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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
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 | ||||||||
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| 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: |
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| 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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