A proteomic approach to analyse the aspirin-mediated lysine acetylome
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Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino-acid side-chains, leading to the possibility that aspirin-mediated lysine acetylation could explain some of its as-yet unexplained drug actions or side-effects. Using isotopically labeled aspirin-d3, in combination with acetylated lysine purification and LC-MS/MS, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies endogenous acetylation signals at the majority of detectable endogenous sites, cells tolerate aspirin mediated acetylation very well unless cellular deacetylases are inhibited. Although most endogenous acetylations are amplified by orders of magnitude, lysine acetylation site occupancies remain very low even after high doses of aspirin. This work shows that while aspirin has enormous potential to alter protein function, in the majority of cases aspirin-mediated acetylations do not accumulate to levels likely to elicit biological effects. These findings are consistent with an emerging model for cellular acetylation whereby stoichiometry correlates with biological relevance, and deacetylases act to minimize the biological consequences non-specific chemical acetylations.
Tatham , M H , Cole , C C , Scullian , P , Wilkie , R P , Westwood , N J , Stark , L A & Hay , R T 2016 , ' A proteomic approach to analyse the aspirin-mediated lysine acetylome ' Molecular and Cellular Proteomics . DOI: 10.1074/mcp.O116.065219
Molecular and Cellular Proteomics
Copyright 2016 by The American Society for Biochemistry and Molecular Biology, Inc. This work has been made available online in accordance with the publisher’s policies. This is the final published version of the work, which was originally published at: https://doi.org/10.1074/mcp.O116.065219
This work is supported by grants from Cancer Research UK (M.H.T & R.T.H) and the Wellcome Trust (R.T.H.).
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