Deoxyribonucleotides 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... 

Salvage Synthesis and Pyrimidine Catabolism (Figure 22.11) Deoxyribonucleotide Biosynthesis and Metabolism (Figure 22.12)... 

As already mentioned, RNR is the metalloenzyme in which the first definitively characterized stable amino acid radical (1), later identified as a tyrosyl radical, was found in 1972. The RNR enzymes catalyse the reduction of ribonucleotides to their corresponding deoxyribonucleotides utilized in DNA biosynthesis. There are three unique classes of this enzyme, differing in composition and cofactor requirements all of them, however, make use of metal ions and free radical chemistry. Excellent reviews on RNRs are available (60, 61, 70, 89-97). 

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... 

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. 

Chapter 23, Nucleotides, deals with the biosynthesis of ribonucleotides, deoxyribonucleotides, the roles of these biomolecules in metabolic processes, and the pathways for their degradation. Medically related topics such as nucleotide metabolism deficiencies or the use of nucleotide analogs in chemotherapy are also considered. 

Chemotherapeutic agents, useful in me treatment of neoplastic diseases, exert their therapeutic effects by modifying me synthesis or functions of nucleic acids (see Chapter 51 and Chapter 58). For example, 6-mercaptopurine inhibits purine-ring biosynthesis, cytarabine inhibits DNA polymerase, alkylating agents crosslink DNA, and hydroxyurea inhibits the conversion of ribonucleotides into deoxyribonucleotides. However, other pharmacologic agents such as chlorpromazine, a... 

Understand the purine and pyrmidine de novo biosynthetic pathways, with special attention to enzymes controlling pathway rates and the properties of such enzymes the positive and negative effectors steps inhibited by the various antitumor agents and their mechanisms final products of the de novo pathways and how the various nucleotides are generated from them and the biosynthesis of deoxyribonucleotides and the attendant mechanisms. 

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. 

Which substance is not required for the biosynthesis of deoxyribonucleotides from ribonucleotides ... 

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

RNRs catalyze the reduction of ribonucleotides to deoxyribonucleotides, which represents the first committed step in DNA biosynthesis and repair.These enzymes are therefore required for all known life forms. Three classes of RNRs have been identified, all of which turn out to be metalloenzymes. The so-called class I RNRs contain a diiron site (see Cobalt Bn Enzymes Coenzymes and Iron-Sulfur Proteins for the other two types of RNRs). As diagrammed in Figure 5, these enzymes generate first a tyrosyl radical proximal to the diiron site in the protein subunit labeled R2, and then a thiyl radical in an adjacent subunit (Rl) that ultimately abstracts a hydrogen atom from the ribonucleotide substrate. This controlled tyrosine/thiol radical transfer must occur over an estimated distance of 35 A, and a highly choreographed proton-coupled electron transfer (PCET) mechanism across intervening aromatic residues has been proposed. Perhaps, even more remarkably,... 

One example of an enzyme-catalyzed reaction involving a radical intermediate is the enzyme ribonucleotide reductase, which catalyzes the conversion of ribonucleotides (used for RNA biosynthesis) to 2 -deoxyribonucleotides (used for DNA biosynthesis), as illustrated in Fig. 16. Spectroscopic studies of the R2 subunit of Escherichia coli ribonucleotide reductase have shown that it can form a stable, long-lived, tyrosyl radical species—the first protein radical to be discovered (13). 

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). 

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