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Mol Cell Proteomics. 2017 Feb;16(2):310-326. doi: 10.1074/mcp.O116.065219. Epub 2016 Dec 2.

A Proteomic Approach to Analyze the Aspirin-mediated Lysine Acetylome.

Author information

1
From the ‡Centre for Gene Regulation and Expression, Sir James Black Centre, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH. UK.
2
§Computational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH. UK.
3
¶Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH. UK.
4
‖School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife. KY16 9ST. UK.
5
**Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU UK.
6
From the ‡Centre for Gene Regulation and Expression, Sir James Black Centre, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH. UK; R.T.Hay@dundee.ac.uk.

Abstract

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 of nonspecific chemical acetylations.

PMID:
27913581
PMCID:
PMC5294217
DOI:
10.1074/mcp.O116.065219
[Indexed for MEDLINE]
Free PMC Article

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