Tyrosyl radical, diiron center and enzyme mechanism in ribonucleotide reductase

Gräslund, Astrid; Ehrenberg, Anders

doi:10.1007/bf03166595

Cited by 3 publications

(2 citation statements)

References 51 publications

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“…The X-band EPR envelope of R2ii, p53R2i and p53R2ii ( Fig. 4 ) were similar to the spectra observed in mammalian R2 and p53R2 reported earlier [49] , [50] . Limitations in the effective expression/purification of the R2i form led to small amounts of protein available for EPR measurements, and the protein concentration in this EPR sample was about one third compared to the other samples.…”

Section: Resultssupporting

confidence: 85%

Studies of Ribonucleotide Reductase in Crucian Carp—An Oxygen Dependent Enzyme in an Anoxia Tolerant Vertebrate

et al. 2012

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The enzyme ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides, the precursors for DNA. RNR requires a thiyl radical to activate the substrate. In RNR of eukaryotes (class Ia RNR), this radical originates from a tyrosyl radical formed in reaction with oxygen (O2) and a ferrous di-iron center in RNR. The crucian carp (Carassius carassius) is one of very few vertebrates that can tolerate several months completely without oxygen (anoxia), a trait that enables this fish to survive under the ice in small ponds that become anoxic during the winter. Previous studies have found indications of cell division in this fish after 7 days of anoxia. This appears nearly impossible, as DNA synthesis requires the production of new deoxyribonucleotides and therefore active RNR. We have here characterized RNR in crucian carp, to search for adaptations to anoxia. We report the full-length sequences of two paralogs of each of the RNR subunits (R1i, R1ii, R2i, R2ii, p53R2i and p53R2ii), obtained by cloning and sequencing. The mRNA levels of these subunits were measured with quantitative PCR and were generally well maintained in hypoxia and anoxia in heart and brain. We also report maintained or increased mRNA levels of the cell division markers proliferating cell nuclear antigen (PCNA), brain derived neurotrophic factor (BDNF) and Ki67 in anoxic hearts and brains. Electron paramagnetic resonance (EPR) measurements on in vitro expressed crucian carp R2 and p53R2 proteins gave spectra similar to mammalian RNRs, including previously unpublished human and mouse p53R2 EPR spectra. However, the radicals in crucian carp RNR small subunits, especially in the p53R2ii subunit, were very stable at 0°C. A long half-life of the tyrosyl radical during wintertime anoxia could allow for continued cell division in crucian carp.

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Section: Resultssupporting

confidence: 85%

Studies of Ribonucleotide Reductase in Crucian Carp—An Oxygen Dependent Enzyme in an Anoxia Tolerant Vertebrate

et al. 2012

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“…These dNTPs are involved in the synthesis of precursors required for DNA synthesis and repairing of all living cells. [1][2][3] RNR regulates the total DNA synthesis so that constant DNA to cell mass ratio is maintained during cell division and cell repair. 4 There are three different types of RNR.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and biological evaluation of diazeno-thiazole derivatives as ribonucleotide reductase inhibitors

Siddique¹,

Jadav²,

Graser

et al. 2017

J PHARM CHEM

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Ribonucleotide reductase(RNR) is a metalloenzyme that catalyses the rate limiting step in DNA synthesis and repair. It causes the reduction of ribonucleotide to 2’-deoxyribonuclotides which are used as precursors for DNA synthesis, thus offering a good target for inhibition of cell synthesis. Experimental results have been proven that RNR inhibitors can be used as antiviral, anticancer or antibacterial agents. Here we report the synthesis of a novel class of diazeno-thiazole derivatives as potent RNR inhibitors. A series of forty molecules were synthesized and evaluated for their RNR inhibitory properties. All compounds were found to be good inhibitors of the RNR. Compound 3iwas found to be most active showing an IC50 value of 0.8 µm. The established SAR study indicated the presence of a polar bridge with an adjacent flexible aromatic ringprerequisite for RNR inhibitory activity. Moreover, compounds having an additional 4-chloro phenyl ring were found to be most potent.

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Ribonucleotide reductase inhibition by p-alkoxyphenols studied by molecular docking and molecular dynamics simulations

Luo

Gräslund

2011

Archives of Biochemistry and Biophysics

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Tyrosyl radical, diiron center and enzyme mechanism in ribonucleotide reductase

Cited by 3 publications

References 51 publications

Studies of Ribonucleotide Reductase in Crucian Carp—An Oxygen Dependent Enzyme in an Anoxia Tolerant Vertebrate

Studies of Ribonucleotide Reductase in Crucian Carp—An Oxygen Dependent Enzyme in an Anoxia Tolerant Vertebrate

Design, Synthesis and biological evaluation of diazeno-thiazole derivatives as ribonucleotide reductase inhibitors

Ribonucleotide reductase inhibition by p-alkoxyphenols studied by molecular docking and molecular dynamics simulations

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