Ribonucleotide reductase and deoxyribonucleotide biosynthesis

See also Regulation of Ribonucleotide Reductase, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis... 

See also Figure 4.3, RNA, De Novo Biosynthesis of Purine Nucleotides, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis, Salvage Routes to Deoxyribonucleotide Synthesis... 

See also Biosynthesis of Thymine Deoxyribonucleotides, Deoxyuridine Nucleotide Metabolism, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis, Regulation of Ribonucleotide Reductase, Drug Design, Nucleotide Analogs in Medicine... 

The control of ribonucleotide reductase activity is affected in the classic feedback fashion by cellular nucleotide concentrations. dATP inhibits the reduction of all four ribonucleoside diphosphates. dTTP inhibits the reduction of only CDP and UDP. ATP is the positive effector for the reduction of these two nucleotides, and both dTTP and dGTP stimulate the reduction of GDP and ADP. Hydroxyurea, an antitumor agent, inhibits ribonucleotide reductase, and this depletes the deoxyribonucleotide supply required for tumor DNA biosynthesis. 

Ribonucleotide reductase controls DNA biosynthesis via various feedback effects involving ribo- and deoxyribonucleotides. 

Hydroxyurea interferes with the synthesis of both pyrimidine and purine nucleotides (see table 23.3). It interferes with the synthesis of deoxyribonucleotides by inhibiting ribonucleotide reductase of mammalian cells, an enzyme that is crucial and probably rate-limiting in the biosynthesis of DNA. It probably acts by disrupting the iron-tyrosyl radical structure at the active site of the reductase. Hydroxyurea is in clinical use as an anticancer agent. 

The evolutionary transition from RNA to DNA is recapitulated in the biosynthesis of DNA in modem organisms. In all cases, the building blocks used in the synthesis of DNA are synthesized from the corresponding building blocks of RNA by the action of enzymes termed ribonucleotide reductases. These enzymes convert ribonucleotides (a base and phosphate groups linked to a ribose sugar) into deoxyribonucleotides (a base and phosphates linked to deoxyribose sugar). 

The role of oxygen in eukaryotic DNA biosynthesis may indeed be a critical one. It has recently been shown that O2 is not only required for initial formation of tyrosyl radical but must be continously present to maintain the radical content and enzyme activity of mammalian ribonucleotide reductase In vivo studies with Ehrlich ascites cells also point to a tight link between oxygen and deoxyribonucleotide supply Anaerobic arrest of cells in G1 phase and block of DNA synthesis can be relieved by addition of deoxycytidine, but not cytidine, to the culture medium. ... 

Various B12 compounds with different upper-axial ligands exist in nature (Fig. 2). Among these, methylcobalamin and 5 -deoxyadenosylcobalamin function as coenzymes of methionine synthase (MetH EC 2.1.1.13) [42], which is involved in methionine biosynthesis, and of methylmalonyl-CoA mutase (EC 5.4.99.2) [43], which is involved in amino acid and odd-chain fatty acid metabolism in mammalian cells. Ribonucleotide reductase (RNR) catalyzes the synthesis of the four deoxyribonucleotides, which are required for DNA replication and repair in all organisms [44]. Cyanobacteria contain... 

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