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Zebularine: A novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases

Lookup NU author(s): Professor Bernard Connolly


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Mechanism-based inhibitors of enzymes, which mimic reactive intermediates in the reaction pathway, have been deployed extensively in the analysis of metabolic pathways and as candidate drugs. The inhibition of cytosine-[C5]-specific DNA methyltransferases (C5 MTases) by oligodeoxynucleotides containing 5-azadeoxycytidine (AzadC) and 5-fluorodeoxycytidine (FdC) provides a well-documented example of mechanism-based inhibition of enzymes central to nucleic acid metabolism. Here, we describe the interaction between the C5 MTase from Haemophilus haemolyticus (M.Hha I) and an oligodeoxynucleotide duplex containing 2-H pyrimidinone, an analogue often referred to as zebularine and known to give rise to high-affinity complexes with MTases. X-ray crystallography has demonstrated the formation of a covalent bond between M.Hha I and the 2-H pyrimidinone-containing oligodeoxynucleotide. This observation enables a comparison between the mechanisms of action of 2-H pyrimidinone with other mechanism- based inhibitors such as FdC. This novel complex provides a molecular explanation for the mechanism of action of the anti-cancer drug zebularine. © 2002 Elsevier Science Ltd. All rights reserved.

Publication metadata

Author(s): Connolly BA; Zhou L; Cheng X; Dickman MJ; Hurd PJ; Hornby DP

Publication type: Article

Publication status: Published

Journal: Journal of Molecular Biology

Year: 2002

Volume: 321

Issue: 4

Pages: 591-599

ISSN (print): 0022-2836

ISSN (electronic):

Publisher: Academic Press


DOI: 10.1016/S0022-2836(02)00676-9

PubMed id: 12206775


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Funder referenceFunder name
R01 GM049245-10NIGMS NIH HHS