描述
Pyrimidines are heterocyclic aromatic organic compounds similar to benzene and pyridine. Cytosine, thymine, and uracil are pyrimidine derivatives. Synthesis of the pyrimidines is less complex than that of the purines, since the base is much simpler This pathway depicts a number of processes including pyrimidine nucleotide biosynthesis, pyrimidine degradation and pyrimidine salvage. Pyrimidine nucleotide biosynthesis begins with carbamoyl phosphate. The carbamoyl phosphate used for pyrimidine nucleotide synthesis is derived from glutamine and bicarbonate and is catalyzed by carbamoyl phosphate synthetase II (CPS-II). Subsequently carbamoyl phosphate is incorporated into the pyrimidine nucleotide biosynthesis pathway through the action of aspartate transcarbamoylase, ATCase which generates carbamoyl aspartate. This is then converted to dihydroorotic acid via carbamoyl aspartate dehydrogenase, which is then converted to orotic acid via dihydroorotate dehydrogenase. The enzyme orotate phosphoribosyltransferase incorporate PRPP to produce orotidine monophosphate (OMP) which is converted to UMP (uridine monopohophsate) via orotidine-5’-phosphate carboxylase. Following completion of UMP synthesis it can be phosphorylated to UTP and utilized as a substrate for CTP synthase for the synthesis of CTP. Specifically, UMP is phosphorylated twice to yield UTP. The first phosphorylation is catalyzed by uridylate kinase and the second by ubiquitous nucleoside diphosphate kinase. Finally UTP is aminated by the action of CTP synthase, generating CTP. Uridine nucleotides are also the precursors for de novo synthesis of the thymine nucleotides. The de novo pathway to thymidine nucleotdie synthesis first requires the use of deoxyUMP from the metabolism of either UDP or CDP. The deoxyUMP is converted to deoxyTMP by the action of thymidylate synthase. The methyl group is donated by N5,N10-methylene THF. In order for the thymidylate synthase reaction to continue, THF must be regenerated from DHF. This is accomplished through the action of dihydrofolate reductase (DHFR). THF is then converted to N5,N10-THF via the action of serine hydroxymethyl transferase. The synthesis of pyrimidines differs in two significant ways from that of purines. First, the ring structure is assembled as a free base, not built upon PRPP. Second, there is no branch in the pyrimidine synthesis pathway. The salvage pathway to dTTP synthesis involves the enzyme thymidine kinase which can use either thymidine or deoxyuridine as a substrate. Uracil can be salvaged to form UMP through the concerted action of uridine phosphorylase and uridine kinase. Formation of dTMP, by salvage of dTMP requires the action of thymine phosphorylase and thymidine kinase while the salvage of deoxycytidine is catalyzed by deoxycytidine kinase. Deoxyadenosine and deoxyguanosine are also substrates for deoxycytidine kinase. In terms of the catabolism of pyrimidines, they are ultimately degraded to CO2, H2O, and urea. Cytosine can be broken down to uracil which can be further broken down to N-carbamoyl-beta-alanine and then to beta-alanine. Thymine is broken down into β-aminoisobutyrate. The β-alanine and β-aminoisobutyrate serve as -NH2 donors in the transamination of α-ketoglutarate to glutamate. A subsequent reaction converts the products to malonyl-CoA or methylmalonyl-CoA (which is converted to succinyl-CoA and can be shunted to the TCA cycle).