Cytidine deaminase reaction

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). 

Figure 2.5 Logarithmic scale comparison of k,d and kuncat (= (rnon) for some representative reactions at 25 °C. The length of each vertical bar represents the rate enhancement. (Wolfenden, 2001). ADC arginine decarboxylase ODC orotidine 5 -phosphate decarboxylase STN staphylococcal nuclease GLU sweet potato /3-amylase FUM fumarase MAN mandelate racemase PEP carboxypeptodase B CDA E. coli cytidine deaminase KSI ketosteroid isomerase CMU chorismate mutase CAN carbonic anhydrase.

The final stage of B cell differentiation where the BCR repertoire is shaped is the germinal centre (GC) reaction. In the T cell dependent GC reaction, the BCR is adapted for its cognate antigen by somatic hypermutation (SMH) and class switch recombination (CSR), both of which are driven by activation induced cytidine deaminase (AID). Since AID induces targeted point mutations in the CDRs of the Ig HCs and Ig LCs, this can dramatically alter the BCR affinity or even its specificity. As AID activity may also result in the formation of an autoreactive BCR, a stringent counterselection of such self-reactive B cells is required. By analysis in human of the BCR repertoire of post-GC IgG+ memory B cells, it was demonstrated that indeed new auto-reactive B cells develop by SHM whereas 20% of naive B cells is self-reactive, up to 40% of the IgG+ memory B cells expressed a true de novo created self-reactive BCR. Apparently, lack of T cell help prevents activation of these self-... 

Before they can be degraded, cytidine and deoxycytidine are converted to uridine and deoxyuridine, respectively, by deamination reactions catalyzed by cytidine deaminase. Similarly, deoxycytidylate (dCMP) is deaminated to form deoxyuridylate (dUMP). The latter molecule is then converted to deoxyuridine by 5 -nucleotidase. Uridine and deoxyuridine are then further degraded by nucleoside... 

It should therefore be possible to design chemical structures, modeled after known or putative reaction intermediates that resemble postulated transition states. They may exhibit high affinities for the reactive sites of enzymes and therefore function as effective, but reversible, inhibitors. A successful example is the potent and specific cytidine deaminase inhibitor 3,4,5,6-tetrahydrouridine, which effectively blocks the conversion of cytidine to uridine. It was similarly demonstrated that 1,6-dihydro-6-hydroxymethylpurine effectively blocked the deamination of adenine to hypoxanthine by adenine deaminase (Eq. 2.13). 

Adverse reactions to gemcitabine are typically mild, including myelosuppression, nausea and vomiting, raised hepatic aminotransferases, and flu-like symptoms. About 10% of patients experience more severe toxicity, most commonly hematological. Patients with cytidine deaminase deficiency are more likely to have early and significant drug-related adverse reactions [40. ... 

Fio. 12-1. Metabolism of uracil, cytosine, and their tibonucleosides. Solid lines, enzyme activity in both animal and microbial cells large-dashed line, enzyme activity in microbial cells only small-dashed lines, reaction not known. Reactions (1) CTP synthetase (2) cytosine deaminase (3) cytidine deaminase (4) uracil phosphoribosyl transferase (5) uridine phosphorylase (6) uiidine-i tidine kinase (7) 5 -nucleotidase. 

Figure 11 Emymatic resolucion of ) 10 at 3 kg scale using immobilized cytidine deaminase. Three kilograms of racemic 10 was incubated at 32 with 30,000 units of immobilized cytidine deaminase in a 300 liter volume in a 780 liter fermentor. Tlie pH was adjusted to 7.0 and maiiv mined constant by the addition of 20% (v/v) acetic acid. Upon completion of the reaction, the mlxtute was pumped out through a 0.1 mm steel mesh, and the retained beads were stored at 4°C. ( ) pH ( ) conversion % deamination of racemic 10). (Reproduced from Ref. 57 with the permission of Buttetwonh Heinemann.)...

RNA editing This process involves insertion, deletion or modification of nucleotides in the pre-mRNA. The result of one or more of these modifications is that the mRNA is sufficiently modified fhat the properties of the proteins that are produced are slightly different in different tissues. A cytidine base can be converted to uracil in mRNA in a reaction catalysed by a deaminase enzyme. This can result... 

The synthesis of deoxyuridine, cytidine, deoxycytidine and thymidine nucleotides from UMP (Fig. 6.13) involves three reactions CTP synthetase, ribonucleotide reductase, and thymidylate synthase (80). The first enzyme converts UTP into CTP and the second catalyzes the conversion of CDP, UDP, ADP and GDP into their respective deoxyribonucleotides. The last enzyme, thymidylate synthase, catalyzes the reductive methylation of deoxyUMP at the C-5 position giving deoxyTMP. The human enzyme has been extensively studied as it is a target enzyme in cancer chemotherapy. Besides these three enzymes, two other enzymes are involved in pyrimidine nucleotide synthesis and interconversion. DeoxyCMP deaminase converts deoxyCMP into deoxyUMP and deoxyUTP triphosphatase converts deoxyUTP into deoxyUMP. Giardia lamblia, and Trichomonas vaginalis lack both ribonucleotide reductase and thymidylate synthase and... 

Metabolism of the pyrimidine deoxyribonucleotides is more complex because, in addition to transfer of phosphoryl groups, deamination and methylation reactions occur at this level. Specifically, the thymidine phosphates are derived by methylation of deoxyuridylate, and the latter may be derived from the deoxycytidine phosphates by way of deoxycytidylate deaminase. The deoxycytidine phosphates are not formed by amination of deoxyuridine phosphates, but are derived entirely from the cytidine phosphates by enzymatic reduction (Chapter 16). 

Adenosine (ADA) and cytidine (QD) deaminase are important catabolic enzymes which convert many biologically active analogues into inactive metabolites. Therefore, investigation of substrate activity of new analogues of adenosine or cytidine toward ADA or (DA is of utmost importance. We have already mentioned that adenallene (11c) is a substrate for ADA. Depending on the reaction conditions, deamination can either be ex-... 

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