15(R)-hydroxyeicosatetraenoic acid

evidence_span

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experimental_model

Human cyclooxygenase-1 and -2 expressed in cos-1 cells treated with aspirin and with carbon-14 labelled aspirin, with a mutant series at Ser-516

exposure

Aspirin acetylation, with S516A, S516N, S516Q and S516M substitutions

limitations

Identifies the site by direct labelling and explains the isoform difference by active site volume. Recombinant enzyme in a heterologous cell line.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human enzyme

plain_language

Acetylating the second enzyme does not switch it off; it turns it into a machine that makes something else.

primary_references

[asa-p8175750] Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. (1994). https://pubmed.ncbi.nlm.nih.gov/8175750/ DOI: 10.1016/s0021-9258(17)36820-5

tissue_or_cell_type

Recombinant cyclooxygenase

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 208–219

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cyclooxygenase-1 and -2 expressed in cos-1 cells treated with aspirin and with carbon-14 labelled aspirin, with a mutant series at Ser-516 · source_derived_draft · unverified_draft

### asa-cox2-becomes-a-lipoxygenase Aspirin treatment of human cyclooxygenase-1 caused time-dependent inactivation of oxygenase activity, whereas aspirin treatment of cyclooxygenase-2 produced an enzyme which retained oxygenase activity but formed exclusively 15-hydroxyeicosatetraenoic acid instead of prostaglandin H2, exclusively of the 15R configuration, with Km values for arachidonate of native and aspirin-treated cyclooxygenase-2 about the same, suggesting arachidonate binds to both in a similar manner. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Acetylating the second enzyme does not switch it off; it turns it into a machine that makes something else. organism: Human enzyme tissue_or_cell_type: Recombinant cyclooxygenase experimental_model: Human cyclooxygenase-1 and -2 expressed in cos-1 cells treated with aspirin and with carbon-14 labelled aspirin, with a mutant series at Ser-516 limitations: Identifies the site by direct labelling and explains the isoform difference by active site volume. Recombinant enzyme in a heterologous cell line. exposure: Aspirin acetylation, with S516A, S516N, S516Q and S516M substitutions evidence_span: {"source_cache": "artifacts/aspirin-research/8175750.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ba85af90c62b157cf53032375ca703e8b78eff6ddd22ad627bbd7e65965d8e9", "start_char": 0, "end_char": 1786, "text_sha256": "9ba85af90c62b157cf53032375ca703e8b78eff6ddd22ad627bbd7e65965d8e9"} [asa-p8175750] Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. (1994). https://pubmed.ncbi.nlm.nih.gov/8175750/ DOI: 10.1016/s0021-9258(17)36820-5

evidence_span

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experimental_model

Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs

exposure

Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors

limitations

Quantifies how efficient the new activity is, which most descriptions of the switch do not. Purified and recombinant enzyme rather than intact cells.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Enzyme

plain_language

Two common anti-inflammatories cannot touch the rerouted enzyme, because they needed the serine aspirin has taken.

primary_references

[asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. (1997). https://pubmed.ncbi.nlm.nih.gov/9016346/ DOI: 10.1124/mol.51.1.52

tissue_or_cell_type

Cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 273–284

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs · source_derived_draft · unverified_draft

### asa-fenamates-do-not-block-it The production of 15-HETE by aspirin-modified cyclooxygenase-2 was sensitive to inhibition by most non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors and the inhibition by indomethacin was time-dependent, but two potent structurally related drugs, diclofenac and meclofenamic acid, did not inhibit either the acetylated enzyme or the S516M mutant, so Ser516 plays an important role in the interaction with fenamate inhibitors. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Two common anti-inflammatories cannot touch the rerouted enzyme, because they needed the serine aspirin has taken. organism: Enzyme tissue_or_cell_type: Cyclooxygenase-2 experimental_model: Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs limitations: Quantifies how efficient the new activity is, which most descriptions of the switch do not. Purified and recombinant enzyme rather than intact cells. exposure: Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors evidence_span: {"source_cache": "artifacts/aspirin-research/9016346.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b", "start_char": 0, "end_char": 1899, "text_sha256": "2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b"} [asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. (1997). https://pubmed.ncbi.nlm.nih.gov/9016346/ DOI: 10.1124/mol.51.1.52

evidence_span

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experimental_model

Mutants of the putative acetylation site of human cyclooxygenase-2 expressed in COS-7 cells by recombinant vaccinia virus

exposure

Substitution at Ser516, including methionine, compared with aspirin preincubation

limitations

A second, independent identification of the same residue with a substitution that mimics the acetylated state. Vaccinia-driven expression in a heterologous line.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human enzyme

plain_language

Putting a methionine where the acetyl group would go reproduces the switch without any drug.

primary_references

[asa-p8143845] Mutation of serine-516 in human prostaglandin G/H synthase-2 to methionine or aspirin acetylation of this residue stimulates 15-R-HETE synthesis. (1994). https://pubmed.ncbi.nlm.nih.gov/8143845/ DOI: 10.1016/0014-5793(94)80579-2

tissue_or_cell_type

Recombinant cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 234–245

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mutants of the putative acetylation site of human cyclooxygenase-2 expressed in COS-7 cells by recombinant vaccinia virus · source_derived_draft · unverified_draft

### asa-methionine-mimics-acetyl While prostaglandin synthesis by both isoforms is inhibited by aspirin, 15-R-hydroxyeicosatetraenoic acid synthesis by cyclooxygenase-2 but not cyclooxygenase-1 is stimulated by preincubation with aspirin, and enzyme activity and inhibitor sensitivity studies of mutants provide evidence that Ser516 is the aspirin acetylation site of human cyclooxygenase-2 and that substitution of a methionine at this position can mimic the effects of aspirin acetylation on enzyme activity. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Putting a methionine where the acetyl group would go reproduces the switch without any drug. organism: Human enzyme tissue_or_cell_type: Recombinant cyclooxygenase-2 experimental_model: Mutants of the putative acetylation site of human cyclooxygenase-2 expressed in COS-7 cells by recombinant vaccinia virus limitations: A second, independent identification of the same residue with a substitution that mimics the acetylated state. Vaccinia-driven expression in a heterologous line. exposure: Substitution at Ser516, including methionine, compared with aspirin preincubation evidence_span: {"source_cache": "artifacts/aspirin-research/8143845.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ddf63e3296e1f35a88de948bc23fda6654c2eaf247b1d6d3987e95989c966f93", "start_char": 0, "end_char": 903, "text_sha256": "ddf63e3296e1f35a88de948bc23fda6654c2eaf247b1d6d3987e95989c966f93"} [asa-p8143845] Mutation of serine-516 in human prostaglandin G/H synthase-2 to methionine or aspirin acetylation of this residue stimulates 15-R-HETE synthesis. (1994). https://pubmed.ncbi.nlm.nih.gov/8143845/ DOI: 10.1016/0014-5793(94)80579-2

evidence_span

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experimental_model

Computational modelling of oxygenation stereospecificity in native and aspirin-acetylated cyclooxygenase-2

exposure

A mechanistic hypothesis tested against experimental oxygenation patterns

limitations

A computational model reproducing known patterns, not a new measurement. It offers an explanation for the switch rather than evidence that it occurs.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Enzyme

plain_language

The same bulk that blocks the first enzyme explains why the second one makes mirror-image products.

primary_references

[asa-p23786234] A mechanistic hypothesis for the aspirin-induced switch in lipid mediator production by cyclooxygenase-2. (2013). https://pubmed.ncbi.nlm.nih.gov/23786234/ DOI: 10.1021/ja402870k

tissue_or_cell_type

Cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 351–362

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Computational modelling of oxygenation stereospecificity in native and aspirin-acetylated cyclooxygenase-2 · source_derived_draft · unverified_draft

### asa-steric-shielding-explains-stereochemistry A mechanistic hypothesis identifying steric shielding as the main determinant of oxygenation stereospecificity in cyclooxygenase-2 is supported by a computational model which accurately reproduces experimental oxygenation patterns on both native and aspirin-inhibited enzyme, addressing why Ser530 acetylation shifts the stereochemistry and relative abundance of generated products. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The same bulk that blocks the first enzyme explains why the second one makes mirror-image products. organism: Enzyme tissue_or_cell_type: Cyclooxygenase-2 experimental_model: Computational modelling of oxygenation stereospecificity in native and aspirin-acetylated cyclooxygenase-2 limitations: A computational model reproducing known patterns, not a new measurement. It offers an explanation for the switch rather than evidence that it occurs. exposure: A mechanistic hypothesis tested against experimental oxygenation patterns evidence_span: {"source_cache": "artifacts/aspirin-research/23786234.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bdf3d33c4cc14fc4b2190180d78b68971144966047e654abb59b9ca7a83ab824", "start_char": 0, "end_char": 834, "text_sha256": "bdf3d33c4cc14fc4b2190180d78b68971144966047e654abb59b9ca7a83ab824"} [asa-p23786234] A mechanistic hypothesis for the aspirin-induced switch in lipid mediator production by cyclooxygenase-2. (2013). https://pubmed.ncbi.nlm.nih.gov/23786234/ DOI: 10.1021/ja402870k

evidence_span

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experimental_model

Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs

exposure

Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors

limitations

Quantifies how efficient the new activity is, which most descriptions of the switch do not. Purified and recombinant enzyme rather than intact cells.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Enzyme

plain_language

The rerouted enzyme works well enough that arachidonate does not pile up and spill into other pathways.

primary_references

[asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. (1997). https://pubmed.ncbi.nlm.nih.gov/9016346/ DOI: 10.1124/mol.51.1.52

tissue_or_cell_type

Cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 260–271

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs · source_derived_draft · unverified_draft

### asa-the-new-activity-is-efficient Both the S516M mutant and the aspirin-acetylated form of cyclooxygenase-2 synthesise 15(R)-HETE with apparent Km values for arachidonic acid within tenfold of untreated enzyme and with similar time courses of turnover-dependent inactivation, and the conversion of arachidonic acid to 15-HETE by acetylated cyclooxygenase-2 is an efficient process providing a unique mechanism among non-steroidal anti-inflammatory drugs that will not lead to arachidonic acid accumulation or shunting to other biosynthetic pathways. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The rerouted enzyme works well enough that arachidonate does not pile up and spill into other pathways. organism: Enzyme tissue_or_cell_type: Cyclooxygenase-2 experimental_model: Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs limitations: Quantifies how efficient the new activity is, which most descriptions of the switch do not. Purified and recombinant enzyme rather than intact cells. exposure: Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors evidence_span: {"source_cache": "artifacts/aspirin-research/9016346.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b", "start_char": 0, "end_char": 1899, "text_sha256": "2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b"} [asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. (1997). https://pubmed.ncbi.nlm.nih.gov/9016346/ DOI: 10.1124/mol.51.1.52

evidence_span

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experimental_model

Site-directed mutagenesis of mouse COX-2 residues predicted from comparison of the two isoform crystal structures

exposure

Val-434, Arg-513, Val-523, Val-228 and Gly-533 mutated towards their cyclooxygenase-1 equivalents, then acetylated

limitations

Explains the isoform difference residue by residue. Murine enzyme, and the L-shaped substrate configuration is an inference from the mutant product profiles.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Mouse enzyme

plain_language

Three amino acids are the whole difference between an enzyme aspirin kills and one aspirin repurposes.

primary_references

[asa-p10692466] Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete. (2000). https://pubmed.ncbi.nlm.nih.gov/10692466/ DOI: 10.1074/jbc.275.9.6586

tissue_or_cell_type

Cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 247–258

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of mouse COX-2 residues predicted from comparison of the two isoform crystal structures · source_derived_draft · unverified_draft

### asa-three-residues-decide Acetylated cyclooxygenase-2 is essentially a lipoxygenase making 15(R)- and 11(R)-hydroxyeicosatetraenoic acid whereas acetylated cyclooxygenase-1 is unable to oxidise arachidonic acid to any products, and site-directed mutagenesis of Val-434, Arg-513 and Val-523 in mouse cyclooxygenase-2 to their cyclooxygenase-1 equivalents abrogated 11- and 15-HETE production after aspirin treatment, confirming these residues as the major isoform selectivity determinants; V228F and G533A produced wild-type-like profiles but on acetylation neither could make HETE products, suggesting arachidonic acid orientates in an L-shaped binding configuration. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Three amino acids are the whole difference between an enzyme aspirin kills and one aspirin repurposes. organism: Mouse enzyme tissue_or_cell_type: Cyclooxygenase-2 experimental_model: Site-directed mutagenesis of mouse COX-2 residues predicted from comparison of the two isoform crystal structures limitations: Explains the isoform difference residue by residue. Murine enzyme, and the L-shaped substrate configuration is an inference from the mutant product profiles. exposure: Val-434, Arg-513, Val-523, Val-228 and Gly-533 mutated towards their cyclooxygenase-1 equivalents, then acetylated evidence_span: {"source_cache": "artifacts/aspirin-research/10692466.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da1ede1fbf95d6f42d4bb15dc08b5d1869549a7cd94cbfa9da9f9865fd780ff", "start_char": 0, "end_char": 2055, "text_sha256": "9da1ede1fbf95d6f42d4bb15dc08b5d1869549a7cd94cbfa9da9f9865fd780ff"} [asa-p10692466] Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete. (2000). https://pubmed.ncbi.nlm.nih.gov/10692466/ DOI: 10.1074/jbc.275.9.6586

evidence_span

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experimental_model

Coincubations of human umbilical vein endothelial cells and neutrophils with physical characterisation of the products

exposure

Aspirin compared against indomethacin, salicylate and dexamethasone, with interleukin-1-beta induction and several costimuli

limitations

The comparator set is what makes this strong: three other anti-inflammatory drugs including salicylate failed to produce the same products. It is a cell coincubation, and the nanomolar activity is measured on adhesion in vitro.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human cells

plain_language

Aspirin, and not the other anti-inflammatories tested, makes the body build a mediator it otherwise never makes.

primary_references

[asa-p7568157] Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. (1995). https://pubmed.ncbi.nlm.nih.gov/7568157/ DOI: 10.1073/pnas.92.21.9475

tissue_or_cell_type

Endothelium and neutrophils

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 312–323

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coincubations of human umbilical vein endothelial cells and neutrophils with physical characterisation of the products · source_derived_draft · unverified_draft

### asa-aspirin-triggers-lipoxins Aspirin triggered transcellular biosynthesis of a previously unrecognised class of eicosanoids during coincubations of human umbilical vein endothelial cells and neutrophils, generated with aspirin but not by indomethacin, salicylate or dexamethasone, enhanced by interleukin-1-beta which induced cyclooxygenase-2 but not 15-lipoxygenase; four products proved to be 15R-epimers of lipoxins, two were potent inhibitors of leukotriene B4-mediated neutrophil adhesion to endothelium, with 15-epi-lipoxin A4 active in the nanomolar range, an example of a drug pirating endogenous biosynthetic mechanisms to trigger new mediators. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Aspirin, and not the other anti-inflammatories tested, makes the body build a mediator it otherwise never makes. organism: Human cells tissue_or_cell_type: Endothelium and neutrophils experimental_model: Coincubations of human umbilical vein endothelial cells and neutrophils with physical characterisation of the products limitations: The comparator set is what makes this strong: three other anti-inflammatory drugs including salicylate failed to produce the same products. It is a cell coincubation, and the nanomolar activity is measured on adhesion in vitro. exposure: Aspirin compared against indomethacin, salicylate and dexamethasone, with interleukin-1-beta induction and several costimuli evidence_span: {"source_cache": "artifacts/aspirin-research/7568157.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d9e7b80265068fb60f67e97c9d46de7a25e0099151b6d7fbc688f70a29ee9b9b", "start_char": 0, "end_char": 2036, "text_sha256": "d9e7b80265068fb60f67e97c9d46de7a25e0099151b6d7fbc688f70a29ee9b9b"} [asa-p7568157] Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. (1995). https://pubmed.ncbi.nlm.nih.gov/7568157/ DOI: 10.1073/pnas.92.21.9475