Thymidine-cytosine deaminase

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

H. Corban-Wllhelm, W.E. Hull, G. Becker, U. Bauder-Wust, D. Greullch, J. Debus, Cytosine deaminase and thymidine kinase gene therapy In a dunning rat prostate... 

Abbreviations not defined in text GCV, ganciclovir, ACV, acyclovir CPA, cyclophosphamide IFA, ifosfamide ThdPase, thymidine phosphorylase dFUr, 5 -deoxy-5-fluorouridine CK, deoxycytidine kinase ara-C, cytosine arabinoside CD, cytosine deaminase 5-FC, 5-fluorocytosine gpt, guanine phosphoribosyl transferase 6TX, 6-thioxanthine CB 1954, 5(-aziridine-l-yl)-2,4-dinitrobenzamide 5-FU, 6-fluorouracil MTX, methotrexate TMTX, trimetrexate Pgp, P-gylcoprotein AAG, 3-methyladenine DNA glycosylase Topo 1, topoisomerase I Topo 11, topoisomerase 11 ADH, aldehyde dehydrogenase BR, ribonucleotide reductase. 

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. 

FIG. 6.13 Mammalian pyrimidine salvage and interconversion pathways. Enzymes listed in Figs 6.13-6.17 are as follows (1) deoxyCMP deaminase (2) thymidylate synthase (3) ribonucleotide reductase (4) deoxyuridine triphosphatase (5) CTP synthetase (6) nucleotide kinase (7) deoxyTMP kinase (8) nucleotide diphosphokinase (9) non-specific phosphatase or nucleotidase (10) cytidine kinase (11) pyrimidine phos-phorylase or hydrolase (12) uracil PRTase (13) cytidine deaminase (14) thymidine kinase (15) cytidine phosphotransferase (16) uridine phosphotransferase (17) thymidine phosphotransferase (18) deoxyribo-nucleotide phosphotransferase (19) cytosine PRTase. 

On the other hand, the most potent among these in the cytosine series are DMDC (3a) and FDMDC (3b), the cytotoxicities of which are comparable to that of SMDC (li). It is important to note that FDMDC would act as a 5-fluorocytosine derivative but not as a 5-fluorouracil derivative via the deamination by cytidine deaminase since DMDC was reported not to be a substrate of cytidine deaminase from mouse kidney.33 The 5-methylcytosine derivative 3f was about 170 times less active than DMDC and FDMDC. The other 5-halogeno- and 5-ethyl derivatives, 3c-e and h, were found to be devoid of the activity. Therefore, it is conceivable that the order of cytotoxicity might be related to the substrate specificity of the first activation enzymes, such as thymidine kinase or deoxycytidine kinase. 

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