Uridine-cytidine kinase

Uridine-cytidine kinase is an important enzyme in pyrimidine nucleotide biosynthesis through the salvage pathway. In addition, this enzyme is also responsible for the 5 -phosphorylation of pyrimidine nucleoside analogs used 

Inhibitors of uridine-cytidine kinase were explored in the 1980s, but there has been little or no recent activity in this field. 

Although no recent activity has been reported in this field, it remains possible that more potent inhibitors of this enzyme have potential applications as anticancer therapeutics. It is also possible that the combination of salvage uridine-cytidine monophosphate synthesis inhibitors with inhibitors of de novo uridine-cytidine monophosphate synthesis (such as PALA or pyrazofurin) may result in more efficacious cancer therapeutics. 

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An important difference between the two compounds is that azacytidine (2) incorporates into RNA, while decitabine (1) acts on DNA. Within cells, decitabine (1) is phosphorylated by deoxycytidine kinase, and after conversion to decitabine triphosphate, it is incorporated into DNA in place of deoxycytidine triphosphate. Azacitidine (2) is phosphorylated by uridine-cytidine kinase and eventually incorporated into RNA, inhibiting the processing of ribosomal RNA and ultimately protein synthesis. Azacitidine (2) can also inhibit DNMTs when azacytidine diphophate is reduced to decitabine diphosphate, which is further phosporylated by kinases to dcitabine triphosphate and incorporated into DNA. Because of the inefficiency of these extra steps, the hypomethylating potency of 2 is believed to be one fifth to one tenth that of l.6-8... 

Thus, uridine-cytidine kinase converts uridine and cytidine to UMP and CMP, respectively thymidine kinase converts thymidine to dTMP and adenosine kinase converts adenosine to AMP. Specific kinases convert monophospho-nucleotides to dinucleotides using ATP as a phosphate donor. The conversion of diphosphonucleotides to triphosphonucleotides is carried out by a nonspecific nucleoside diphosphate kinase. This includes both the ribo- and deoxy-ribonucleotides. Cytosine and its nucleoside and nucleotide transformations are often associated with the metabolism of uracil and its nucleosides and nucleotides. Note that UTP can give rise to CTP (Figure 10.9), and also that, in the presence of cytidine deaminase, cytidine can be converted to uridine. 

We will discuss small molecule inhibitors of three main classes of nonprotein kinases sugar kinases, nucleoside kinases and lipid kinases. This chapter will be limited to discussion of the inhibition of human kinases. Several non-human non-protein kinases have been the focus of drug development efforts as well, including choline kinase for inhibition of Plasmodium, uridine-cytidine kinase as an anti-parasitic target and thymidine kinase inhibitors as an anti-mycobacterial treatment or for treatment of Herpes simplex viral infections. These applications will not be discussed in this chapter. Peptide... 

Figure 6.2 Uridine-cytidine kinase substrate and inhibitors.

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Two routes are known by which the free base, uracU, can enter the ribonucleotide pool. One proceeds by the sequential actions of uridine phosphorylase and uridine-cytidine kinase (reactions 5 and 6, Fig. 12-1) this route is discussed below. The other route is by way of a single-step phosphoribosyltransferase reaction specific for uracil (reaction 4, Fig. 12-1) ... 

Uridine-cytidine kinase from a rat hepatoma has been partly purified this enzyme will accept several nucleoside triphosphates as substrates and appears to be subject to allosteric inhibition by CTP and UTP (21). 

ATP uridine 5 -phospho-transferase Uridine-cytidine kinase... 

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