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Issue 21, 2018
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NMR analyses on N-hydroxymethylated nucleobases – implications for formaldehyde toxicity and nucleic acid demethylases

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Abstract

Formaldehyde is produced in cells by enzyme-catalysed demethylation reactions, including those occurring on N-methylated nucleic acids. Formaldehyde reacts with nucleobases to form N-hydroxymethylated adducts that may contribute to its toxicity/carcinogenicity when added exogenously, but the chemistry of these reactions has been incompletely defined. We report NMR studies on the reactions of formaldehyde with canonical/modified nucleobases. The results reveal that hydroxymethyl hemiaminals on endocyclic nitrogens, as observed with thymidine and uridine monophosphates, are faster to form than equivalent hemiaminals on exocyclic nitrogens; however, the exocyclic adducts, as formed with adenine, guanine and cytosine, are more stable in solution. Nucleic acid demethylase (FTO)-catalysed hydroxylation of (6-methyl)adenosine results in (6-hydroxymethyl)adenosine as the major observed product; by contrast no evidence for a stable 3-hydroxymethyl adduct was accrued with FTO-catalysed oxidation of (3-methyl)thymidine. Collectively, our results imply N-hydroxymethyled adducts of nucleic acid bases, formed either by reactions with formaldehyde or via demethylase catalysis, have substantially different stabilities, with some being sufficiently stable to have functional roles in disease or the regulation of nucleic acid/nucleobase activity.

Graphical abstract: NMR analyses on N-hydroxymethylated nucleobases – implications for formaldehyde toxicity and nucleic acid demethylases

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Publication details

The article was received on 28 Mar 2018, accepted on 29 Mar 2018 and first published on 16 May 2018


Article type: Paper
DOI: 10.1039/C8OB00734A
Citation: Org. Biomol. Chem., 2018,16, 4021-4032
  • Open access: Creative Commons BY license
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    NMR analyses on N-hydroxymethylated nucleobases – implications for formaldehyde toxicity and nucleic acid demethylases

    S. Shishodia, D. Zhang, A. H. El-Sagheer, T. Brown, T. D. W. Claridge, C. J. Schofield and R. J. Hopkinson, Org. Biomol. Chem., 2018, 16, 4021
    DOI: 10.1039/C8OB00734A

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