-dimensional structure of the noncovalent oligomer of DHOase and ATCase from the Aquifex aeolicus organism shows three active site loops that are disordered in the free, inactive fonn, and are ordered in the complex [3]. In this project, a peptide was designed and synthesized to mimic the contact interface between the Aquifex aeolicus DHOase and ATCase domains, aimed at disrupting their physical association and/or functional interaction. A decrease in activity of this enzyme complex would result in a reduction in the rate of de novo pyrimidine biosynthesis, diminishing the precursors for DNA in proliferating cells.
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