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Title: Zebularine: A Novel DNL Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases

Abstract

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.HhaI) 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.HhaI 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.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
980688
Report Number(s):
BNL-93606-2010-JA
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US201015%%2073
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Journal of Molecular Biology
Additional Journal Information:
Journal Volume: 321; Journal Issue: 4; Journal ID: ISSN 0022-2836
Country of Publication:
United States
Language:
English
Subject:
04 OIL SHALES AND TAR SANDS; BIOLOGICAL PATHWAYS; COMPLEXES; CRYSTALLOGRAPHY; DNA; DRUGS; ENZYMES; HAEMOPHILUS; INHIBITION; INTERACTIONS; METABOLISM; METHYLATION; NUCLEIC ACIDS; PROGRAMMING LANGUAGES; RISE; national synchrotron light source

Citation Formats

Zhou, L, Cheng, X, Connolly, B, Dickman, M, Hurd, P, and Hornby, D. Zebularine: A Novel DNL Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases. United States: N. p., 2009. Web.
Zhou, L, Cheng, X, Connolly, B, Dickman, M, Hurd, P, & Hornby, D. Zebularine: A Novel DNL Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases. United States.
Zhou, L, Cheng, X, Connolly, B, Dickman, M, Hurd, P, and Hornby, D. Thu . "Zebularine: A Novel DNL Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases". United States.
@article{osti_980688,
title = {Zebularine: A Novel DNL Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases},
author = {Zhou, L and Cheng, X and Connolly, B and Dickman, M and Hurd, P and Hornby, D},
abstractNote = {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.HhaI) 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.HhaI 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.},
doi = {},
journal = {Journal of Molecular Biology},
issn = {0022-2836},
number = 4,
volume = 321,
place = {United States},
year = {2009},
month = {1}
}