Cytidine deaminase types

Luo K, Wang T, Liu B, Tian C, XiaoZ, Kappes J, YuXF (2007) Cytidine deaminases APOBEC3G and APOBEC3F interact with human immunodeficiency virus type 1 integrase and inhibit proviral DNA formation. J Virol 81(13) 7238-7248... 

The in vivo metabolism of capecitabine (1) to the active tumor cytotoxic substance 5-fluorouracil (5) is now fairly well understood. When capecitabine is administered orally it is delivered to the small intestine, where it is not a substrate for thymidine phosphorylase in intestinal tissue, and so passes through the intestinal mucosa as an intact molecule and into the bloodstream. When 1 reaches the liver, the carbamate moiety is hydrolyzed through the action of carboxylesterase enzymes, liberating 5 -deoxy-5-fluorocytidine (5 -DFCR, 10). DFUR is partially stable in systemic circulation, but eventually diffuses into tumor cell tissue where it is transformed into 5 -deoxy-5-fluorouridine (5 -DFUR, 9) by cytidine deaminase, an enzyme present in high concentrations in various types of human cancers compared to adjacent healthy cells (although it is present in significantly lower levels in the liver). Within the tumor, 5-... 

To produce larger quantities of Epivir, the 5 -nucleotidase route was inefficient, and other approaches were investigated. One such route considered was the enantioselective deamination of ( )-10 with cytidine deaminase (EC 3-5.4.5) (Figure 3) (57). Because of earlier work with adenosine deaminase to obtain optically pure carbovir at the kilogram scale, we envisaged that the resolution of ( )-10 may also be amenable to fijrther scale-up. However, unlike adenosine deaminase, cytidine deaminase was not commercially available and had not been widely used for preparative transformations. Initially, cytidine deaminase was partially purified by ammonium sulfate fractionation (55-75% saturation) from a clarified cell extract of a wild-type E. coli B. Enzyme (0.3 units) was incubated... 

The chart in Fig. 2 shows an alternate path for the formation of dUMP by direct deamination of dCMP. This may be how cytidine could be converted to thymidylate in the cases cited above [125,126]. However, this deaminase is not usually detected in E. coli but is induced by infection with T(even) phages [132,133]. It has also been purified from chick embryo and mammalian tissues, and its properties have been extensively analyzed [134-136]. It acts as a typical allosteric enzyme in both the phage-infected E. coli and animal systems. Homotropic substrate interaction is evident, and this is modified by dCTP as an activator, and by dTTP (sometimes dGMP) as an allosteric inhibitor. This type of control apparently functions to regulate the level of dTTP by feedback inhibition and by activation when the supply of dTTP is depleted. Cytidine deaminase (EC 3.5.4.5) isolated from sheep liver [137] appears to have the same allosteric properties, with the same positive and negative effectors, as those of dCMP deaminase. The latter enzyme is also induced by phage infection in B. subtiUs, and in contrast to the deaminase from all other sources it does not show allosteric inhibition or activation by any nucleotide [138]. 

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