Component

A reducing cosubstrate of the peroxidase

A reducing cosubstrate of the peroxidase. Species, exposure and limitations are retained in each linked claim.

4 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. Reduction of prostaglandin H synthase compound II to native enzyme by phenol proceeded with a second-order rate constant of 5.3 x 10(5) per molar per second and by hydroquinone at 2.1 x 10(6), rapid scan spectra also showed reduction of compound I to compound II by both so that reduction of both compounds is a one-electron process, and the results suggest the tyrosyl radical detected in the presence of oxidizing agents is formed by intramolecular electron transfer from the tyrosyl residue to the porphyrin pi-cation radical and tends to disappear in the presence of sufficient reducing substrate.

    A reducing cosubstrate of the peroxidase → Prostaglandin H synthase compound II source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/1727638.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "028284c7b657c213a3052d362a0a5d050b1678d9ab3c5403b8e68d3631494c0c", "start_char": 0, "end_char": 1789, "text_sha256": "028284c7b657c213a3052d362a0a5d050b1678d9ab3c5403b8e68d3631494c0c"}
    experimental_model
    Rapid scan spectrometry and transient state kinetics of prostaglandin H synthase compound II reduction
    exposure
    Phenol and hydroquinone as reducing cosubstrates, with indomethacin
    limitations
    Measures the reduction step directly with rate constants rather than inferring it from inhibition. It uses phenol and hydroquinone rather than paracetamol, which is recorded on the claim.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Enzyme
    plain_language
    A phenol hands the enzyme one electron at a time, and enough of it makes the radical the enzyme needs disappear.
    primary_references
    [apap-p1727638] Reduction of prostaglandin H synthase compound II by phenol and hydroquinone, and the effect of indomethacin. (1992). https://pubmed.ncbi.nlm.nih.gov/1727638/ DOI: 10.1016/0003-9861(92)90070-d
    tissue_or_cell_type
    Purified prostaglandin H synthase

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 142–153

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rapid scan spectrometry and transient state kinetics of prostaglandin H synthase compound II reduction · source_derived_draft · unverified_draft

    ### apap-one-electron-reduction Reduction of prostaglandin H synthase compound II to native enzyme by phenol proceeded with a second-order rate constant of 5.3 x 10(5) per molar per second and by hydroquinone at 2.1 x 10(6), rapid scan spectra also showed reduction of compound I to compound II by both so that reduction of both compounds is a one-electron process, and the results suggest the tyrosyl radical detected in the presence of oxidizing agents is formed by intramolecular electron transfer from the tyrosyl residue to the porphyrin pi-cation radical and tends to disappear in the presence of sufficient reducing substrate. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: A phenol hands the enzyme one electron at a time, and enough of it makes the radical the enzyme needs disappear. organism: Enzyme tissue_or_cell_type: Purified prostaglandin H synthase experimental_model: Rapid scan spectrometry and transient state kinetics of prostaglandin H synthase compound II reduction limitations: Measures the reduction step directly with rate constants rather than inferring it from inhibition. It uses phenol and hydroquinone rather than paracetamol, which is recorded on the claim. exposure: Phenol and hydroquinone as reducing cosubstrates, with indomethacin evidence_span: {"source_cache": "artifacts/paracetamol-research/1727638.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "028284c7b657c213a3052d362a0a5d050b1678d9ab3c5403b8e68d3631494c0c", "start_char": 0, "end_char": 1789, "text_sha256": "028284c7b657c213a3052d362a0a5d050b1678d9ab3c5403b8e68d3631494c0c"} [apap-p1727638] Reduction of prostaglandin H synthase compound II by phenol and hydroquinone, and the effect of indomethacin. (1992). https://pubmed.ncbi.nlm.nih.gov/1727638/ DOI: 10.1016/0003-9861(92)90070-d
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. The potency of acetaminophen against both purified ovine cyclooxygenase-1 and human cyclooxygenase-2 was increased approximately 30-fold by the presence of glutathione peroxidase and glutathione, giving half-maximal inhibitory concentrations of 33 and 980 micromolar respectively, acetaminophen was found to be a good reducing agent of both enzymes, and the results are consistent with a mechanism in which it reduces the active oxidized form of the enzyme to the resting form, so that inhibition would be more effective under conditions of low peroxide concentration, consistent with the known tissue selectivity.

    Paracetamol → Cyclooxygenase-1 (PTGS1) source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/11370851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eeda4b163828f2cc2a4341c4810df6bf6c683d6165eeb09479104f185e52ca4", "start_char": 0, "end_char": 1086, "text_sha256": "4eeda4b163828f2cc2a4341c4810df6bf6c683d6165eeb09479104f185e52ca4"}
    experimental_model
    Purified ovine cyclooxygenase-1 and human cyclooxygenase-2 assayed with and without a peroxide-removing system
    exposure
    Acetaminophen with and without glutathione peroxidase and glutathione
    limitations
    Adding a peroxide-removing system is the manipulation that reveals the mechanism, because it changes potency thirtyfold without changing the drug. Purified enzyme, so the concentrations are not tissue concentrations.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Sheep and human enzyme
    plain_language
    Take the peroxide away and the same drug becomes thirty times stronger, which is the whole mechanism in one experiment.
    primary_references
    [apap-p11370851] Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. (2001). https://pubmed.ncbi.nlm.nih.gov/11370851/ DOI: 10.1006/abbi.2000.2232
    tissue_or_cell_type
    Purified cyclooxygenase

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 77–88

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified ovine cyclooxygenase-1 and human cyclooxygenase-2 assayed with and without a peroxide-removing system · source_derived_draft · unverified_draft

    ### apap-potency-depends-on-peroxide The potency of acetaminophen against both purified ovine cyclooxygenase-1 and human cyclooxygenase-2 was increased approximately 30-fold by the presence of glutathione peroxidase and glutathione, giving half-maximal inhibitory concentrations of 33 and 980 micromolar respectively, acetaminophen was found to be a good reducing agent of both enzymes, and the results are consistent with a mechanism in which it reduces the active oxidized form of the enzyme to the resting form, so that inhibition would be more effective under conditions of low peroxide concentration, consistent with the known tissue selectivity. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Take the peroxide away and the same drug becomes thirty times stronger, which is the whole mechanism in one experiment. organism: Sheep and human enzyme tissue_or_cell_type: Purified cyclooxygenase experimental_model: Purified ovine cyclooxygenase-1 and human cyclooxygenase-2 assayed with and without a peroxide-removing system limitations: Adding a peroxide-removing system is the manipulation that reveals the mechanism, because it changes potency thirtyfold without changing the drug. Purified enzyme, so the concentrations are not tissue concentrations. exposure: Acetaminophen with and without glutathione peroxidase and glutathione evidence_span: {"source_cache": "artifacts/paracetamol-research/11370851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eeda4b163828f2cc2a4341c4810df6bf6c683d6165eeb09479104f185e52ca4", "start_char": 0, "end_char": 1086, "text_sha256": "4eeda4b163828f2cc2a4341c4810df6bf6c683d6165eeb09479104f185e52ca4"} [apap-p11370851] Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. (2001). https://pubmed.ncbi.nlm.nih.gov/11370851/ DOI: 10.1006/abbi.2000.2232
    Complete structured claim and evidence

  2. Salicylate inhibits prostaglandin H synthase-1 and -2 with a potency inversely related to ambient hydroperoxide concentrations and its inhibition of synthase-1 was prevented by 12-hydroperoxyeicosatetraenoic acid, but unlike typical phenolic inhibitors such as acetaminophen, salicylate was ineffective as a reducing cosubstrate for the peroxidase activity, implicating the cyclooxygenase site as its target; 12-HPETE does not prevent inhibition of the manganese-reconstituted enzyme by salicylate, indicating that reversal by hydroperoxides depends on electron transfer between the cyclooxygenase and peroxidase active sites.

    Salicylate / salicylic acid → Paracetamol source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/12538810.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0", "start_char": 0, "end_char": 1592, "text_sha256": "23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0"}
    experimental_model
    Prostaglandin H synthase inhibition by salicylate compared with phenolic inhibitors, using manganese-reconstituted enzyme
    exposure
    Salicylate and benzoic acid analogues, with 12-hydroperoxyeicosatetraenoic acid and prostaglandin G2
    limitations
    Recorded here because it separates paracetamol from salicylate mechanistically while showing both are peroxide-sensitive. The work is on salicylate, which is stated on the claim.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Enzyme
    plain_language
    Two drugs that both stop working when peroxide is high, reaching that point by different routes.
    primary_references
    [apap-p12538810] Inhibition of prostaglandin H2 synthases by salicylate is dependent on the oxidative state of the enzymes. (2003). https://pubmed.ncbi.nlm.nih.gov/12538810/ DOI: 10.1124/jpet.102.042853
    tissue_or_cell_type
    Prostaglandin H synthase

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 168–179

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prostaglandin H synthase inhibition by salicylate compared with phenolic inhibitors, using manganese-reconstituted enzyme · source_derived_draft · unverified_draft

    ### apap-salicylate-is-not-a-cosubstrate Salicylate inhibits prostaglandin H synthase-1 and -2 with a potency inversely related to ambient hydroperoxide concentrations and its inhibition of synthase-1 was prevented by 12-hydroperoxyeicosatetraenoic acid, but unlike typical phenolic inhibitors such as acetaminophen, salicylate was ineffective as a reducing cosubstrate for the peroxidase activity, implicating the cyclooxygenase site as its target; 12-HPETE does not prevent inhibition of the manganese-reconstituted enzyme by salicylate, indicating that reversal by hydroperoxides depends on electron transfer between the cyclooxygenase and peroxidase active sites. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Two drugs that both stop working when peroxide is high, reaching that point by different routes. organism: Enzyme tissue_or_cell_type: Prostaglandin H synthase experimental_model: Prostaglandin H synthase inhibition by salicylate compared with phenolic inhibitors, using manganese-reconstituted enzyme limitations: Recorded here because it separates paracetamol from salicylate mechanistically while showing both are peroxide-sensitive. The work is on salicylate, which is stated on the claim. exposure: Salicylate and benzoic acid analogues, with 12-hydroperoxyeicosatetraenoic acid and prostaglandin G2 evidence_span: {"source_cache": "artifacts/paracetamol-research/12538810.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0", "start_char": 0, "end_char": 1592, "text_sha256": "23bbb8a6c280cfcae85e304695c2a93f2c748c804befc1e006f415f4f8dfaed0"} [apap-p12538810] Inhibition of prostaglandin H2 synthases by salicylate is dependent on the oxidative state of the enzymes. (2003). https://pubmed.ncbi.nlm.nih.gov/12538810/ DOI: 10.1124/jpet.102.042853
    Complete structured claim and evidence

  3. Relatively low concentrations of acetaminophen from 20 to 200 micromolar stimulate prostaglandin H synthase activity in ram seminal vesicle microsomes whereas concentrations above 10 millimolar inhibit the conversion of arachidonic acid to prostaglandin G2, both activities apparently involving reduction of oxidized complexes of the enzyme and roughly correlating with the electrochemical half-wave oxidation potentials of a series of hydroxyacetanilides, consistent with common intermediate enzyme forms for both cyclooxygenase and hydroperoxidase catalysed reactions of which one is reduced at low drug concentrations to stimulate and another at higher concentrations to inhibit.

    Paracetamol → Cyclooxygenase-1 (PTGS1) source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"}
    experimental_model
    Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation
    exposure
    Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin
    limitations
    Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Sheep
    plain_language
    At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.
    primary_references
    [apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9
    tissue_or_cell_type
    Seminal vesicle microsomes

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 116–127

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation · source_derived_draft · unverified_draft

    ### apap-stimulates-then-inhibits Relatively low concentrations of acetaminophen from 20 to 200 micromolar stimulate prostaglandin H synthase activity in ram seminal vesicle microsomes whereas concentrations above 10 millimolar inhibit the conversion of arachidonic acid to prostaglandin G2, both activities apparently involving reduction of oxidized complexes of the enzyme and roughly correlating with the electrochemical half-wave oxidation potentials of a series of hydroxyacetanilides, consistent with common intermediate enzyme forms for both cyclooxygenase and hydroperoxidase catalysed reactions of which one is reduced at low drug concentrations to stimulate and another at higher concentrations to inhibit. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons. organism: Sheep tissue_or_cell_type: Seminal vesicle microsomes experimental_model: Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation limitations: Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic. exposure: Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin evidence_span: {"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"} [apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9
    Complete structured claim and evidence

In the sources

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