Deaminases, cytidine

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

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... 

Geborek, P., Mansson, B., Hellmer, G. and Saxne, T. (1992). Cytidine deaminase and lactoferrin in inflammatory synovial fluids - indicators of local polymorphonuclear cell function. Br. J. Rheumatol. 31, 235-240. 

Cytidine deaminase Cytidine phosphinamide analogue 8.3 x 103 7.8 x 10"6 25 hours... 

Some of the above mentioned studies also use two-layer ONIOM QM MM approaches to include the full protein in an MM description. Other examples of QM MM calculations of metal enzymes include heme oxygenase [89], nitrate reductase [90] and peptide deformylase [91]. Finally, we note that the ONIOM (I IF Amber) potential energy surface has been directly used in a molecular dynamics study (ONIOM/MD) of cytidine deaminase [92],... 

Asymmetric routes to lamivudine have recently been reviewed. A number of these are biocatalytic, the most elegant of which is a highly enantioselective kinetic resolution process based on the use of cytidine deaminase from E. coli. The process is particularly impressive given that the reaction site is five atoms away from the nearest chiral centre (Scheme 1.38). 

Cytosine arabinoside (araC) is used as an effective chemotherapeutic agent for cancer, although resistance to this drug may eventually develop. In certain cases, resistance is related to an increase in the enzyme cytidine deaminase in the tumor cells. This enzyme would inactivate araC to form... 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

Morgan, H.D., Dean, W., Coker, H.A., Reik, W. and Petersen-Mahrt, S.K (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues implications for epigenetic reprogramming. The Journal of Bioh ad Chemistry, 279, 52353-52360. 

Xiang, S.B., Short, S.A., Wolfenden, R. and Carter, C.W. (1995) Transition-state selectivity for a single hydroxyl group during catalysis by cytidine deaminase. Biochemistry, 34, 4516-4523. 

Laliberte, J., Marquez, V.E. and Momparler, R.L. (1992) Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2 -deoxycytidine by human cytidine deaminase. 

Raynal, N.J., Bernstein, M.L. and Momparler, R.L. (2009) Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of5-aza-2 -deoxycytidine. Cancer Chemotherapy and Pharmacology, 63, 411-416. 

CYSTATHIONINE /3-LYASE CYTIDINE DEAMINASE CYTIDYLATE KINASE Cytochrome be, complex,... 

Fig. 2. Mechanisms causing resistance to antitumor treatment. ATM. ataxia telangiectasia gene, (Westphal et al., 1998 Xu and Baltimore, 1996), bcl-2/bax (Farrow and Brown, 1996, Zunino et al., 1997 Haq and Zanke, 1998), bcr/abl (McGahon et al., 1994), BCRP, breast cancer resistance protein (Doyle et d., 1998 Ross et al, 1999) bleomycin hydrolase (El-Deiry, 1997), BRCAl (Husain et al., 1998 Chen et al., 1998), BRCA2 (Chen et al., 1998 Chen et 1999), c-abl (White and Prives, 1999), c-jun (Sanchez-Perez and Perona, 1999), cytidine deaminase (El-Deiry, 1997), DNA poip, DNA polymerase p (Ochs et al., 1999), dihydrofolate reductase (Schimke, 1986), DT-diaphorase (Riley and Workman, 1992 Fitzsimmons et al., 1996 El-Deiry, 1997), EGR-1 (Ahmed et al., 1996), fos (Niimi et al., 1991), glucosylceramide synthase...

Bouffard DY, Laliberte J, Momparler RL. Kinetic studies on 2, 2 -difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol 1993 45(9) 1857—1861. 

Hyper-IgM syndrome can also arise if there is an intrinsic B cell defect that prevents B cells from switching to production of immunoglobulins other than IgM due to a mutation in the gene that codes for the mRNA-editing enzyme known as activation-induced cytidine deaminase (110). 

Revy, P., Muto, T, Levy, Y, etal. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome. Cell 102, 565-575 (2000). 

Capecitabine is a fluoropyrimidine carbamate prodrug with 70-80% oral bioavailability. It undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5 -deoxy-5-fluorocytidine. This is converted to 5 -deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5 -deoxy-5-fluorouridine metabolite is then hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer. 

An example of a successful application of affinity chromatography is the isolation of the enzyme cytidine deaminase from cells of E. coli. Cytidine was linked covalently via long spacer arms to the agarose beads as in the following diagram ... 

A cell extract was subjected to ammonium sulfate fractionation and the dialyzed protein was then poured through the affinity column which held the cytidine deaminase molecules because of their affinity for the cytidine structures that were bound to the agarose. 

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