Direct reversal of DNA alkylation damage.

Department of Chemistry, The University of Chicago, Illinois 60637, USA.
Chemical Reviews (Impact Factor: 45.66). 03/2006; 106(2):215-32. DOI: 10.1021/cr0404702
Source: PubMed

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    ABSTRACT: Recent work of Nam and co-workers [J. Yoon, S. A. Wilson, Y. K. Jang, M. S. Seo, K. Nehru, B. Hedman, K. O. Hodgson, E. Bill, E. I. Solomon and W. Nam, Angew. Chem. Int. Ed., 2009, 48, 1257] on a biomimetic iron complex implicated a mixture of iron(IV)-oxo and iron(V)-oxo intermediates but the latter could not be spectroscopically characterized, hence its involvements was postulated. To gain insight into the relative activity of these iron(IV)-oxo versus iron(V)-oxo intermediates, we have performed an extensive density functional theory (DFT) study into the chemical properties of the chemical system of Nam et al, namely [Fe(O)(BQEN)(NCCH3)]2+/3+ with BQEN = N,N’-dimethyl-N,N’-bis(8-quinolyl)ethane-1,2-diamine and their reactivity in hydrogen atom abstraction from ethylbenzene. We show that the perceived iron(V)-oxo species actually is an iron(IV)-oxo ligand cation radical, similar to cytochrome P450 compound I. Moreover, this intermediate has an extremely large electron affinity and therefore can abstract electrons from substrates readily. In our particular system, this means that prior to the hydrogen atom abstraction, an electron is abstracted to form an iron(IV)-oxo species, which subsequently abstracts a hydrogen atom from substrate. Thus, our calculations show for the first time how some nonheme iron complexes react by long-range electron transfer and others directly via hydrogen atom abstraction. We have rationalized our results with detailed thermochemical cycles that explain the observed reactivity patterns.
    Physical Chemistry Chemical Physics 09/2014; · 4.20 Impact Factor
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    ABSTRACT: Cellular RNAs carry diverse chemical modifications that used to be regarded as static and having minor roles in 'fine-tuning' structural and functional properties of RNAs. In this Review, we focus on reversible methylation through the most prevalent mammalian mRNA internal modification, N(6)-methyladenosine (m(6)A). Recent studies have discovered protein 'writers', 'erasers' and 'readers' of this RNA chemical mark, as well as its dynamic deposition on mRNA and other types of nuclear RNA. These findings strongly indicate dynamic regulatory roles that are analogous to the well-known reversible epigenetic modifications of DNA and histone proteins. This reversible RNA methylation adds a new dimension to the developing picture of post-transcriptional regulation of gene expression.
    Nature Reviews Genetics 03/2014; · 39.79 Impact Factor
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    ABSTRACT: Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.
    Nucleic Acids Research 12/2014; · 8.81 Impact Factor


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