The ribonucleotide reductases — A unique group of metalloenzymes essential for cell proliferation

Lammers, Manfred; Follmann, Hartmut

doi:10.1007/bfb0111318

Cited by 152 publications

(73 citation statements)

References 315 publications

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“…The tyrosyl radical exhibits a characteristic EPR doublet signal at g = 2.0047. The activity of RR is directly proportional to the amount of tyrosyl radical in protein R2 [1][2][3][4][5][6]. The three-dimensional crystal structure of *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Reduction of the tyrosyl radical and the iron center in protein R2 of ribonucleotide reductase from mouse, herpes simplex virus and E. coli by p‐alkoxyphenols

et al. 1995

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The rate of reduction of the tyrosyl radical in the small subunit of ribonucleotide reductase (protein R2) from E. coli, mouse, and herpes simplex virus (HSV-2) by a series of p-alkoxyphenols with different alkyl chains, have been studied by stopped-flow UV-vis and stopped-flow EPR spectroscopy. The reduction and release of iron in R2 by the inhibitors was followed using bathophenanthroline as chelator of Fe 2+. p-Alkoxyphenols reduce the mouse R2 tyrosyl radical 1-2 orders of magnitude faster than the HSV-2 and E. coli radical. In contrast to E. coli, the iron center in R2 from mouse and HSV-2 is reduced by the inhibitors. For mouse R2, the rate of reduction of the tyrosyl radical increases in parallel with increasing alkyl chain length of the inhibitor, an observation which may be important for the design of new antiproliferative drugs.

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Section: Introductionmentioning

confidence: 99%

Reduction of the tyrosyl radical and the iron center in protein R2 of ribonucleotide reductase from mouse, herpes simplex virus and E. coli by p‐alkoxyphenols

et al. 1995

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“…Ribonucleotide reductases are uniquely responsible for converting nucleotides to deoxynucleotides in vivo (1)(2)(3)(4). In contrast to most enzymes that play essential roles in metabolism in both prokaryotes and eukaryotes, the reductases do not appear, at least superficially, to have been evolutionarily conserved.…”

mentioning

confidence: 99%

Cloning, sequencing, and expression of the adenosylcobalamin-dependent ribonucleotide reductase from Lactobacillus leichmannii.

Booker

Stubbe

1993

Proc. Natl. Acad. Sci. U.S.A.

102

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Ribonucleoside-triphosphate reductase (RTPR, EC 1.17.4.2) from Lactobacilus kichmannUi, a monomeric adenosylcobalamin-requiring enzyme, catalyzes the conversion of nucleoside triphosphates to deoxynucleoside triphosphates. The gene for this enzyme has been cloned and sequenced. In contrast to expectations based on mechanistic considerations, there is no statisticafly signicant sequence homology with the Escherichia coli reductase that requires a dinuclear-iron center and tyrosyl radical cofactor. The RTPR has been overexpressed and purified to homogeneity, yielding 90 mg of protein from 2.5 g of bacteria. Initial characterization of the recombinant RTPR indicates that its properties are identical to those of the RTPR isolated from L. kichmannu.Ribonucleotide reductases are uniquely responsible for converting nucleotides to deoxynucleotides in vivo (1-4). In contrast to most enzymes that play essential roles in metabolism in both prokaryotes and eukaryotes, the reductases do not appear, at least superficially, to have been evolutionarily conserved. In Escherichia coli, mammals, and herpesviruses, the enzymes possess two subunits, Rl and R2, each of which is homodimeric (a2132). The R2 subunit possesses a dinuclear iron center-tyrosyl radical cofactor that is essential for nucleotide reduction. The Rl subunit contains the binding sites for the NDP substrates and dNTP allosteric effectors, and the cysteines that are oxidized concomitant with substrate reduction. The ribonucleoside-triphosphate reductase (RTPR, EC 1.17.4.2) from Lactobacillus leichmannii, the structurally simplest of all known reductases, is a monomer and requires adenosylcobalamin (AdoCbl) as a cofactor (5).Despite these diverse cofactors and quarternary structures, evidence suggests that the E. coli and L. leichmannii enzymes exhibit common patterns ofregulation and chemical mechanisms of reduction. The similarities in the allosteric regulatory properties are evident from investigations of the requirement for specific dNTPs to affect the reduction of specific purine and pyrimidine nucleotides (2, 6, 7). The similarities in mechanism of reduction are evident from investigations employing isotopically labeled nucleotide substrates and from investigations of the mechanisms of inhibition by 2'-chloro-2'-deoxynucleotides (3). With respect to the mechanism of reduction, both enzymes are proposed to initiate catalysis by generation of a protein radical that abstracts the hydrogen atom from the 3' carbon of the nucleotide substrate (3). The difference between the two enzymes is most apparent when considering the manner in which the two distinctly different cofactors give rise to the protein radical. For the E. coli reductase, it is proposed that the tyrosyl radical on the R2 subunit generates by long-range electron transfer a protein radical on the Rl subunit, which initiates turnover of the nucleotide (1, 8). The L. leichmanniiThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby...

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“…On the other hand the allosteric behaviors of ATP and dATP on the reduction of CDP and that of dTTP on the reduction of GDP are very similar to the effects of the nucleotides in the adenosylcobalamin-independent reductases. It has been pointed out before that although the various ribonucleotide reductases differ in subunit structure and cofactor requirement, they all catalyze the reduction of ribonucleotides by a similar mechanism [2,16]. Because the enzyme from M. thermoautotrophicum is unique in its extreme sensitivity to oxygen, it may present yet another type differing in structure and catalytic site.…”

Section: Thermoautotrophicummentioning

confidence: 99%

“…Ribonucleotide reductases (EC 1.17.4) catalyze the irreversible reduction of the four common ribonucleoside 5 '-phosphates to the corresponding 2'-deoxyribonucleoside 5'-phosphates, an essential and rate-controlling step in DNA synthesis and cell proliferation [1][2][3]. Thus far three types of reductases have been described.…”

Section: Introductionmentioning

confidence: 99%

Ribonucleotide reductase in cell extracts of Methanobacterium thermoautotrophicum

Hogenkamp¹,

Follmann²,

Thauer³

1987

FEBS Letters

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Cell free extracts of Methanobacterium thermoautrophicum were found to catalyze the reduction of CDP and GDP provided that the cells were harvested, disrupted and the extracts assayed under strictly anaerobic conditions. Ribonucleotide reduction is not affected by adenosylcobalamin and cell extracts do not catalyze the tritium exchange reaction between [5-3Hz]adenosylcobalamin and water. The reduction of CDP requires ATP and that of GDP requires dTTP as positive allosteric effectors. In contrast, dATP at low concentration stimulates CDP reduction while at higher concentrations it inhibits the reductase reaction.

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The ribonucleotide reductases — A unique group of metalloenzymes essential for cell proliferation

Cited by 152 publications

References 315 publications

Reduction of the tyrosyl radical and the iron center in protein R2 of ribonucleotide reductase from mouse, herpes simplex virus and E. coli by p‐alkoxyphenols

Reduction of the tyrosyl radical and the iron center in protein R2 of ribonucleotide reductase from mouse, herpes simplex virus and E. coli by p‐alkoxyphenols

Cloning, sequencing, and expression of the adenosylcobalamin-dependent ribonucleotide reductase from Lactobacillus leichmannii.

Ribonucleotide reductase in cell extracts of Methanobacterium thermoautotrophicum

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