Article
Multiple enzyme activities of Escherichia coli MutT protein for sanitization of DNA and RNA precursor pools.
Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
Biochemistry (impact factor:
3.42).
06/2005;
44(17):6670-4.
DOI:10.1021/bi047550k
pp.6670-4
Source: PubMed
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Citations (0)
- Cited In (5)
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Article: Sublethal RNA oxidation as a mechanism for neurodegenerative disease.
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ABSTRACT: Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.International Journal of Molecular Sciences 06/2008; 9(5):789-806. · 2.60 Impact Factor -
Chapter: Prevention of the Mutagenicity and Cytotoxicity of Oxidized Purine Nucleotides
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ABSTRACT: Damage to nucleic acids is particularly hazardous because the genetic information in genomic DNA, such as nuclear and mitochondrial DNA, can be altered. Damage accumulated in cellular DNAs often initiates programmed cell death, as well as mutagenesis. The former may cause degenerative diseases, and the latter may result in neoplasia and hereditary diseases. The accumulation of oxidative damage in cellular DNA or RNA is a result of the incorporation of oxidized nucleotides generated in nucleotide pools, as well as a result of their direct oxidation. Recent progress in studies of the sanitization of nucleotide pools, in addition to DNA repair, have revealed the significance of the oxidation of free nucleotides to be unexpectedly large, in comparison to the direct oxidation of DNA.06/2009: pages 40-53; -
Article: Diverse substrate recognition and hydrolysis mechanisms of human NUDT5.
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ABSTRACT: Human NUDT5 (hNUDT5) hydrolyzes various modified nucleoside diphosphates including 8-oxo-dGDP, 8-oxo-dADP and ADP-ribose (ADPR). However, the structural basis of the broad substrate specificity remains unknown. Here, we report the crystal structures of hNUDT5 complexed with 8-oxo-dGDP and 8-oxo-dADP. These structures reveal an unusually different substrate-binding mode. In particular, the positions of two phosphates (α and β phosphates) of substrate in the 8-oxo-dGDP and 8-oxo-dADP complexes are completely inverted compared with those in the previously reported hNUDT5-ADPR complex structure. This result suggests that the nucleophilic substitution sites of the substrates involved in hydrolysis reactions differ despite the similarities in the chemical structures of the substrates and products. To clarify this hypothesis, we employed the isotope-labeling method and revealed that 8-oxo-dGDP is attacked by nucleophilic water at Pβ, whereas ADPR is attacked at Pα. This observation reveals that the broad substrate specificity of hNUDT5 is achieved by a diversity of not only substrate recognition, but also hydrolysis mechanisms and leads to a novel aspect that enzymes do not always catalyze the reaction of substrates with similar chemical structures by using the chemically equivalent reaction site.Nucleic Acids Research 07/2011; 39(20):8972-83. · 8.03 Impact Factor
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Keywords
8-OxoGua
accurate DNA replication
cellular metabolic processes
corresponding nucleoside monophosphates
degrade 8-oxo-GDP
dGDP
Escherichia coli
GDP
misincorporation
multiple enzyme activities
MutT possesses
MutT protein
normal counterpart
nucleic acids
nucleotide pools
reactive oxygen species
related nucleoside monophosphate
ribonucleoside triphosphates