Synthesis Is Regulated by Both Activators and Inhibitors

Deoxyribonucleotide Synthesis Is Regulated by Both Activators and Inhibitors 

The manner in which the reduction of ribonucleotides to deoxyribonucleotides is regulated has been studied with reductases from relatively few species. The enzymes from E. coli and from Novikoff s rat liver tumor have a complex pattern of inhibition and activation (fig. 23.25). ATP activates the reduction of both CDP and UDP. As dTTP is formed by metabolism of both dCDP and dUDP, it activates GDP reduction, and as dGTP accumulates, it activates ADP reduction. Finally, accumulation of dATP causes inhibition of the reduction of all substrates. This regulation is reinforced by dGTP inhibition of the reduction of GDP, UDP, and CDP and by dTTP inhibition of the reduction of the pyrimidine substrates. Because evidence suggests that ribonucleotide reductase may be the rate-limiting step in deoxyribonucleotide synthesis in at least some animal cells, these allosteric effects may be important in controlling deoxyribonucleotide synthesis. 

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. 

Enzyme Synthesis Also Contributes to Regulation of Deoxyribonucleotides during the Cell Cycle 

Many of the enzymes participating in de novo synthesis of deoxyribonucleotide triphosphates, as well as those responsible for interconversion of deoxyribonucleotides, increase in activity when cells prepare for DNA synthesis. The need for increased DNA synthesis occurs under three circumstances (1) when the cell proceeds from the G0, or resting, stage of the cell cycle to the S, or synthetic or replication, stage (fig. 23.26) (2) when it performs repair after extensive DNA damage and (3) after infection of quiescent cells with virus. When cells leave G0, for example, enzymes such as thymidylate synthase and ribonucleotide reductase, increase as well as the corresponding mRNAs. These increases in enzyme amount supplement allosteric controls that increase the activity of each enzyme molecule. Corresponding decreases in amounts of these enzymes and their mRNAs occur when DNA synthesis is completed. 

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Purine Biosynthesis Is Regulated at Two Levels Pyrimidine Biosynthesis Is Regulated at the Level of Carbamoyl Aspartate Formation Deoxyribonucleotide Synthesis Is Regulated by Both Activators and Inhibitors... 

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