Pyrimidine Cytosine deaminases

Many yeasts are inhibited by 5-fluorocytosine and a block in the synthesis of 5-fluorouridylic acid by loss of cytosine deaminase or of nracil phosphoribosyltransferase is sufficient to cause resistance. Mntational loss of pyrimidine salvage enzymes has been frequently observed. 

The deaminase domains are members of the cytosine deaminase superfamily. They bind catalytically essential Zn ions through complexation by one histidine and two cysteine residues. The reductase domains are members of the dihydrofolate reductase superfamily. In fact, the reactions catalyzed by pyrimidine reductase and dihydrofolate reductase are closely similar. Early in vivo work had shown that the hydride ion is incorporated into the 1 position. ... 

Phosphodiesterases, phosphatases, 5 -nucleotidases, 3 -nucleotidases and phosphotransferases have been discussed in the section on purine breakdown. Some of these enzymes also act on pyrimidine nucleotides, yielding either the nucleoside or the free base. Cytosine deaminases have been found in yeast and E. coli. Cyti-dine and cytidylic acid deaminases are present in extract of most mammalian tissue. The properties of these enzymes are still poorly understood. 

After administration of 50 mg/kg, drug serum levels are depleted in an apparently haphazard fashion in relation to body size. The monkey and man metabolize the drug at a rate greater than any other species studied. However, in this instance there is a reasonable explanation for this deviation. Cytosine arabinoside is metabolized to uracil arabinoside under control of a pyrimidine nucleoside deaminase. The enzyme has a unique distribution in tissues and animal... 

S90). In these studies, it appeared that cytosine and 5-methylcytosine were deaminated to uracil and thymine, respectively, before further catabolism (896), which was in accord with earlier results on the degradation of aminopyrimidines in bacteria (S9S-S96), Even thou cell-free extracts were imable to oxidize cytosine, intact bacteria did metabolize the amino-pyrimidine to m acil, which was in turn oxidized (391). Apparently these bacterial extracts did not contain cytosine deaminase. However, cytosine deaminase has been foimd in yeast cells as well as in cell-free extracts and intact cells of E. coli (396,397). 

Resistance to purine and pyrimidine antimetabolites, such as adenosine arabinoside and cytosine arabinoside. by neoplastic cells that produce deaminases has stimulated a search... 

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. 

The obligatory biosynthetic role of the enzyme is evident in pyrimidine auxotrophs of bacteria which have an absolute requirement for cytidine [124,125]. The requirement is due to the genetic loss of the CTP synthetase and is manifested only when cytidine is allowed to remain intact by other mutations which deplete both cytidine deaminase and phosphorylase. Such mutants provide a unique system where two separate and noninterconvertible channels are maintained for the independent flow of cytosine and uracil metabolites. They have been used to study the origins and feedback regulation of the intracellular nucleotide pools independently derived from either cytidine or uracil [125,126]. 

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