Pergolizzi, Giulia, Cominetti, Marco, Butt, Julea N. ORCID: https://orcid.org/0000-0002-9624-5226, Field, Robert A., Bowater, Richard
ORCID: https://orcid.org/0000-0002-2745-7807 and Wagner, Gerd K.
(2015)
Base-modified NAD and AMP derivatives and their activity against bacterial DNA ligases.
Organic & Biomolecular Chemistry, 13.
pp. 6380-6398.
ISSN 1477-0520
Abstract
We report the chemical synthesis and conformational analysis of a collection of 2-, 6- and 8-substituted derivatives of β-NAD+ and AMP, and their biochemical evaluation against NAD+-dependent DNA ligases from Escherichia coli and Mycobacterium tuberculosis. Bacterial DNA ligases are validated anti-microbial targets, and new strategies for their inhibition are therefore of considerable scientific and practical interest. Our study includes several pairs of β-NAD+ and AMP derivatives with the same substitution pattern at the adenine base. This has enabled the first direct comparison of co-substrate and inhibitor behaviour against bacterial DNA ligases. Our results suggest that an additional substituent in position 6 or 8 of the adenine base in β-NAD+ is detrimental for activity as either co-substrate or inhibitor. In contrast, substituents in position 2 are not only tolerated, but appear to give rise to a new mode of inhibition, which targets the conformational changes these DNA ligases undergo during catalysis. Using a molecular modelling approach, we highlight that these findings have important implications for our understanding of ligase mechanism and inhibition, and may provide a promising starting point for the rational design of a new class of inhibitors against NAD+-dependent DNA ligases.
Item Type: | Article |
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Uncontrolled Keywords: | dna ligase,bioorganic chemistry,nucleic acids,nad,biochemistry,organic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Science > School of Pharmacy Faculty of Science > School of Chemistry |
Depositing User: | Pure Connector |
Date Deposited: | 24 Jul 2015 22:32 |
Last Modified: | 21 Oct 2022 00:54 |
URI: | https://ueaeprints.uea.ac.uk/id/eprint/53591 |
DOI: | 10.1039/c5ob00294j |
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