Deoxycytidine monophosphate kinase

Zalcitabine enters cells by both carrier-mediated transport and passive diffusion. It is converted to the monophosphate by deoxycytidine kinase and undergoes further phosphorylation by deoxycytidine monophosphate kinase... 

CARNOSINE SYNTHETASE CHAPERONES CHOLINE KINASE CHOLOYL-CoA SYNTHETASE COBALAMIN ADENOSYLTRANSFERASE 4-COUMAROYL-CoA SYNTHETASE CREATINE KINASE CTP SYNTHETASE CYTIDYLATE KINASE 2-DEHYDRO-3-DEOXYGLUCONOKINASE DEHYDROGLUCONOKINASE DEOXYADENOSINE KINASE DEOXYADENYLATE KINASE DEOXYCYTIDINE KINASE (DEOXYjNUCLEOSIDE MONOPHOSPHATE KINASE DEOXYTHYMIDINE KINASE DEPHOSPHO-CoA KINASE DETHIOBIOTIN SYNTHASE DIACYLGLYCEROL KINASE DIHYDROFOLATE SYNTHETASE DNA GYRASES DNA REVERSE GYRASE ETHANOLAMINE KINASE EXONUCLEASE V... 

An enzyme partially purified from yeast acts upon the nucleotides of adenine, guanine, and uridine to carry out transphosphorylation (Eqs. 33) to 36)] 112-116). Nucleoside monophosphate kinases have been partially purified from E. coli, which catalyzes the formation of triphosphates of deoxyadenine, deoxyguanosine, thymidine, and deoxycytidine from their corresponding 5 -monophosphates, in the presence of ATP 116, 117). 

P-D-Arabinofuranosylcytosine [147-94-4] (ara-C, 16), C H N O, reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephaUtis (33), although several negative results have also been reported (34) (Fig. 2). Ara-C, also known as cytarabine, is quite toxic and is only recommended for very severe viral infections. It is rapidly deaminated in humans to the relatively inactive ara-U Ara-C is converted in the cell to the 5 -monophosphate by deoxycytidine kinase, followed by formation of the corresponding di- and triphosphate. The triphosphate has been shown to inhibit DNA polymerase. 

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

Van Rompay, A.R. Johansson, M. Karlsson, A. Phosphorylation of deoxycytidine analog monophosphates by UMP-CMP kinase molecular characterization of the human enzyme. Mol. Pharmacol., 56, 562-569 (1999)... 

Fludarabine phosphate (2-fluoro-arabinofuranosyladenine monophosphate) is rapidly dephosphorylated to 2-fluoro-arabinofuranosyladenine and then phosphorylated intracellularly by deoxycytidine kinase to the triphosphate. This metabolite interferes with DNA synthesis through inhibition of DNA polymerase- and ribonucleotide reductase, and it also induces apoptosis. Fludarabine phosphate is used chiefly in the treatment of low-grade non-Hodgkin s lymphoma and chronic lymphocytic leukemia (CLL). Fludarabine phosphate is given parentally and is excreted primarily in the urine its dose-limiting toxicity is myelosuppression. 

Figure 22.17 shows the complicated de novo and salvage pathways for the synthesis of dTTP. The de novo pathways start at the top with either UDP or CDP and lead to dTTP. The salvage pathways begin with deoxycytidine, deoxyuridine, or deoxythymidine nucleosides, which are each converted to nucleoside monophosphates in the first step by appropriate kinases. 

Nucleoside kinases are a class of enzymes that catalyze the phosphorylation of nucleosides to make nucleoside monophosphates (Figure 22.2) as part of nucleotide biosynthetic salvage pathways. ATP provides the energy and phosphate for the reaction. Example enzymes include thymidine kinase, deoxycytidine kinase, and deoxyguanosine kinase. 

The kinase which converts deoxycytidine to its 5 -monophosphate has been studied most extensively in preparations from calf thymus 35, 36). The preferred substrate is deoxycytidine, for which the Michaelis constant (5 X 10 M) is much lower than that of two other substrates, deoxyadenosine and deoxyguanosine. Cytidine, uridine, and thymidine are not phosphorylated by this enzyme. Deoxycytidine kinase is subject to a complex pattern of allosteric regulation by nucleotides. The end product of deoxycytidine phosphorylation, dCTP, is a potent inhibitor this inhibition is reversed by dTTP. The enzyme has a rather broad specificity for the phosphate donor, with the triphosphates of the natural ribo- and deoxyribonucleosides being substrates the inactivity of dCTP is a notable exception. 

---