Cytidine 5 -triphosphate synthase

Scheme 50 Transformation of UTP mediated by cytidine 5 -triphosphate synthase...

Cytidine 5 -triphosphate synthase (CTPS, EC 6.3.4.2) catalyzes the formation of cytidine 5 -triphosphate (CTP) from uridine 5 -triphosphate (UTP), the last committed steps in pyrimidine nucleotide biosynthesis (Scheme 50) [178, 179]. The reaction proceeds by an ATP-dependent phosphorylation and requires ammonia. CTPS is a relevant target in some forms of cancers (i.e. non lymphocytic leukaemia) [180],... 

The production of CTP by amination of UTP. The conversion of the pyrimidine ring of uracil to cytosine occurs at the level of the nucleotide triphosphate. The enzyme responsible for this conversion is known as cytidine triphosphate synthase. 

ADP and inorganic phosphate (fig. 23.14). Both the mammalian and bacterial cytidine triphosphate synthases can use ammonia as a donor in place of glutamine, but this reaction is of no physiological significance because the Km for ammonia is very high and the reaction rate low. 

Mutation of one of the two enzyme activities of UMP synthase leads to orotic aciduria, characterized by accumulation of its first substrate orotic acid and insufficient levels of the product UMP, which reduces availability of uridine triphosphate (UTP) and cytidine triphosphate (CTP) for use in nucleic acid synthesis. 

Molecules with structures as diverse as carbamoyl-phosphate, tryptophan, and cytidine triphosphate are feedback inhibitors of the E. coli glutamine synthase. The feedback inhibition is cumulative, with each metabolite exerting a partial inhibition on the enzyme. Why would complete inhibition of the glutamine synthase by a single metabolite be metaboli-cally unsound ... 

Aspartate carbamyltransferase 2 dihydroorotase 3 orotate reductase 4 orotate phosphoribosyl-transferase 5 orotidine-5 -phosphate decarboxylase 6 cytidylate kinase, nucleotide diphosphate kinase 7 cytidine triphosphate synthetase 8 nucleoside monophosphate kinase, ribonucleoside diphosphate reductase, phosphatase 9 thymidylate synthase... 

The de novo pathway to 2 -deoxythymidine monophosphate (dTMP) synthesis first requires the use of dUMP (2 -deoxyuridine-5 -monophosphate) from the metabolism of either UDP or CDP (cytidine diphosphate). The hydrolysis of dUTP (2 -deoxyuridine-5 -triphosphate) to dUMP and subsequent methylation at C-5 by the action of thymidylate synthase, using A, A i°-methylenetetrahydrofolate (THF) as the methyl donor, generate dTMP (Figure 6.54). The latter is subsequently phosphorylated to deoxy-thymidine triphosphate (dTTP) used in DNA synthesis and repair. 

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