Structure, function, and mechanism of ribonucleotide reductases

Kolberg, Matthias; Strand, Kari R.; Graff, Pål; Andersson, K. Kristoffer

doi:10.1016/j.bbapap.2004.02.007

Cited by 276 publications

(261 citation statements)

References 240 publications

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“…[24] The radicals derived from these species are formed in unrelated subunits or domains and are submitted to the active site located in a subunit, which is related among all three types of ribonucleotide reductase. At the active site a conserved cysteine residue is converted to a thiyl radical, which initiates catalysis by hydrogen atom abstraction from C-3 of the ribose moiety of a ribonucleotide.…”

Section: Alternatives To Coenzyme B 12 Dependent Eliminasesmentioning

confidence: 99%

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B₁₂ Dependent Mutases

Buckel

Kratky

Golding

2005

Chemistry A European J

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Coenzyme B12 initiates radical chemistry in two types of enzymatic reactions, the irreversible eliminases (e.g., diol dehydratases) and the reversible mutases (e.g., methylmalonyl-CoA mutase). Whereas eliminases that use radical generators other than coenzyme B12 are known, no alternative coenzyme B12 independent mutases have been detected for substrates in which a methyl group is reversibly converted to a methylene radical. We predict that such mutases do not exist. However, coenzyme B12 independent pathways have been detected that circumvent the need for glutamate, beta-lysine or methylmalonyl-CoA mutases by proceeding via different intermediates. In humans the methylcitrate cycle, which is ostensibly an alternative to the coenzyme B12 dependent methylmalonyl-CoA pathway for propionate oxidation, is not used because it would interfere with the Krebs cycle and thereby compromise the high-energy requirement of the nervous system. In the diol dehydratases the 5'-deoxyadenosyl radical generated by homolysis of the carbon-cobalt bond of coenzyme B12 moves about 10 A away from the cobalt atom in cob(II)alamin. The substrate and product radicals are generated at a similar distance from cob(II)alamin, which acts solely as spectator of the catalysis. In glutamate and methylmalonyl-CoA mutases the 5'-deoxyadenosyl radical remains within 3-4 A of the cobalt atom, with the substrate and product radicals approximately 3 A further away. It is suggested that cob(II)alamin acts as a conductor by stabilising both the 5'-deoxyadenosyl radical and the product-related methylene radicals.

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Section: Alternatives To Coenzyme B 12 Dependent Eliminasesmentioning

confidence: 99%

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B₁₂ Dependent Mutases

Buckel

Kratky

Golding

2005

Chemistry A European J

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“…14,15,16,17 In the 1970s it was discovered that HCTs are inhibitors of the enzyme ribonucleotide reductase (RNR), 18,19 which catalyzes the rate determining step of DNA synthesis, namely the reduction of ribonucleotides to the corresponding 2'-deoxyribonucleotides. 20 Several mechanisms of RNR inhibition by thiosemicarbazones and especially Triapine have been proposed. 18,21 The until recently favored mechanistic scheme was that Triapine forms an iron(III) complex within the cell, which is reduced to Fe(II)-Triapine by intracellular reductants.…”

Section: Introductionmentioning

confidence: 99%

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

et al. 2014

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The nickel(II), copper(II) and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H 2 L 1 ) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazonehave been synthesized and characterized by elemental analysis, one-and two-dimensional 1 H and 13 C NMR spectroscopy, CD, UV−vis and ESI mass spectrometry. Compounds 13, 6 and 7 have been also studied by single crystal X-ray diffraction. Magnetic properties and solid state high-field EPR spectra of 2 over the range 50420 GHz were investigated. The complex formation processes of L-Pro-FTSC with nickel(II) and zinc(II) have been studied in aqueous solution due to the excellent water solubility of the complexes via pH-potentiometry, UV−vis and 1 H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds.3

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“…~ .-"X~'~-:" ........ His 118(173) Conserved residues participating in the proposed hydrogen-bonded long-range electron transfer chain between substrate (adenine diphosphate, ADP) site in protein R1 and the iron/tyrosyl radical site in protein R2 of Escherichia coli ribonucleotide reductase[10,11,2,43,50]. Mouse protein R2 nurnbering is given in parentheses.…”

mentioning

confidence: 99%

Tyrosyl radical, diiron center and enzyme mechanism in ribonucleotide reductase

Gräslund

Ehrenberg

2007

Appl. Magn. Reson.

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In this minireview we will describe work where electron paramagnetic resonance spectroscopy has been used as the major methodology to identify and study the function of an amino acidbased free radical in enzyme function. For many redox processes in biochemistry the interplay between redox-active metal ions and free radicals turns out to be a recurring theme. Seen in this perspective, the enzyme we will describe here, ribonucleotide reductase, is related to several other important enzyme systems, including photosystem II.

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Structure, function, and mechanism of ribonucleotide reductases

Cited by 276 publications

References 240 publications

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B₁₂ Dependent Mutases

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B₁₂ Dependent Mutases

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

Tyrosyl radical, diiron center and enzyme mechanism in ribonucleotide reductase

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Structure, function, and mechanism of ribonucleotide reductases

Cited by 276 publications

References 240 publications

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B12 Dependent Mutases

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B12 Dependent Mutases

Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

Tyrosyl radical, diiron center and enzyme mechanism in ribonucleotide reductase

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About

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B₁₂ Dependent Mutases

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B₁₂ Dependent Mutases