De Novo Pyrimidine Nucleotide Metabolism

Figure 22.10 illustrates the pathway for de novo pyrimidine biosynthesis. It differs from de novo purine synthesis in that the pyrimidine ring is synthesized separate from the ribose sugar (in purines, the ring is built upon the sugar - see Figure 22.4). In addition, de novo pyrimidine biosynthesis is not branched. Synthesis leads to UMP, from which CTP is ultimately made. By contrast, de novo purine biosynthesis branches after IMP is produced (Figure 22.6).

The first step in the pathway, formation of carbamoyl aspartate from aspartate and carbamoyl phosphate, is the primary regulatory point in the pathway. The enzyme, aspartate transcarbamoylase (ATCase) (see here), is activated by ATP and inhibited by CTP, which is the end product of the pathway. Another point of regulation is CTP synthetase, which is feedback inhibited by CTP and activated by GTP. In bacteria, synthesis of ATCase subunits is inhibited by high levels of UTP. The inverted regulatory effects of purine and pyrimidines in the pathway are yet another way cells maintain a proper balance of nucleotides.

In eukaryotes, enzymes 1-3 of Figure 22.10 are all part of a single multifunctional polypeptide chain called CAD. In mammals, reactions 5 and 6 are catalyzed by a single protein called UMP synthase.