A Proteomic Approach to Analyze the Aspirin-mediated Lysine Acetylome

Tatham, Michael H.; Callebaut, Christian; Scullion, Paul; Wilkie, Ross; Westwood, Nicholas J.; Stark, Lesley A.; Hay, Ronald T.

doi:10.1074/mcp.o116.065219

Cited by 49 publications

(40 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another recent proteomic study by Tatham and co-workers used 3 H-labeled aspirin to identify sites of aspirin-mediated acetylation in HeLa cells by mass spectrometry [ 124 ]. In this approach, the use of tritiated aspirin results in a +3 Da mass shift relative to normal acetate and allows more accurate discrimination of aspirin-mediated acetylation versus endogenous acetylation.…”

Section: The Role Of Platelets In the Clotting Cascadementioning

confidence: 99%

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Ornelas

Millward

Menter

et al. 2017

Cancer Metastasis Rev

167

158

View full text Add to dashboard Cite

After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin’s chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

show abstract

Section: The Role Of Platelets In the Clotting Cascadementioning

confidence: 99%

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Ornelas

Millward

Menter

et al. 2017

Cancer Metastasis Rev

167

158

View full text Add to dashboard Cite

show abstract

“…Although this electrostatic hypothesis is unconventional, it is not unreasonable. Pharmacological agents such as aspirin, the simplest aryl ester, can transfer acetyl groups directly to lysine residues of ϳ100 different proteins (12)(13)(14)(15). In general, the neutralization of a single lysine-⑀-NH 3 ϩ in a protein is expected to have a large effect on its overall net charge because proteins are predicted to have low values of net charge to begin with ("low" defined as Z between Ϫ10 and ϩ10) (16).…”

mentioning

confidence: 99%

Lysine acylation in superoxide dismutase-1 electrostatically inhibits formation of fibrils with prion-like seeding

Rasouli

Abdolvahabi²,

Croom³

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

The acylation of lysine residues in superoxide dismutase-1 (SOD1) has been previously shown to decrease its rate of nucleation and elongation into amyloid-like fibrils linked to amyotrophic lateral sclerosis. The chemical mechanism underlying this effect is unclear, hydrophobic/steric effects electrostatic effects. Moreover, the degree to which the acylation might alter the prion-like seeding of SOD1 has not been addressed. Here, we acylated a fraction of lysine residues in SOD1 with groups of variable hydrophobicity, charge, and conformational entropy. The effect of each acyl group on the rate of SOD1 fibril nucleation and elongation were quantified with thioflavin-T (ThT) fluorescence, and we performed 594 iterate aggregation assays to obtain statistically significant rates. The effect of the lysine acylation on the prion-like seeding of SOD1 was assayed in spinal cord extracts of transgenic mice expressing a G85R SOD1-yellow fluorescent protein construct. Acyl groups with >2 carboxylic acids diminished self-assembly into ThT-positive fibrils and instead promoted the self-assembly of ThT-negative fibrils and amorphous complexes. The addition of ThT-negative, acylated SOD1 fibrils to organotypic spinal cord failed to produce the SOD1 inclusion pathology that typically results from the addition of ThT-positive SOD1 fibrils. These results suggest that chemically increasing the net negative surface charge of SOD1 via acylation can block the prion-like propagation of oligomeric SOD1 in spinal cord.

show abstract

“…The prolongation of the period before the onset of death related to malignancy was found to be approximately five years for esophageal, pancreatic, brain, and lung cancers, and was even higher for gastric, colon, and prostate cancers [2,37]. This effect of ASA is currently explained by its ability to acetylate proteins other than COX-1 [38]. Recently, it has been demonstrated that ASA also decreases the expression of the hypoxia-inducible factor 1alpha (HIF1α), a key regulator of genes that are involved in metabolism under hypoxic conditions and a major determinant of tumor cell stabilization [39,40].…”

Section: Discussionmentioning

confidence: 99%

Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid

Minno

Porro

Turnu

et al. 2019

JCM

View full text Add to dashboard Cite

Given to its ability to irreversibly acetylate the platelet cyclooxygenase-1 enzyme, acetylsalicylic acid (ASA) is successfully employed for the prevention of cardiovascular disease. Recently, an antitumoral effect of ASA in colorectal cancer has been increasingly documented. However, the molecular and metabolic mechanisms by which ASA exerts such effect is largely unknown. Using a new, untargeted liquid chromatography–mass spectrometry approach, we have analyzed urine samples from seven healthy participants that each ingested 100 mg of ASA once daily for 1 week. Of the 2007 features detected, 25 metabolites differing after ASA ingestion (nominal p < 0.05 and variable importance in projection (VIP) score > 1) were identified, and pathway analysis revealed low levels of glutamine and of metabolites involved in histidine and purine metabolisms. Likewise, consistent with an altered fatty acid β-oxidation process, a decrease in several short- and medium-chain acyl-carnitines was observed. An abnormal β-oxidation and a lower than normal glutamine availability suggests reduced synthesis of acetyl-Co-A, as they are events linked to one another and experimentally related to ASA antiproliferative effects. While giving an example of how untargeted metabolomics allows us to explore new clinical applications of drugs, the present data provide a direction to be pursued to test the therapeutic effects of ASA—e.g., the antitumoral effect—beyond cardiovascular protection.

show abstract

A Proteomic Approach to Analyze the Aspirin-mediated Lysine Acetylome

Cited by 49 publications

References 50 publications

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Lysine acylation in superoxide dismutase-1 electrostatically inhibits formation of fibrils with prion-like seeding

Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid

Contact Info

Product

Resources

About