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Adenosine tetraphosphoadenosine drives a continuous ATP-release assay for aminoacyl-tRNA synthetases and other adenylate-forming enzymes

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Lloyd, Adrian J., Potter, Nicola J., Fishwick, Colin W. G., Roper, David I. and Dowson, Christopher G. (2013) Adenosine tetraphosphoadenosine drives a continuous ATP-release assay for aminoacyl-tRNA synthetases and other adenylate-forming enzymes. ACS Chemical Biology, 8 (10). pp. 2157-2163. doi:10.1021/cb400248f

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Official URL: http://dx.doi.org/10.1021/cb400248f

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Abstract

Aminoacyl-tRNA synthetases are essential for the correct linkage of amino acids to cognate tRNAs to maintain the fidelity of protein synthesis. Tractable, continuous assays are valuable for characterizing the functions of synthetases and for their exploitation as drug targets. We have exploited the unexplored ability of these enzymes to consume adenosine tetraphosphoadenosine (diadenosine 5′,5‴ P1 P4 tetraphosphate; Ap4A) and produce ATP to develop such an assay. We have used this assay to probe the stereoselectivity of isoleucyl-tRNAIle and Valyl-tRNAVal synthetases and the impact of tRNA on editing by isoleucyl-tRNAIle synthetase (IleRS) and to identify analogues of intermediates of these enzymes that might allow targeting of multiple synthetases. We further report the utility of Ap4A-based assays for identification of synthetase inhibitors with nanomolar to millimolar affinities. Finally, we demonstrate the broad application of Ap4A utilization with a continuous Ap4A-driven RNA ligase assay.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Aminoacyl-tRNA synthetases
Journal or Publication Title: ACS Chemical Biology
Publisher: American Chemical Society
ISSN: 1554-8929
Official Date: 18 October 2013
Dates:
DateEvent
18 October 2013Published
30 July 2013Accepted
11 April 2013Submitted
Volume: 8
Number: 10
Number of Pages: 7
Page Range: pp. 2157-2163
DOI: 10.1021/cb400248f
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Funder: Medical Research Council (Great Britain) (MRC)

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