Ribonucleotide reductase formation

From these data it seems feasible that a Co(II)-species is generated during catalysis, and that homolysis of the Co—C-bond is a prerequisite for enzyme catalysis in ribonucleotide reductase. However, the kinetics of appearance of the Co(II)-signal indicates that the rate of formation of Co(II) is much slower than either the rate of ribonucleotide reduction... 

Domino reactions are not only useful for the construction of molecules, but also for their degradation. This concept is often encountered in nature. Thus, ribonucleotide reductases (RNRs) are enzymes that catalyze the formation of DNA monomers from ribonucleotides by radical mediated 2 -deoxygenation. This process has also been studied... 

The realization of the widespread occurrence of amino acid radicals in enzyme catalysis is recent and has been documented in several reviews (52-61). Among the catalytically essential redox-active amino acids glycyl [e.g., anaerobic class III ribonucleotide reductase (62) and pyruvate formate lyase (63-65)], tryptophanyl [e.g., cytochrome peroxidase (66-68)], cysteinyl [class I and II ribonucleotide reductase (60)], tyrosyl [e.g., class I ribonucleotide reductase (69-71), photosystem II (72, 73), prostaglandin H synthase (74-78)], and modified tyrosyl [e.g., cytochrome c oxidase (79, 80), galactose oxidase (81), glyoxal oxidase (82)] are the most prevalent. The redox potentials of these protein residues are well within the realm of those achievable by biological oxidants. These redox enzymes have emerged as a distinct class of proteins of considerable interest and research activity. 

Figure 13.4 A proposed mechanism for all three classes of ribonucleotide reductases. Classes I and II RNRs require an active site Glu residue and a pair of redox-active Cys. Class HI RNRs lack the Glu and one of the Cys, and use formate as the reductant. (From Stubbe etal., 2001. Copyright 2001, with permission from Elsevier.)...

Studies on three different iron-sulfur enzyme systems, which all require S-adenosyl methionine—lysine 2,3-aminomutase, pyruvate formate lyase and anaerobic ribonucleotide reductase—have led to the identification of SAM as a major source of free radicals in living cells. As in the dehydratases, these systems have a [4Fe-4S] centre chelated by only three cysteines with one accessible coordination site. The cluster is active only in the reduced... 

Ribonucleotide reductase is required for the formation of the deoxyribonucleotides for DNA synthesis. Figure 1-18-2 shows its role in dTMP synthesis, and Figure 1-18-3 shows all four nucleotide substrates ... 

Lewis base adducts, 25 64, 68-69 metal exchange reactions, 25 57 NMR spectra, 25 93-95 pyrolysis, 25 107 silicide formation, 25 110 tetracarbonylsilyl hydride reaction with isoprene, 25 75 reductive elimination, 25 81 site, formation, ribonucleotide reductase, 43 372-375... 

C. Formation of deoxyribonudeotides by reduction of the 2 -hydroxyl group of the ribose sugars on the ribonucleoside diphosphates ADP and GDP is catalyzed by ribonucleotide reductase (Figure 10-3). 

Cytarabine Inhibits DNA chain elongation, DNA synthesis and repair inhibits ribonucleotide reductase with reduced formation of dNTPs incorporation of cytarabine triphosphate into DNA AML, ALL, CML in blast crisis Nausea and vomiting, myelosuppression with neutropenia and thrombocytopenia, cerebellar ataxia... 

Dinuclear iron centres occur in several proteins. They either bind or activate dioxygen or they are hydrolases. Ribonucleotide reductase (RR) of the so-called class I type contains one such centre in the R2 protein in combination with a tyrosyl radical, both being essential for enzymatic activity which takes place in the R1 protein subunit. The diiron centre activates dioxygen to generate the tyrosyl radicals which in turn initiate the catalytic reaction in the R1 subunit. The interplay between the tyrosyl free radical in R2 and the formation of deoxyribonucleotides in R1 which also is proposed to involve a protein backbone radical is a topic of lively interest at present but is outside the scope of this review. Only a few recent references dealing with this aspect are mentioned without any further discussion.158 159 1 1,161... 

Stubbe, J. Riggs-Gelasco, P. (1998) Harnessing free radicals formation and function of the tyrosyl radical in ribonucleotide reductase. Trends Biochem. Sci. 23, 438-443. 

The reactions catalyzed by B12 may be grouped into two classes those catalyzed by methylcobalamin and those catalyzed by cofactor B,2. The former reactions include formation of methionine from homocysteine, methanogenesis (formation of methylmercury is an important side reaction), and synthesis of acetate from carbon dioxide (82). The latter reactions include the ribonucleotide reductase reaction and a variety of isomerization reactions (82). Since dehydration and deamination have been studied quite extensively and very possibly proceed via [Pg.257]

So far, two types of aminomutase have been investigated in detail. Lysine 2,3-aminomutase from Clostridium subterminale SB4 is the example par excellence for the SAM-dependent type of aminomutase. Several other enzymes belonging to the same family are known. Examples are biotin synthase [82], pyruvate formate lyase [83, 84], and anaerobic ribonucleotide reductase [85]. 

The regulation of ribonucleotide reductase is complex, with many feedback reactions used to keep the supplies of deoxynu-cleotides in balance. For example, dGTP and dTTP are feedback inhibitors of their own formation. Each is also an activator of the synthesis of the complementary nucleotide (dCDP or dADP), while dATP is an inhibitor of the reductions to make dADP, dCDP, dGDP, and dUDP. These control functions keep the supply of deoxynu-cleotides in balance, so that a roughly equivalent amount of each remains available for DNA synthesis. 

Cho KB, V Pelmenschikov, A Graslund, PEM Siegbahn (2004) Density functional calculations on class III ribonucleotide reductase Substrate reaction mechanism with two formates. J. Phys. Chem. B 108 (6) 2056-2065... 

Hydroxyurea is a simple molecule (Fig. 15-17) which inhibits ribonucleotide reductase. This enzyme accepts the four NDPs, UDP, CDP, ADP and GDP, as substrates and reduces them to the corresponding dNDP. The mechanism of catalysis involves the formation of an unusual tyrosyl radical cation which then induces formation of a radical form of the NDP substrate. Hydroxyurea quenches this tyrosyl radical cation intermediate leading to depletion of all four dNTPs required as substrates for the synthesis of DNA. 

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