{"id":"aba771fc-24a0-5c0a-a4df-ac9579993285","stable_key":"e0ea2d6a-7429-5e9f-b774-41e5e3288da3:e-sig-delta-te-acid-allosteric","predicate":"noncompetitively-inhibits","statement":"Pein and colleagues interpreted delta-tocotrienol-13′-carboxychromanol inhibition of human 5-LO as reversible and allosteric: activity inhibition persisted when arachidonic acid was varied, and immobilized metabolite captured the enzyme despite excess arachidonic acid.","claim_class":"hypothesis_link","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"9b3dfb4f-6663-5677-b758-7a60079a6597","mechanism_event_label":"One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site.","subject":{"id":"726a3b23-4bde-5324-82ef-a895a1750c07","slug":"delta-tocotrienol-13-carboxychromanol","display_name":"Delta-tocotrienol-13′-carboxychromanol","entity_type_key":"small_molecule"},"object":{"id":"c9794ec0-addc-51de-b505-3e54fcedc94d","slug":"alox5","display_name":"Arachidonate 5-lipoxygenase (ALOX5)","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"9b3dfb4f-6663-5677-b758-7a60079a6597","stable_key":"e0ea2d6a-7429-5e9f-b774-41e5e3288da3:e-sig-delta-te-acid-allosteric-event","event_type":"biochemical_relationship","label":"One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site.","description":"Pein and colleagues interpreted delta-tocotrienol-13′-carboxychromanol inhibition of human 5-LO as reversible and allosteric: activity inhibition persisted when arachidonic acid was varied, and immobilized metabolite captured the enzyme despite excess arachidonic acid.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"39f9446f-52a6-502d-b507-91137726f82c","slug":"arachidonic-acid","display_name":"AA","entity_type_key":"small_molecule"},"role":"substrate and pull-down competitor","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"726a3b23-4bde-5324-82ef-a895a1750c07","slug":"delta-tocotrienol-13-carboxychromanol","display_name":"Delta-tocotrienol-13′-carboxychromanol","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c9794ec0-addc-51de-b505-3e54fcedc94d","slug":"alox5","display_name":"Arachidonate 5-lipoxygenase (ALOX5)","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Purified 5-LO 0.5 µg in PBS pH 7.4, EDTA 1 mM and ATP 1 mM; 10 min compound preincubation at 4°C, then 5–80 µM arachidonic acid and 2 mM CaCl2 at 37°C. Reported IC50 35–40 nM; pull-down competitor arachidonic acid 100 µM.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Binding-site assignment combines biochemical evidence with docking and mutagenesis, not a solved inhibitor-bound structure. Park 2022 explicitly disputes the noncompetitive interpretation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Vitamin E research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-e","display_name":"Vitamin E","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Cell-free enzyme","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"cef8c59c-cf57-52c7-97ee-117d97fd1277","evidence_kind":"source_excerpt","locator":"Lines 1024-1035","start_line":1024,"end_line":1035,"excerpt":"### e-sig-delta-te-acid-allosteric\nPein and colleagues interpreted delta-tocotrienol-13′-carboxychromanol inhibition of human 5-LO as reversible and allosteric: activity inhibition persisted when arachidonic acid was varied, and immobilized metabolite captured the enzyme despite excess arachidonic acid.\nCondition category: normal\nnutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site.\norganism: Homo sapiens\ntissue_or_cell_type: Cell-free enzyme\nexperimental_model: Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down\nlimitations: Binding-site assignment combines biochemical evidence with docking and mutagenesis, not a solved inhibitor-bound structure. Park 2022 explicitly disputes the noncompetitive interpretation.\nexposure: Purified 5-LO 0.5 µg in PBS pH 7.4, EDTA 1 mM and ATP 1 mM; 10 min compound preincubation at 4°C, then 5–80 µM arachidonic acid and 2 mM CaCl2 at 37°C. Reported IC50 35–40 nM; pull-down competitor arachidonic acid 100 µM.\ncross_nutrient: false\n[pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5","model_system":"Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"3ac41dba-4727-5116-a556-ac3bbb0dc41c","stable_key":"import-e0ea2d6a-7429-5e9f-b774-41e5e3288da3","title":"Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"a90b6565e092c6a2da07f74cf758792c2cf63b40746260c8ff12bd64322c36f4","revision_id":"956793d1-23e4-5397-9291-25c1732a8e02","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"019b6eab-b80f-5a42-80ea-875511b72401","title":"Does delta-tocotrienol-13′-COOH inhibit 5-LOX allosterically or competitively?","kind":"contradiction","status":"open","why":"The same metabolite and human 5-LOX receive different mechanistic classifications. Park 2022 explicitly challenges the published allosteric interpretation; this goes beyond different potency estimates.","resolution":"Unresolved across assay systems. Retain Pein substrate-variation/pull-down/mutant evidence alongside Park oxygen-consumption kinetics. Neither paper supplies an inhibitor-bound enzyme structure, and different enzyme, substrate and lipid conditions may contribute.","created_at":"2026-09-17 13:41:37","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/019b6eab-b80f-5a42-80ea-875511b72401","sides":[{"conflict_id":"019b6eab-b80f-5a42-80ea-875511b72401","ordinal":0,"label":"Pein 2018: reversible allosteric/noncompetitive interpretation","revision_id":"956793d1-23e4-5397-9291-25c1732a8e02","start_line":1024,"end_line":1035,"quote":"### e-sig-delta-te-acid-allosteric\nPein and colleagues interpreted delta-tocotrienol-13′-carboxychromanol inhibition of human 5-LO as reversible and allosteric: activity inhibition persisted when arachidonic acid was varied, and immobilized metabolite captured the enzyme despite excess arachidonic acid.\nCondition category: normal\nnutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site.\norganism: Homo sapiens\ntissue_or_cell_type: Cell-free enzyme\nexperimental_model: Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down\nlimitations: Binding-site assignment combines biochemical evidence with docking and mutagenesis, not a solved inhibitor-bound structure. Park 2022 explicitly disputes the noncompetitive interpretation.\nexposure: Purified 5-LO 0.5 µg in PBS pH 7.4, EDTA 1 mM and ATP 1 mM; 10 min compound preincubation at 4°C, then 5–80 µM arachidonic acid and 2 mM CaCl2 at 37°C. Reported IC50 35–40 nM; pull-down competitor arachidonic acid 100 µM.\ncross_nutrient: false\n[pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5","source_key":"import-e0ea2d6a-7429-5e9f-b774-41e5e3288da3","source_title":"Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17)","claim_ids":["aba771fc-24a0-5c0a-a4df-ac9579993285"]},{"conflict_id":"019b6eab-b80f-5a42-80ea-875511b72401","ordinal":1,"label":"Park 2022: competitive initial-rate kinetics","revision_id":"956793d1-23e4-5397-9291-25c1732a8e02","start_line":1037,"end_line":1048,"quote":"### e-sig-delta-te-acid-competitive\nPark and colleagues classified Delta-tocotrienol-13′-carboxychromanol as a competitive inhibitor of human recombinant 5-LOX, with Ki 0.8 µM; oxygen-consumption kinetics showed increased apparent substrate requirement without an apparent decrease in Vmax.\nCondition category: normal\nnutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase.\norganism: Homo sapiens\ntissue_or_cell_type: Cell-free enzyme\nexperimental_model: Human recombinant 5-LOX oxygen-electrode initial-rate kinetics\nlimitations: Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts.\nexposure: 10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM.\ncross_nutrient: false\n[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884","source_key":"import-e0ea2d6a-7429-5e9f-b774-41e5e3288da3","source_title":"Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17)","claim_ids":["5fe8dcb6-1c1c-51dd-a5fc-b8f4d93547a0"]}]}],"corrections":[],"research":null}