Deoxycytidylate deaminase

This enzyme [EC 3.5.4.12], also called deoxycytidylate deaminase, catalyzes the hydrolysis of dCMP to produce... 

Thymidylate is synthesized from dUMP, which may be formed by two pathways in cells. The major precursor of dUMP is dCMP, which is converted to dUMP by deoxycytidylate deaminase ... 

A second enzyme on the pathway to dTTP that is subject to allosteric control is deoxycytidylate deaminase, which supplies dUMP for thymidylate synthesis. The enzyme in mammalian cells, yeast, and bacteriophage T2-infected E. coli. is allosterically activated by dCTP (hydroxymethyl dCTP for the phage enzyme) and inhibited by dTTP. 

The deoxyuridylate (dUMP) produced by dephosphorylation of the dUDP product of ribonucleotide reductase is not a component of DNA, but its methylated derivative deoxythymidylate (dTMP) is. The methylation of dUMP is catalyzed by thymidylate synthase, which utilizes N5,N10-methylene THF. As the methylene group is transferred, it is reduced to a methyl group, while the folate coenzyme is oxidized to form dihydrofolate. THF is regenerated from dihydrofolate by dihydrofolate reductase and NADPH. (This reaction is the site of action of some anticancer drugs, such as methotrexate.) Deoxyuridylate can also be synthesized from dCMP by deoxycytidylate deaminase. 

The Regulatory Influence of Allosteric Effectors on Deoxycytidylate Deaminases Frank Maley and Gladys F. Maley... 

There is no evidence for the enzyme deamination of cytidine 5 -phosphates, although deoxycytidylate deaminase is a well known enzyme [118,119]. The direct conversion of cytidine compounds to uridine ones occurs by the deamination of cytidine or cytosine. 

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). 

The conversion of cytosine nucleosides to DNA thymidylate has been demonstrated repeatedly since the original work of Reichard and Estbom (21). Maley and Maley (22) showed that labeled deoxycytidylate was converted to DNA thymidylate in a DNA-synthesizing system prepared from chick embryo and, thus, the existence of a deoxycytidylate deaminase was indicated. This enzyme, which is described below, and the cytidine-deoxycytidine deaminase activity are the only deaminases for cytosine derivatives known to occur in animal cells. 

The ribonucleotide reductases form deoxycytidine phosphates which are destined for incorporation into DNA these nucleotides are diverted to some extent into the deoxyuridylate pool, and thence into the thymine nucleotides, through the action of deoxycytidylate deaminase. This diversionary flow into the thymine pathway is regulated by the demand for the terminal products, dTTP and dCTP the valve controlling this flow is deoxycytidylate deaminase, the activity of which is subject to allosteric regulation by dTTP and dCTP. 

Deoxycytidylate deaminase was first isolated from sea urchin e s by Scarano and has since been demonstrated in many animal tissues the deaminases from spleen and chick embryo have been partly purified (23, 24). The enzyme requires that the substrate must be a 4-aminopyrimidine deoxyribonucleoside 5 -monophosphate, and will accept the following substituents at the pyrimidine 5-position methyl, hydroxymethyl, fluoro, iodo, and bromo. Notably, the following are not deaminated cytidine, deoxycytidine, eytidylate, dCDP, and dCTP. The concentration of this enzyme in cells appears to be related to their proliferative state in that the enzyme is found in growing tissues, but activities are low in adult tissues such as liver. 

Deoxycytidylate deaminase is evidently absent from a number of bacterial species, includii E. coli, S. typhimvrium, and B. subtilts. Accordingly, in these cells the deoxycytidine phosphates do not contribute to the synthesis of the thymidine phosphates in the manner described above for animal cells. However, enzymes catalyzing the deamination of dCTP have been demonstrated in E. ccU and S. typhimvrium the latter enzyme has been partly purified and shown to deaminate dCTP, but not CTP, dCDP, CDP, eytidylate, nor deoxycytidine (26). The formation of dUTP by this enzyme, followed by the action of the specific dUTP pyrophosphatase, would consitutue a route for the formation of deoxyuridylate ... 

Schweiger, M., Gold, L. M. Escherichia coli and Bacillus subtilis phage deoxyribonucleic acid-directed deoxycytidylate deaminase synthesis in Escherichia coli extracts. J. biol. Chem. 245, 5022-5025 (1970). 

Trimble, R. B., Maley, G. F., Maley, F. The in vitro s5mthesis of T2 bacteriophage-induced deoxycytidylate deaminase and its regulation by allosteric effectors. Arch. Biochem. Biophys. 153, 515-525 (1972b). 

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... 

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