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NMR Analyses on N-Hydroxymethylated Nucleobases – Implications for Formaldehyde Toxicity and Nucleic Acid Demethylases

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posted on 09.04.2018, 10:53 by S. Shishodia, D. Zhang, A. H. El-Sagheer, T. Brown, T. D. W. Claridge, C. J. Schofield, Richard Hopkinson
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.

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Citation

Organic and Biomolecular Chemistry, 2018, 16, pp. 4021-4032

Author affiliation

/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Chemistry

Version

VoR (Version of Record)

Published in

Organic and Biomolecular Chemistry

Publisher

Royal Society of Chemistry

issn

1472-7781

eissn

1364-5463

Copyright date

2018

Available date

21/07/2018

Language

en

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